Sommaire du brevet 2234061

(12) Demande de brevet:	(11) CA 2234061
(54) Titre français:	AGONISTES MULTIFONCTIONNELS DES RECEPTEURS HEMATOPOIETIQUES
(54) Titre anglais:	MULTI-FUNCTIONAL HEMATOPOIETIC RECEPTOR AGONISTS
Statut:	Réputée abandonnée et au-delà du délai pour le rétablissement - en attente de la réponse à l’avis de communication rejetée

Données bibliographiques

(51) Classification internationale des brevets (CIB):	C12N 05/07 (2010.01) A61K 38/00 (2006.01) A61K 38/19 (2006.01) A61K 48/00 (2006.01) C07K 14/52 (2006.01) C07K 14/53 (2006.01) C07K 14/54 (2006.01) C07K 19/00 (2006.01) C12N 15/19 (2006.01) C12N 15/62 (2006.01)
(72) Inventeurs :	FENG, YIQING (Etats-Unis d'Amérique) STATEN, NICHOLAS R. (Etats-Unis d'Amérique) BAUM, CHARLES M. (Etats-Unis d'Amérique) SUMMERS, NEENA L. (Etats-Unis d'Amérique) CAPARON, MAIRE H. (Etats-Unis d'Amérique) BAUER, S. C. (Etats-Unis d'Amérique) ZURFLUH, LINDA L. (Etats-Unis d'Amérique) MCKEARN, JOHN P. (Etats-Unis d'Amérique) KLEIN, BARBARA KURE (Etats-Unis d'Amérique) LEE, STEPHEN C. (Etats-Unis d'Amérique) MCWHERTER, CHARLES A. (Etats-Unis d'Amérique) GIRI, JUDITH G. (Etats-Unis d'Amérique)
(73) Titulaires :	G.D. SEARLE & CO.
(71) Demandeurs :	G.D. SEARLE & CO. (Etats-Unis d'Amérique)
(74) Agent:	OSLER, HOSKIN & HARCOURT LLP
(74) Co-agent:
(45) Délivré:
(86) Date de dépôt PCT:	1996-10-04
(87) Mise à la disponibilité du public:	1997-04-10
Requête d'examen:	2001-10-01
Licence disponible:	S.O.
Cédé au domaine public:	S.O.
(25) Langue des documents déposés:	Anglais

Traité de coopération en matière de brevets (PCT):	Oui
(86) Numéro de la demande PCT:	PCT/US1996/015774
(87) Numéro de publication internationale PCT:	US1996015774
(85) Entrée nationale:	1998-04-06

(30) Données de priorité de la demande:

Numéro de la demande	Pays / territoire	Date
60/004,834	(Etats-Unis d'Amérique)	1995-10-05

Abrégés

Abrégé français

Nouvelles protéines multifonctionnelles agonistes des récepteurs hématopoiétiques, ADN codant ces protéines multifonctionnelles agonistes des récepteurs hématopoiétiques, leurs méthodes d'obtention et leurs méthodes d'utilisation.

Abrégé anglais

Disclosed are novel multi-functional hematopoietic receptor agonist proteins,
DNAs which encode the multi-functional hematopoietic receptor agonists
proteins, methods of making the multi-functional hematopoietic receptor
agonists proteins and methods of using the multi-functional hematopoietic
receptor agonists proteins.

Revendications

Note : Les revendications sont présentées dans la langue officielle dans laquelle elles ont été soumises.

507
WHAT IS CLAIMED IS:
1. A hematopoietic protein comprising; an amino acid
sequence of the formula:
R1-L1-R2, R2-L1-R1, R1-R2, or R2-R1
wherein R1 and R2 are independently selected from the
group consisting of;
(I) A polypeptide comprising; a modified human G-CSF
amino acid sequence of the formula:
1 10
Xaa Xaa Xaa Gly Pro Ala Ser Ser Leu Pro Gln Ser Xaa
Leu Leu Xaa Xaa Xaa Glu Gln Val Xaa Lys Xaa Gln Gly Xaa Gly
Ala Xaa Leu Gln Glu Xaa Leu Xaa Ala Thr Tyr Lys Leu Xaa Xaa
Xaa Glu Xaa Xaa Val Xaa Xaa Gly His Ser Xaa Gly Ile Pro Trp
Ala Pro Leu Ser Ser Xaa Pro Ser Xaa Ala Leu Xaa Leu Ala Gly
Xaa Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu
100
Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu
110
Xaa Thr Leu Gln Xaa Asp Val Ala Asp Phe Ala Xaa Thr Ile Trp
120 130
Gln Gln Met Glu Xaa Xaa Gly Met Ala Pro Ala Leu Gln Pro Thr
140
Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Xaa Gln Xaa Xaa Ala
150 160
Gly Gly Val Leu Val Ala Ser Xaa Leu Gln Xaa Phe Leu Xaa Xaa

508
170
Ser Tyr Arg Val Leu Xaa Xaa Leu Ala Gln Pro (SEQ ID NO:1)
wherein
Xaa at position 1 is Thr, Ser, Arg, Tyr or Gly;
Xaa at position 2 is Pro or Leu;
Xaa at position 3 is Leu, Arg, Tyr or Ser;
Xaa at position 13 is Phe, Ser, His, Thr or Pro;
Xaa at position 16 is Lys, Pro, Ser, Thr or His;
Xaa at position 17 is Cys, Ser, Gly, Ala, Ile, Tyr or Arg;
Xaa at position 18 is Leu, Thr, Pro, His, Ile or Cys;
Xaa at position 22 is Arg, Tyr, Ser, Thr or Ala;
Xaa at position 24 is Ile, Pro, Tyr or Leu;
Xaa at position 27 is Asp, or Gly;
Xaa at position 30 is Ala, Ile, Leu or Gly;
Xaa at position 34 is Lys or Ser;
Xaa at position 36 is Cys or Ser;
Xaa at position 42 is Cys or Ser;
Xaa at position 43 is His, Thr, Gly, Val, Lys, Trp, Ala,
Arg, Cys, or Leu;
Xaa at position 44 is Pro, Gly, Arg, Asp, Val, Ala, His,
Trp, Gln, or Thr;
Xaa at position 46 is Glu, Arg, Phe, Arg, Ile or Ala;
Xaa at position 47 is Leu or Thr;
Xaa at position 49 is Leu, Phe, Arg or Ser;
Xaa at position 50 is Leu, Ile, His, Pro or Tyr;
Xaa at position 54 is Leu or His;
Xaa at position 64 is Cys or Ser;
Xaa at position 67 is Gln, Lys, Leu or Cys;
Xaa at position 70 is Gln, Pro, Leu, Arg or Ser;
Xaa at position 74 is Cys or Ser;
Xaa at position 104 is Asp, Gly or Val;
Xaa at position 108 is Leu, Ala, Val, Arg, Trp, Gln or Gly;
Xaa at position 115 is Thr, His, Leu or Ala;
Xaa at position 120 is Gln, Gly, Arg, Lys or His
Xaa at position 123 is Glu, Arg, Phe or Thr
Xaa at position 144 is Phe, His, Arg, Pro, Leu, Gln or Glu;
Xaa at position 146 is Arg or Gln;
Xaa at position 147 is Arg or Gln;
Xaa at position 156 is His, Gly or Ser;
Xaa at position 159 is Ser, Arg, Thr, Tyr, Val or Gly;
Xaa at position 162 is Glu, Leu, Gly or Trp;
Xaa at position 163 is Val, Gly, Arg or Ala;
Xaa at position 169 is Arg, Ser, Leu, Arg or Cys;
Xaa at position 170 is His, Arg or Ser;
wherein optionally 1-11 amino acids from the N-terminus and
1-5 from the C-terminus can optionally be deleted from said
modified human G-CSF amino acid sequence; and

509
wherein the N-terminus is joined to the C-terminus directly
or through a linker capable of joining the N-terminus to the
C-terminus and having new C- and N-termini at amino acids;
38-39 62-63 123-124
39-40 63-64 124-125
40-41 64-65 125-126
41-42 65-66 126-127
42-43 66-67 128-129
43-44 67-68 128-129
45-46 68-69 129-130
48-49 69-70 130-131
49-50 70-71 131-132
52-53 71-72 132-133
53-54 91-92 133-134
54-55 92-93 134-135
55-56 93-94 135-136
56-57 94-95 136-137
57-58 95-96 137-138
58-59 96-97 138-139
59-60 97-98 139-140
60-61 98-99 140-141
61-62 99-100 141-142
or 142-143
respectively;
(II) A polypeptide comprising; a modified human IL-3
amino acid sequence of the formula:
Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Thr Ser Trp Val Asn
1 5 10 15
Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

510
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
100 105
Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
110 115 120
Xaa Xaa Xaa Gln Gln Thr Thr Leu Ser Leu Ala Ile Phe
125 130 (SEQ ID NO:2)
wherein Xaa at position 17 is Ser, Lys, Gly, Asp, Met, Gln, or Arg;
Xaa at position 18 is Asn, His, Leu, Ile, Phe, Arg, or Gln;
Xaa at position 19 is Met, Phe, Ile, Arg, Gly, Ala, or Cys;
Xaa at position 20 is Ile, Cys, Gln, Glu, Arg, Pro, or Ala;
Xaa at position 21 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gln, Asn,
Thr, Ser or Val;
Xaa at position 22 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn, Gln,
Leu, Val or Gly;
Xaa at position 23 is Ile, Val, Ala, Gly, Trp, Lys, Phe,
Leu, Ser, or Arg;
Xaa at position 24 is Ile, Gly, Val, Arg, Ser, Phe, or Leu;
Xaa at position 25 is Thr, His, Gly, Gln, Arg, Pro, or Ala;
Xaa at position 26 is His, Thr, Phe, Gly, Arg, Ala, or Trp;
Xaa at position 27 is Leu, Gly, Arg, Thr, Ser, or Ala;
Xaa at position 28 is Lys, Arg, Leu, Gln, Gly, Pro, Val or Trp;
Xaa at position 29 is Gln, Asn, Leu, Pro, Arg, or Val;
Xaa at position 30 is Pro, His, Thr, Gly, Asp, Gln, Ser, Leu, or Lys;
Xaa at position 31 is Pro, Asp, Gly, Ala, Arg, Leu, or Gln;
Xaa at position 32 is Leu, Val, Arg, Gln, Asn, Gly, Ala, or Glu;

511
Xaa at position 33 is Pro, Leu, Gln, Ala, Thr, or Glu;
Xaa at position 34 is Leu, Val, Gly, Ser, Lys, Glu, Gln, Thr,
Arg, Ala, Phe, Ile or Met;
Xaa at position 35 is Leu, Ala, Gly, Asn, Pro, Gln, or Val;
Xaa at position 36 is Asp, Leu, or Val;
Xaa at position 37 is Phe, Ser, Pro, Trp, or Ile;
Xaa at position 38 is Asn, or Ala;
Xaa at position 40 is Leu, Trp, or Arg;
Xaa at position 41 is Asn, Cys, Arg, Leu, His, Met, or Pro;
Xaa at position 42 is Gly, Asp, Ser, Cys, Asn, Lys, Thr, Leu,
Val, Glu, Phe, Tyr, Ile, Met or Ala;
Xaa at position 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys,
Gln, Arg, Thr, Gly or Ser;
Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp,
Glu, Asn, Gln, Ala or Pro;
Xaa at position 45 is Gln, Pro, Phe, Val, Met, Leu, Thr, Lys,
Trp, Asp, Asn, Arg, Ser, Ala, Ile, Glu or His;
Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gln,
Lys, His, Ala, Tyr, Ile, Val or Gly;
Xaa at position 47 is Ile, Gly, Val, Ser, Arg, Pro, or His;
Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, His, Phe, Glu,
Lys, Thr, Ala, Met, Val or Asn;
Xaa at position 49 is Met, Arg, Ala, Gly, Pro, Asn, His, or Asp;
Xaa at position 50 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser,
Ala, Ile, Val, His, Phe, Met or Gln;
Xaa at position 51 is Asn, Arg, Met, Pro, Ser, Thr, or His;
Xaa at position 52 is Asn, His, Arg, Leu, Gly, Ser, or Thr;
Xaa at position 53 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Met;
Xaa at position 54 is Arg, Asp, Ile, Ser, Val, Thr, Gln, Asn,
Lys, His, Ala or Leu;
Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gly;
Xaa at position 56 is Pro, Gly, Cys, Ser, Gln, Glu, Arg, His,
Thr, Ala, Tyr, Phe, Leu, Val or Lys;
Xaa at position 57 is Asn or Gly;
Xaa at position 58 is Leu, Ser, Asp, Arg, Gln, Val, or Cys;

512
Xaa at position 59 is Glu Tyr, His, Leu, Pro, or Arg;
Xaa at position 60 is Ala, Ser, Pro, Tyr, Asn, or Thr;
Xaa at position 61 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser;
Xaa at position 62 is Asn, His, Val, Arg, Pro, Thr, Asp, or Ile;
Xaa at position 63 is Arg, Tyr, Trp, Lys, Ser, His, Pro, or Val;
Xaa at position 64 is Ala, Asn, Pro, Ser, or Lys;
Xaa at position 65 is Val, Thr, Pro, His, Leu, Phe, or Ser;
Xaa at position 66 is Lys, Ile, Arg, Val, Asn, Glu, or Ser;
Xaa at position 67 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His;
Xaa at position 68 is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His;
Xaa at position 69 is Gln, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leu;
Xaa at position 70 is Asn, Leu, Val, Trp, Pro, or Ala;
Xaa at position 71 is Ala, Met, Leu, Pro, Arg, Glu, Thr, Gln,
Trp, or Asn;
Xaa at position 72 is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp;
Xaa at position 73 is Ala, Glu, Asp, Leu, Ser, Gly, Thr, or Arg;
Xaa at position 74 is Ile, Met, Thr, Pro, Arg, Gly, Ala;
Xaa at position 75 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser,
Gln, or Leu;
Xaa at position 76 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp;
Xaa at position 77 is Ile, Ser, Arg, Thr, or Leu;
Xaa at position 78 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg;
Xaa at position 79 is Lys, Thr, Asn, Met, Arg, Ile, Gly, or Asp;
Xaa at position 80 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg;
Xaa at position 81 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys;
Xaa at position 82 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn,
His, Thr, Ser, Ala, Tyr, Phe, Ile, Met or Val;
Xaa at position 83 is Pro, Ala, Thr, Trp, Arg, or Met;
Xaa at position 84 is Cys, Glu, Gly, Arg, Met, or Val;
Xaa at position 85 is Leu, Asn, Val, or Gln;
Xaa at position 86 is Pro, Cys, Arg, Ala, or Lys;
Xaa at position 87 is Leu, Ser, Trp, or Gly;
Xaa at position 88 is Ala, Lys, Arg, Val, or Trp;
Xaa at position 89 is Thr, Asp, Cys, Leu, Val, Glu, His, Asn, or Ser;
Xaa at position 90 is Ala, Pro, Ser, Thr, Gly, Asp, Ile, or Met;

513
Xaa at position 91 is Ala, Pro, Ser, Thr, Phe, Leu, Asp, or His;
Xaa at position 92 is Pro, Phe, Arg, Ser, Lys, His, Ala, Gly, Ile or
Leu;
Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, or Arg;
Xaa at position 94 is Arg, Ile, Ser, Glu, Leu, Val, Gln, Lys, His,
Ala, or Pro;
Xaa at position 95 is His, Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn,
Lys, Ser, Ala, Trp, Phe, Ile, or Tyr;
Xaa at position g6 is Pro, Lys, Tyr, Gly, Ile, or Thr;
Xaa at position 97 is Ile, Val, Lys, Ala, or Asn;
Xaa at position 98 is His, Ile, Asn, Leu, Asp, Ala, Thr,
Glu, Gln, Ser, Phe, Met, Val, Lys, Arg, Tyr or Pro;
Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gln,
Gly, Ser, Phe, or His;
Xaa at position 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Gln, or Pro;
Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Val,
Tyr, Glu, Asn, Ser, Ala, Gly, Ile, Leu, or Gln;
Xaa at position 102 is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro;
Xaa at position 103 is Asp, or Ser;
Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu,
Gln, Lys, Ala, Phe, or Gly;
Xaa at position 105 is Asn, Pro, Ala, Phe, Ser, Trp, Gln, Tyr,
Leu, Lys, Ile, Asp, or His;
Xaa at position 106 is Glu, Ser, Ala, Lys, Thr, Ile, Gly, or Pro;
Xaa at position 108 is Arg, Lys, Asp, Leu, Thr, Ile, Gln, His, Ser,
Ala or Pro;
Xaa at position 109 is Arg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly;
Xaa at position 110 is Lys, Ala, Asn, Thr, Leu, Arg, Gln, His, Glu,
Ser, or Trp;
Xaa at position 111 is Leu, Ile, Arg, Asp, or Met;
Xaa at position 112 is Thr, Val, Gln, Tyr, Glu, His, Ser, or Phe;
Xaa at position 113 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp,
Lys, Leu, Ile, Val or Asn;
Xaa at position 114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu;
Xaa at position 115 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr,

514
Trp, or Met;
Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu,
Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gln, or Ile;
Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro;
Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr;
Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg;
Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gln;
Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly;
Xaa at position 122 is Gln, Ser, Met, Trp, Arg, Phe, Pro, His,
Ile, Tyr, or Cys;
Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu;
wherein from 1 to 14 amino acids can optionally be deleted
from the N-terminus and/or from 1 to 15 amino acids can
optionally be deleted from the C-terminus of said modified
human IL-3 amino acid sequence; wherein from 0 to 44 of the
amino acids designated by Xaa are different from the
corresponding amino acids of native (1-133) human
interleukin-3; and
wherein the N-terminus is joined to the C-terminus directly
or through a linker (L2), capable of joining the N-terminus
to the C-terminus and having new C- and N-termini at amino
acids;
26-27 49-50 83-84
27-28 50-51 84-85
28-29 51-52 85-86
29-30 52-53 86-87
30-31 53-54 87-88
31-32 54-55 88-89
32-33 64-65 89-90
33-34 65-66 90-91
34-35 66-67 91-92
35-36 67-68 92-93
36-37 68-69 97-98
37-38 69-70 98-99
38-39 70-71 99-100
39-40 71-72 100-101
40-41 72-73 101-102

515
41-42 82-83 102-103
or 103-104
respectively;
(III) A polypeptide comprising; a modified human c-mpl
ligand amino acid sequence of the formula:
SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSer
1 5 10 15
HisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrPro
ValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGlu
ThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla
AlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGly
GlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnXaaXaaXaa
100 105 110
XaaGlyArgThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHis
115 120 125 130
LeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysVal
135 140 145 150
Arg (SEQ ID NO:256)
153
wherein;
Xaa at position 112 is deleted or Leu, Ala, Val, Ile, Pro,
Phe, Trp, or Met;
Xaa at position 113 is deleted or Pro, Phe, Ala, Val, Leu,
Ile, Trp, or Met;
Xaa at position 114 is deleted or Pro, Phe, Ala, Val, Leu,
Ile, Trp, or Met;
Xaa at position 115 is deleted or Gln, Gly, Ser, Thr, Tyr,

516
or Asn; and
wherein the N-terminus is joined to the C-terminus directly
or through a linker (L2) capable of joining the N-terminus
to the C-terminus and having new C- and N-termini at amino
acids;
26-27 51-52 108-109
27-28 52-53 109-110
28-29 53-54 110-111
29-30 54-55 111-112
30-31 55-56 112-113
32-33 56-57 113-114
33-34 57-58 114-115
34-35 58-59 115-116
36-37 59-60 116-117
37-38 78-79 117-118
38-39 79-80 118-119
40-41 80-81 119-120
41-42 81-82 120-121
42-43 82-83 121-122
43-44 83-84 122-123
44-45 84-85 123-124
46-47 85-86 124-125
47-48 86-87 125-126
48-49 87-88 126-127
50-51 88-89 or 127-128
respectively;
(IV) A polypeptide comprising; a modified human IL-3
amino acid sequence of the formula:
Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Thr Ser Trp Val Asn
1 5 10 15
Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa

517
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
100 105
Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
110 115 120
Xaa Xaa Xaa Gln Gln Thr Thr Leu Ser Leu Ala Ile Phe
125 130 (SEQ ID NO:2)
wherein Xaa at position 17 is Ser, Lys, Gly, Asp, Met, Gln, or Arg
Xaa at position 18 is Asn, His, Leu, Ile, Phe, Arg, or Gln;
Xaa at position 19 is Met, Phe, Ile, Arg, Gly, Ala, or Cys;
Xaa at position 20 is Ile, Cys, Gln, Glu, Arg, Pro, or Ala;
Xaa at position 21 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gln, Asn,
Thr, Ser or Val;
Xaa at position 22 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn, Gln,
Leu, Val or Gly;
Xaa at position 23 is Ile, Val, Ala, Gly, Trp, Lys, Phe,
Leu, Ser, or Arg;
Xaa at position 24 is Ile, Gly, Val, Arg, Ser, Phe, or Leu;
Xaa at position 25 is Thr, His, Gly, Gln, Arg, Pro, or Ala;
Xaa at position 26 is His, Thr, Phe, Gly, Arg, Ala, or Trp;
Xaa at position 27 is Leu, Gly, Arg, Thr, Ser, or Ala;
Xaa at position 28 is Lys, Arg, Leu, Gln, Gly, Pro, Val or Trp;
Xaa at position 29 is Gln, Asn, Leu, Pro, Arg, or Val;

518
Xaa at position 30 is Pro, His, Thr, Gly, Asp, Gln, Ser, Leu, or Lys;
Xaa at position 31 is Pro, Asp, Gly, Ala, Arg, Leu, or Gln;
Xaa at position 32 is Leu, Val, Arg, Gln, Asn, Gly, Ala, or Glu;
Xaa at position 33 is Pro, Leu, Gln, Ala, Thr, or Glu;
Xaa at position 34 is Leu, Val, Gly, Ser, Lys, Glu, Gln, Thr,
Arg, Ala, Phe, Ile or Met;
Xaa at position 35 is Leu, Ala, Gly, Asn, Pro, Gln, or Val;
Xaa at position 36 is Asp, Leu, or Val;
Xaa at position 37 is Phe, Ser, Pro, Trp, or Ile;
Xaa at position 38 is Asn, or Ala;
Xaa at position 40 is Leu, Trp, or Arg;
Xaa at position 41 is Asn, Cys, Arg, Leu, His, Met, or Pro;
Xaa at position 42 is Gly, Asp, Ser, Cys, Asn, Lys, Thr, Leu,
Val, Glu, Phe, Tyr, Ile, Met or Ala;
Xaa at position 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys,
Gln, Arg, Thr, Gly or Ser;
Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp,
Glu, Asn, Gln, Ala or Pro;
Xaa at position 45 is Gln, Pro, Phe, Val, Met, Leu, Thr, Lys,
Trp, Asp, Asn, Arg, Ser, Ala, Ile, Glu or His;
Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gln,
Lys, His, Ala, Tyr, Ile, Val or Gly;
Xaa at position 47 is Ile, Gly, Val, Ser, Arg, Pro, or His;
Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, His, Phe, Glu,
Lys, Thr, Ala, Met, Val or Asn;
Xaa at position 49 is Met, Arg, Ala, Gly, Pro, Asn, His, or Asp;
Xaa at position 50 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser,
Ala, Ile, Val, His, Phe, Met or Gln;
Xaa at position 51 is Asn, Arg, Met, Pro, Ser, Thr, or His;
Xaa at position 52 is Asn, His, Arg, Leu, Gly, Ser, or Thr;
Xaa at position 53 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Met;
Xaa at position 54 is Arg, Asp, Ile, Ser, Val, Thr, Gln, Asn,
Lys, His, Ala or Leu;
Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gly;
Xaa at position 56 is Pro, Gly, Cys, Ser, Gln, Glu, Arg, His,

519
Thr, Ala, Tyr, Phe, Leu, Val or Lys;
Xaa at position 57 is Asn or Gly;
Xaa at position 58 is Leu, Ser, Asp, Arg, Gln, Val, or Cys;
Xaa at position 59 is Glu Tyr, His, Leu, Pro, or Arg;
Xaa at position 60 is Ala, Ser, Pro, Tyr, Asn, or Thr;
Xaa at position 61 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser;
Xaa at position 62 is Asn, His, Val, Arg, Pro, Thr, Asp, or Ile;
Xaa at position 63 is Arg, Tyr, Trp, Lys, Ser, His, Pro, or Val;
Xaa at position 64 is Ala, Asn, Pro, Ser, or Lys;
Xaa at position 65 is Val, Thr, Pro, His, Leu, Phe, or Ser;
Xaa at position 66 is Lys, Ile, Arg, Val, Asn, Glu, or Ser;
Xaa at position 67 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His;
Xaa at position 68 is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His;
Xaa at position 69 is Gln, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leu;
Xaa at position 70 is Asn, Leu, Val, Trp, Pro, or Ala;
Xaa at position 71 is Ala, Met, Leu, Pro, Arg, Glu, Thr, Gln,
Trp, or Asn;
Xaa at position 72 is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp;
Xaa at position 73 is Ala, Glu, Asp, Leu, Ser, Gly, Thr, or Arg;
Xaa at position 74 is Ile, Met, Thr, Pro, Arg, Gly, Ala;
Xaa at position 75 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser,
Gln, or Leu;
Xaa at position 76 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp;
Xaa at position 77 is Ile, Ser, Arg, Thr, or Leu;
Xaa at position 78 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg;
Xaa at position 79 is Lys, Thr, Asn, Met, Arg, Ile, Gly, or Asp;
Xaa at position 80 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg;
Xaa at position 81 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys;
Xaa at position 82 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn,
His, Thr, Ser, Ala, Tyr, Phe, Ile, Met or Val;
Xaa at position 83 is Pro, Ala, Thr, Trp, Arg, or Met;
Xaa at position 84 is Cys, Glu, Gly, Arg, Met, or Val;
Xaa at position 85 is Leu, Asn, Val, or Gln;
Xaa at position 86 is Pro, Cys, Arg, Ala, or Lys;
Xaa at position 87 is Leu, Ser, Trp, or Gly;

520
Xaa at position 88 is Ala, Lys, Arg, Val, or Trp;
Xaa at position 89 is Thr, Asp, Cys, Leu, Val, Glu, His, Asn, or Ser;
Xaa at position 90 is Ala, Pro, Ser, Thr, Gly, Asp, Ile, or Met;
Xaa at position 91 is Ala, Pro, Ser, Thr, Phe, Leu, Asp, or His;
Xaa at position 92 is Pro, Phe, Arg, Ser, Lys, His, Ala, Gly, Ile or
Leu;
Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, or Arg;
Xaa at position 94 is Arg, Ile, Ser, Glu, Leu, Val, Gln, Lys, His,
Ala, or Pro;
Xaa at position 95 is His, Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn,
Lys, Ser, Ala, Trp, Phe, Ile, or Tyr;
Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr;
Xaa at position 97 is Ile, Val, Lys, Ala, or Asn;
Xaa at position 98 is His, Ile, Asn, Leu, Asp, Ala, Thr,
Glu, Gln, Ser, Phe, Met, Val, Lys, Arg, Tyr or Pro;
Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gln,
Gly, Ser, Phe, or His;
Xaa at position 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Gln, or Pro,
Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Val,
Tyr, Glu, Asn, Ser, Ala, Gly, Ile, Leu, or Gln;
Xaa at position 102 is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro;
Xaa at position 103 is Asp, or Ser;
Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu,
Gln, Lys, Ala, Phe, or Gly;
Xaa at position 105 is Asn, Pro, Ala, Phe, Ser, Trp, Gln, Tyr,
Leu, Lys, Ile, Asp, or His;
Xaa at position 106 is Glu, Ser, Ala, Lys, Thr, Ile, Gly, or Pro;
Xaa at position 108 is Arg, Lys, Asp, Leu, Thr, Ile, Gln, His, Ser,
Ala or Pro;
Xaa at position 109 is Arg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly;
Xaa at position 110 is Lys, Ala, Asn, Thr, Leu, Arg, Gln, His, Glu,
Ser, or Trp;
Xaa at position 111 is Leu, Ile, Arg, Asp, or Met;
Xaa at position 112 is Thr, Val, Gln, Tyr, Glu, His, Ser, or Phe;
Xaa at position 113 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp,

521
Lys, Leu, Ile, Val or Asn;
Xaa at position 114 is Tyr, Cys, His, Ser, Arp, Arg, or Leu;
Xaa at position 115 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr,
Trp, or Met;
Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu,
Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gln, or Ile;
Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro;
Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr;
Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg;
Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gln;
Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly;
Xaa at position 122 is Gln, Ser, Met, Trp, Arg, Phe, Pro, His,
Ile, Tyr, or Cys;
Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu;
wherein from 1 to 14 amino acids can optionally be deleted
from the N-terminus and/or from 1 to 15 amino acids can
optionally be deleted from the C-terminus of said modified
human IL-3 amino acid sequence; and wherein from 1 to 44 of
the amino acids designated by xaa are different from the
corresponding amino acids of native (1-133) human
interleukin-3; and
(V) a colony stimulating factor;
and wherein L1 is a linker capable of linking R1 to R2;
with the proviso that at least R1 or R2 is selected
from the polypeptide of formula (I) , (II), or (III); and
said hematopoietic protein can optionally be
immediately preceded by (methionine-1), (alanine-1) or
(methionine-2, alanine-1).

522
2. A hematopoietic protein comprising; an amino acid
sequence of the formula:
R1-L1-R2, R2-L1-R1, R1-R2, or R2-R1
wherein R1 and R2 are independently selected from the
group consisting of;
(I) A polypeptide comprising; a modified human G-CSF
amino acid sequence of the formula:
1 10
Xaa Xaa Xaa Gly Pro Ala Ser Ser Leu Pro Gln Ser Xaa
Leu Leu Xaa Xaa Xaa Glu Gln Val Xaa Lys Xaa Gln Gly Xaa Gly
Ala Xaa Leu Gln Glu Xaa Leu Xaa Ala Thr Tyr Lys Leu Xaa Xaa
Xaa Glu Xaa Xaa Val Xaa Xaa Gly His Ser Xaa Gly Ile Pro Trp
Ala Pro Leu Ser Ser Xaa Pro Ser Xaa Ala Leu Xaa Leu Ala Gly
Xaa Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu
100
Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu
110
Xaa Thr Leu Gln Xaa Asp Val Ala Asp Phe Ala Xaa Thr Ile Trp
120 130
Gln Gln Met Glu Xaa Xaa Gly Met Ala Pro Ala Leu Gln Pro Thr
140
Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Xaa Gln Xaa Xaa Ala
150 160
Gly Gly Val Leu Val Ala Ser Xaa Leu Gln Xaa Phe Leu Xaa Xaa
170
Ser Tyr Arg Val Leu Xaa Xaa Leu Ala Gln Pro (SEQ ID NO:1)

523
wherein
Xaa at position 1 is Thr, Ser, Arg, Tyr or Gly;
Xaa at position 2 is Pro or Leu;
Xaa at position 3 is Leu, Arg, Tyr or Ser;
Xaa at position 13 is Phe, Ser, His, Thr or Pro;
Xaa at position 16 is Lys, Pro, Ser, Thr or His;
Xaa at position 17 is Cys, Ser, Gly, Ala, Ile, Tyr or Arg;
Xaa at position 18 is Leu, Thr, Pro, His, Ile or Cys;
Xaa at position 22 is Arg, Tyr, Ser, Thr or Ala;
Xaa at position 24 is Ile, Pro, Tyr or Leu;
Xaa at position 27 is Asp, or Gly;
Xaa at position 30 is Ala, Ile, Leu or Gly;
Xaa at position 34 is Lys or Ser;
Xaa at position 36 is Cys or Ser;
Xaa at position 42 is Cys or Ser;
Xaa at position 43 is His, Thr, Gly, Val, Lys, Trp, Ala,
Arg, Cys, or Leu;
Xaa at position 44 is Pro, Gly, Arg, Asp, Val, Ala, His,
Trp, Gln, or Thr;
Xaa at position 46 is Glu, Arg, Phe, Arg, Ile or Ala;
Xaa at position 47 is Leu or Thr;
Xaa at position 49 is Leu, Phe, Arg or Ser;
Xaa at position 50 is Leu, Ile, His, Pro or Tyr;
Xaa at position 54 is Leu or His;
Xaa at position 64 is Cys or Ser;
Xaa at position 67 is Gln, Lys, Leu or Cys;
Xaa at position 70 is Gln, Pro, Leu, Arg or Ser;
Xaa at position 74 is Cys or Ser;
Xaa at position 104 is Asp, Gly or Val;
Xaa at position 108 is Leu, Ala, Val, Arg, Trp, Gln or Gly;
Xaa at position 115 is Thr, His, Leu or Ala;
Xaa at position 120 is Gln, Gly, Arg, Lys or His
Xaa at position 123 is Glu, Arg, Phe or Thr
Xaa at position 144 is Phe, His, Arg, Pro, Leu, Gln or Glu;
Xaa at position 146 is Arg or Gln;
Xaa at position 147 is Arg or Gln;
Xaa at position 156 is His, Gly or Ser;
Xaa at position 159 is Ser, Arg, Thr, Tyr, Val or Gly;
Xaa at position 162 is Glu, Leu, Gly or Trp;
Xaa at position 163 is Val, Gly, Arg or Ala;
Xaa at position 169 is Arg, Ser, Leu, Arg or Cys;
Xaa at position 170 is His, Arg or Ser;
wherein optionally 1-11 amino acids from the N-terminus and
1-5 from the C-terminus can be deleted from said modified
human G-CSF amino acid sequence; and

524
wherein the N-terminus is joined to the C-terminus directly
or through a linker capable of joining the N-terminus to the
C-terminus and having new C- and N-termini at amino acids;
38-39 62-63 123-124
39-40 63-64 124-125
40-41 64-65 125-126
41-42 65-66 126-127
42-43 66-67 128-129
43-44 67-68 128-129
45-46 68-69 129-130
48-49 69-70 130-131
49-50 70-71 131-132
52-53 71-72 132-133
53-54 91-92 133-134
54-55 92-93 134-135
55-56 93-94 135-136
56-57 94-95 136-137
57-58 95-96 137-138
58-59 96-97 138-139
59-60 97-98 139-140
60-61 98-99 140-141
61-62 99-100 141-142
or 142-143
respectively;
(II) A polypeptide comprising; a modified human IL-3
amino acid sequence of the formula:
Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Thr Ser Trp val Asn
1 5 10 15
Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa
xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

525
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
100 105
Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
110 115 120
Xaa Xaa Xaa Gln Gln Thr Thr Leu Ser Leu Ala Ile Phe
125 130
wherein Xaa at position 17 is Ser, Lys, Gly, Asp, Met, Gln, or Arg;
Xaa at position 18 is Asn, His, Leu, Ile, Phe, Arg, or Gln;
Xaa at position 19 is Met, Phe, Ile, Arg, Gly, Ala, or Cys;
Xaa at position 20 is Ile, Cys, Gln, Glu, Arg, Pro, or Ala;
Xaa at position 21 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gln, Asn,
Thr, Ser or Val;
Xaa at position 22 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn, Gln,
Leu, Val or Gly;
Xaa at position 23 is Ile, Val, Ala, Gly, Trp, Lys, Phe,
Leu, Ser, or Arg;
Xaa at position 24 is Ile, Gly, Val, Arg, Ser, Phe, or Leu;
Xaa at position 25 is Thr, His, Gly, Gln, Arg, Pro, or Ala;
Xaa at position 26 is His, Thr, Phe, Gly, Arg, Ala, or Trp;
Xaa at position 27 is Leu, Gly, Arg, Thr, Ser, or Ala;
Xaa at position 28 is Lys, Arg, Leu, Gln, Gly, Pro, Val or Trp;
Xaa at position 29 is Gln, Asn, Leu, Pro, Arg, or Val;
Xaa at position 30 is Pro, His, Thr, Gly, Asp, Gln, Ser, Leu, or Lys;
Xaa at position 31 is Pro, Asp, Gly, Ala, Arg, Leu, or Gln;
Xaa at position 32 is Leu, Val, Arg, Gln, Asn, Gly, Ala, or Glu;

526
Xaa at position 33 is Pro, Leu, Gln, Ala, Thr, or Glu;
Xaa at position 34 is Leu, Val, Gly, Ser, Lys, Glu, Gln, Thr,
Arg, Ala, Phe, Ile or Met;
Xaa at position 35 is Leu, Ala, Gly, Asn, Pro, Gln, or Val;
Xaa at position 36 is Asp, Leu, or Val;
Xaa at position 37 is Phe, Ser, Pro, Trp, or Ile;
Xaa at position 38 is Asn, or Ala;
Xaa at position 40 is Leu, Trp, or Arg;
Xaa at position 41 is Asn, Cys, Arg, Leu, His, Met, or Pro;
Xaa at position 42 is Gly, Asp, Ser, Cys, Asn, Lys, Thr, Leu,
Val, Glu, Phe, Tyr, Ile, Met or Ala;
Xaa at position 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys,
Gln, Arg, Thr, Gly or Ser;
Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp,
Glu, Asn, Gln, Ala or Pro;
Xaa at position 45 is Gln, Pro, Phe, Val, Met, Leu, Thr, Lys,
Trp, Asp, Asn, Arg, Ser, Ala, Ile, Glu or His;
Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gln,
Lys, His, Ala, Tyr, Ile, Val or Gly;
Xaa at position 47 is Ile, Gly, Val, Ser, Arg, Pro, or His;
Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, His, Phe, Glu,
Lys, Thr, Ala, Met, Val or Asn;
Xaa at position 49 is Met, Arg, Ala, Gly, Pro, Asn, His, or Asp;
Xaa at position 50 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser,
Ala, Ile, Val, His, Phe, Met or Gln;
Xaa at position 51 is Asn, Arg, Met, Pro, Ser, Thr, or His;
Xaa at position 52 is Asn, His, Arg, Leu, Gly, Ser, or Thr;
Xaa at position 53 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Met;
Xaa at position 54 is Arg, Asp, Ile, Ser, Val, Thr, Gln, Asn,
Lys, his, Ala or Leu;
Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gly;
Xaa at position 56 is Pro, Gly, Cys, Ser, Gln, Glu, Arg, His,
Thr, Ala, Tyr, Phe, Leu, Val or Lys;
Xaa at position 57 is Asn or Gly;
Xaa at position 58 is Leu, Ser, Asp, Arg, Gln, Val, or Cys;

527
Xaa at position 59 is Glu Tyr, His, Leu, Pro, or Arg;
Xaa at position 60 is Ala, Ser, Pro, Tyr, Asn, or Thr;
Xaa at position 61 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser;
Xaa at position 62 is Asn, His, Val, Arg, Pro, Thr, Asp, or Ile;
Xaa at position 63 is Arg, Tyr, Trp, Lys, Ser, His, Pro, or Val;
Xaa at position 64 is Ala, Asn, Pro, Ser, or Lys;
Xaa at position 65 is Val, Thr, Pro, His, Leu, Phe, or Ser;
Xaa at position 66 is Lys, Ile, Arg, Val, Asn, Glu, or Ser;
Xaa at position 67 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His;
Xaa at position 68 is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His;
Xaa at position 69 is Gln, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leu;
Xaa at position 70 is Asn, Leu, Val, Trp, Pro, or Ala;
Xaa at position 71 is Ala, Met, Leu, Pro, Arg, Glu, Thr, Gln,
Trp, or Asn;
Xaa at position 72 is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp;
Xaa at position 73 is Ala, Glu, Asp, Leu, Ser, Gly, Thr, or Arg;
Xaa at position 74 is Ile, Met, Thr, Pro, Arg, Gly, Ala;
Xaa at position 75 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser,
Gln, or Leu;
Xaa at position 76 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp;
Xaa at position 77 is Ile, Ser, Arg, Thr, or Leu;
Xaa at position 78 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg;
Xaa at position 79 is Lys, Thr, Asn, Met, Arg, Ile, Gly, or Asp;
Xaa at position 80 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg;
Xaa at position 81 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys;
Xaa at position 82 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn,
His, Thr, Ser, Ala, Tyr, Phe, Ile, Met or Val;
Xaa at position 83 is Pro, Ala, Thr, Trp, Arg, or Met;
Xaa at position 84 is Cys, Glu, Gly, Arg, Met, or Val;
Xaa at position 85 is Leu, Asn, Val, or Gln;
Xaa at position 86 is Pro, Cys, Arg, Ala, or Lys;
Xaa at position 87 is Leu, Ser, Trp, or Gly;
Xaa at position 88 is Ala, Lys, Arg, Val, or Trp;
Xaa at position 89 is Thr, Asp, Cys, Leu, Val, Glu, His, Asn, or Ser;
Xaa at position 90 is Ala, Pro, Ser, Thr, Gly, Asp, Ile, or Met;

528
Xaa at position 91 is Ala, Pro, Ser, Thr, Phe, Leu, Asp, or His;
Xaa at position 92 is Pro, Phe, Arg, Ser, Lys, His, Ala, Gly, Ile or
Leu;
Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, or Arg;
Xaa at position 94 is Arg, Ile, Ser, Glu, Leu, Val, Gln, Lys, His,
Ala, or Pro;
Xaa at position 95 is His, Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn,
Lys, Ser, Ala, Trp, Phe, Ile, or Tyr;
Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr;
Xaa at position 97 is Ile, Val, Lys, Ala, or Asn;
Xaa at position 98 is His, Ile, Asn, Leu, Asp, Ala, Thr,
Glu, Gln, Ser, Phe, Met, Val, Lys, Arg, Tyr or Pro;
Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gln,
Gly, Ser, Phe, or His;
Xaa at position 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Gln, or Pro;
Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Val,
Tyr, Glu, Asn, Ser, Ala, Gly, Ile, Leu, or Gln;
Xaa at position 102 is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro;
Xaa at position 103 is Asp, or Ser;
Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu,
Gln, Lys, Ala, Phe, or Gly;
Xaa at position 105 is Asn, Pro, Ala, Phe, Ser, Trp, Gln, Tyr,
Leu, Lys, Ile, Asp, or His;
Xaa at position 106 is Glu, Ser, Ala, Lys, Thr, Ile, Gly, or Pro;
Xaa at position 108 is Arg, Lys, Asp, Leu, Thr, Ile, Gln, His, Ser,
Ala or Pro;
Xaa at position 109 is Arg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly;
Xaa at position 110 is Lys, Ala, Asn, Thr, Leu, Arg, Gln, His, Glu,
Ser, or Trp;
Xaa at position 111 is Leu, Ile, Arg, Asp, or Met;
Xaa at position 112 is Thr, Val, Gln, Tyr, Glu, His, Ser, or Phe;
Xaa at position 113 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp,
Lys, Leu, Ile, Val or Asn;
Xaa at position 114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu;
Xaa at position 115 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr,

529
Trp, or Met;
Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu,
Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gln, or Ile;
Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro;
Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr;
Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg;
Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gln;
Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly;
Xaa at position 122 is Gln, Ser, Met, Trp, Arg, Phe, Pro, His,
Ile, Tyr, or Cys;
Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu;
wherein from 1 to 14 amino acids can optlonally be deleted
from the N-terminus and/or from 1 to 15 amino acids can
optionally be deleted from the C-terminus of said modified
human IL-3 amino acid sequence; and wherein from 0 to 44 of
the amino acids designated by Xaa are different from the
corresponding amino acids of native (1-133) human
interleukin-3; and
wherein the N-terminus is joined to the C-terminus directly
or through a linker (L2) capable of joining the N-terminus
to the C-terminus and having new C- and N-termini at amino
acids;
26-27 49-50 83-84
27-28 50-51 84-85
28-29 51-52 85-86
29-30 52-53 86-87
30-31 53-54 87-88
31-32 54-55 88-89
32-33 64-65 89-90
33-34 65-66 90-91
34-35 66-67 91-92
35-36 67-68 92-93
36-37 68-69 97-98
37-38 69-70 98-99
38-39 70-71 99-100
39-40 71-72 100-101
40-41 72-73 101-102

530
41-42 82-83 102-103
or 103-104
respectively;
(III) A polypeptide comprising; a modified human c-mpl
ligand amino acid sequence of the formula:
SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSer
1 5 10 15
HisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrPro
ValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGlu
ThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla
AlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGly
GlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnXaaXaaXaa
100 105 110
XaaGlyArgThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHis
115 120 125 130
LeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysVal
135 140 145 150
Arg (SEQ ID NO:256)
153
wherein;
Xaa at position 112 is deleted or Leu, Ala, Val, Ile, Pro,
Phe, Trp, or Met;
Xaa at position 113 is deleted or Pro, Phe, Ala, Val, Leu,
Ile, Trp, or Met;
Xaa at position 114 is deleted or Pro, Phe, Ala, Val, Leu,
Ile, Trp, or Met;
Xaa at position 115 is deleted or Gln, Gly, Ser, Thr, Tyr,

531
or Asn; and
wherein the N-terminus is joined to the C-terminus directly
or through a linker (L2) capable of joining the N-terminus
to the C-terminus and having new C- and N-termini at amino
acids;
52-53 108-109
53-54 109-110
54-55 110-111
55-56 111-112
56-57 112-113
57-58 113-114
58-59 114-115
59-60 115-116
78-79 116-117
79-80 117-118
80-81 118-119
81-82 119-120
82-83 120-121
83-84 121-122
84-85 122-123
85-86 123-124
86-87 124-125
87-88 125-126
88-89 126-127
or 127-128
respectively;
(IV) A polypeptide comprising; a modified human IL-3
amino acid sequence of the formula:
Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Thr Ser Trp Val Asn
1 5 10 15
Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa xaa
Xaa Xaa Xaa Xaa Xaa Xaa xaa xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa

532
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
100 105
Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
110 115 120
Xaa Xaa Xaa Gln Gln Thr Thr Leu Ser Leu Ala Ile Phe
125 130
wherein Xaa at position 17 is Ser, Lys, Gly, Asp, Met, Gln, or Arg;
Xaa at position 18 is Asn, His, Leu, Ile, Phe, Arg, or Gln;
Xaa at positlon 19 is Met, Phe, Ile, Arg, Gly, Ala, or Cys;
Xaa at position 20 is Ile, Cys, Gln, Glu, Arg, Pro, or Ala;
Xaa at position 21 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gln, Asn,
Thr, Ser or Val;
Xaa at position 22 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn, Gln,
Leu, Val or Gly;
Xaa at position 23 is Ile, Val, Ala, Gly, Trp, Lys, Phe,
Leu, Ser, or Arg;
Xaa at position 24 is Ile, Gly, Val, Arg, Ser, Phe, or Leu;
Xaa at position 25 is Thr, His, Gly, Gln, Arg, Pro, or Ala;
Xaa at position 26 is His, Thr, Phe, Gly, Arg, Ala, or Trp;
Xaa at position 27 is Leu, Gly, Arg, Thr, Ser, or Ala;
Xaa at position 28 is Lys, Arg, Leu, Gln, Gly, Pro, Val or Trp;
Xaa at position 29 is Gln, Asn, Leu, Pro, Arg, or Val;

533
Xaa at position 30 is Pro, His, Thr, Gly, Asp, Gln, Ser, Leu, or Lys;
Xaa at position 31 is Pro, Asp, Gly, Ala, Arg, Leu, or Gln;
Xaa at position 32 is Leu, Val, Arg, Gln, Asn, Gly, Ala, or Glu;
Xaa at position 33 is Pro, Leu, Gln, Ala, Thr, or Glu;
Xaa at position 34 is Leu, Val, Gly, Ser, Lys, Glu, Gln, Thr,
Arg, Ala, Phe, Ile or Met;
Xaa at position 35 is Leu, Ala, Gly, Asn, Pro, Gln, or Val;
Xaa at position 36 is Asp, Leu, or Val;
Xaa at position 37 is Phe, Ser, Pro, Trp, or Ile;
Xaa at position 38 is Asn, or Ala;
Xaa at position 40 is Leu, Trp, or Arg;
Xaa at position 41 is Asn, Cys, Arg, Leu, His, Met, or Pro;
Xaa at position 42 is Gly, Asp, Ser, Cys, Asn, Lys, Thr, Leu,
Val, Glu, Phe, Tyr, Ile, Met or Ala;
Xaa at position 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys,
Gln, Arg, Thr, Gly or Ser;
Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp,
Glu, Asn, Gln, Ala or Pro;
Xaa at position 45 is Gln, Pro, Phe, Val, Met, Leu, Thr, Lys,
Trp, Asp, Asn, Arg, Ser, Ala, Ile, Glu or His;
Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gln,
Lys, His, Ala, Tyr, Ile, Val or Gly;
Xaa at position 47 is Ile, Gly, Val, Ser, Arg, Pro, or His;
Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, His, Phe, Glu,
Lys, Thr, Ala, Met, Val or Asn;
Xaa at position 49 is Met, Arg, Ala, Gly, Pro, Asn, His, or Asp;
Xaa at position 50 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser,
Ala, Ile, Val, His, Phe, Met or Gln;
Xaa at position 51 is Asn, Arg, Met, Pro, Ser, Thr, or His;
Xaa at position 52 is Asn, His, Arg, Leu, Gly, Ser, or Thr;
Xaa at position 53 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Met;
Xaa at position 54 is Arg, Asp, Ile, Ser, Val, Thr, Gln, Asn,
Lys, His, Ala or Leu;
Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gly;
Xaa at position 56 is Pro, Gly, Cys, Ser, Gln, Glu, Arg, His,

534
Thr, Ala, Tyr, Phe, Leu, Val or Lys;
Xaa at position 57 is Asn or Gly;
Xaa at position 58 is Leu, Ser, Asp, Arg, Gln, Val, or Cys;
Xaa at position 59 is Glu Tyr, His, Leu, Pro, or Arg;
Xaa at position 60 is Ala, Ser, Pro, Tyr, Asn, or Thr;
Xaa at position 61 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser;
Xaa at position 62 is Asn, His, Val, Arg, Pro, Thr, Asp, or Ile;
Xaa at position 63 is Arg, Tyr, Trp, Lys, Ser, His, Pro, or Val;
Xaa at position 64 is Ala, Asn, Pro, Ser, or Lys;
Xaa at position 65 is Val, Thr, Pro, His, Leu, Phe, or Ser;
Xaa at position 66 is Lys, Ile, Arg, Val, Asn, Glu, or Ser;
Xaa at position 67 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His;
Xaa at position 68 is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His;
Xaa at position 69 is Gln, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leu;
Xaa at position 70 is Asn, Leu, Val, Trp, Pro, or Ala;
Xaa at position 71 is Ala, Met, Leu, Pro, Arg, Glu, Thr, Gln,
Trp, or Asn;
Xaa at position 72 is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp;
Xaa at position 73 is Ala, Glu, Asp, Leu, Ser, Gly, Thr, or Arg;
Xaa at position 74 is Ile, Met, Thr, Pro, Arg, Gly, Ala;
Xaa at position 75 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser,
Gln, or Leu;
Xaa at position 76 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp;
Xaa at position 77 is Ile, Ser, Arg, Thr, or Leu;
Xaa at position 78 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg;
Xaa at position 79 is Lys, Thr, Asn, Met, Arg, Ile, Gly, or Asp;
Xaa at position 80 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg;
Xaa at position 81 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys;
Xaa at position 82 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn,
His, Thr, Ser, Ala, Tyr, Phe, Ile, Met or Val;
Xaa at position 83 is Pro, Ala, Thr, Trp, Arg, or Met;
Xaa at position 84 is Cys, Glu, Gly, Arg, Met, or Val;
Xaa at position 85 is Leu, Asn, Val, or Gln;
Xaa at position 86 is Pro, Cys, Arg, Ala, or Lys;
Xaa at position 87 is Leu, Ser, Trp, or Gly;

535
Xaa at position 88 is Ala, Lys, Arg, Val, or Trp;
Xaa at position 89 is Thr, Asp, Cys, Leu, Val, Glu, His, Asn, or Ser;
Xaa at position 90 is Ala, Pro, Ser, Thr, Gly, Asp, Ile, or Met;
Xaa at position 91 is Ala, Pro, Ser, Thr, Phe, Leu, Asp, or His;
Xaa at position 92 is Pro, Phe, Arg, Ser, Lys, His, Ala, Gly, Ile or
Leu;
Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, or Arg;
Xaa at position 94 is Arg, Ile, Ser, Glu, Leu, Val, Gln, Lys, His,
Ala, or Pro;
Xaa at position 95 is His, Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn,
Lys, Ser, Ala, Trp, Phe, Ile, or Tyr;
Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr;
Xaa at position 97 is Ile, Val, Lys, Ala, or Asn;
Xaa at position 98 is His, Ile, Asn, Leu, Asp, Ala, Thr,
Glu, Glu, Ser, Phe, Met, Val, Lys, Arg, Tyr or Pro;
Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gln,
Gly, Ser, Phe, or His;
Xaa at position 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Gln, or Pro;
Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Val,
Tyr, Glu, Asn, Ser, Ala, Gly, Ile, Leu, or Gln;
Xaa at position 102 is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro;
Xaa at position 103 is Asp, or Ser;
Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu,
Gln, Lys, Ala, Phe, or Gly;
Xaa at position 105 is Asn, Pro, Ala, Phe, Ser, Trp, Gln, Tyr,
Leu, Lys, Ile, Asp, or His;
Xaa at position 106 is Glu, Ser, Ala, Lys, Thr, Ile, Gly, or Pro;
Xaa at position 108 is Arg, Lys, Asp, Leu, Thr, Ile, Gln, His, Ser,
Ala or Pro;
Xaa at position 109 is Arg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly;
Xaa at position 110 is Lys, Ala, Asn, Thr, Leu, Arg, Gln, His, Glu,
Ser, or Trp;
Xaa at position 111 is Leu, Ile, Arg, Asp, or Met;
Xaa at position 112 is Thr, Val, Gln, Tyr, Glu, His, Ser, or Phe;
Xaa at position 113 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp,

536
Lys, Leu, Ile, Val or Asn;
Xaa at position 114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu;
Xaa at position 115 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr,
Trp, or Met;
Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu,
Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gln, or Ile;
Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro;
Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr;
Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg;
Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gln;
Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly;
Xaa at position 122 is Gln, Ser, Met, Trp, Arg, Phe, Pro, His,
Ile, Tyr, or Cys;
Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu;
wherein from 1 to la amino acids can optionally be deleted
from the N-terminus and/or from 1 to 15 amino acids can
optionally be deleted from the C-terminus of said modified
human IL-3 amino acid sequence; and wherein from 1 to 44 of
the amino acids designated by Xaa are different from the
corresponding amino acids of native (1-133) human
interleukin-3; and
(V) a colony stimulating factor;
and wherein L1 is a linker capable of linking R1 to R2;
with the proviso that at least R1 or R2 is selected
from the polypeptide of formula (I) , (II), or (III); and
said hematopoietic protein can optionally be
immediately preceded by (methionine-1), (alanine-1) or
(methionine-2, alanine-1).

537
3. The hematopoietic protein as recited in claim 1
wherein the polypeptide of (IV) is selected from the from
the group consisting of;
Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys
Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Ala Glu
Asp Val Asp Ile Leu Met Glu Arg Asn Leu Arg Leu Pro Asn Leu
Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly
Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala
Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp
Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu
Glu Gln Ala Gln Glu Gln Gln (SEQ ID NO:225);
Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys
Arg Pro Pro Asn Pro Leu Leu Asp Pro Asn Asn Leu Asn Ser Glu
Asp Met Asp Ile Leu Met Glu Arg Asn Leu Arg Thr Pro Asn Leu
Leu Ala Phe Val Arg Ala Val Lys His Leu Glu Asn Ala Ser Gly
Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala
Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp
Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu
Glu Gln Ala Gln Glu Gln Gln (SEQ ID NO:226);
Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys
Val Pro Pro Ala Pro Leu Leu Asp Ser Asn Asn Leu Asn Ser Glu
Asp Met Asp Ile Leu Met Glu Arg Asn Leu Arg Leu Pro Asn Leu
Leu Ala Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly
Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala
Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp
Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu
Glu Gln Ala Gln Glu Gln Gln (SEQ ID NO:227); and

538
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln (SEQ ID NO:228).
4, The hematopoietic protein as recited in claim 2
wherein the polypeptide of (IV) is selected from the from
the group consisting of;
Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys
Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Ala Glu
Asp Val Asp Ile Leu Met Glu Arg Asn Leu Arg Leu Pro Asn Leu
Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly
Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala
Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp
Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu
Glu Gln Ala Gln Glu Gln Gln (SEQ ID NO:225);
Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys
Arg Pro Pro Asn Pro Leu Leu Asp Pro Asn Asn Leu Asn Ser Glu
Asp Met Asp Ile Leu Met Glu Arg Asn Leu Arg Thr Pro Asn Leu
Leu Ala Phe Val Arg Ala Val Lys His Leu Glu Asn Ala Ser Gly
Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala
Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp
Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu
Glu Gln Ala Gln Glu Gln Gln (SEQ ID NO:226);
Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys

539
Val Pro Pro Ala Pro Leu Leu Asp Ser Asn Asn Leu Asn Ser Glu
Asp Met Asp Ile Leu Met Glu Arg Asn Leu Arg Leu Pro Asn Leu
Leu Ala Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly
Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala
Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp
Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu
Glu Gln Ala Gln Glu Gln Gln (SEQ ID NO:227); and
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln (SEQ ID NO:228).
5. A hematopoietic protein comprising; an amino acid
sequence of the formula:
R1-L1-R2, R2-L1-R1, R1-R2/ or R2-R1
wherein R1 is a polypeptide comprising; a modified
human G-CSF amino acid sequence of the formula:
Xaa Xaa Xaa Gly Pro Ala Ser Ser Leu Pro Gln Ser Xaa
Leu Leu Xaa Xaa Xaa Glu Gln Val Xaa Lys Xaa Gln Gly Xaa Gly
Ala Xaa Leu Gln Glu Xaa Leu Xaa Ala Thr Tyr Lys Leu Xaa Xaa
Xaa Glu Xaa Xaa Val Xaa Xaa Gly His Ser Xaa Gly Ile Pro Trp

540
Ala Pro Leu Ser Ser Xaa Pro Ser Xaa Ala Leu Xaa Leu Ala Gly
Xaa Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu
100
Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu
110
Xaa Thr Leu Gln Xaa Asp Val Ala Asp Phe Ala Xaa Thr Ile Trp
120 130
Gln Gln Met Glu Xaa Xaa Gly Met Ala Pro Ala Leu Gln Pro Thr
140
Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Xaa Gln Xaa Xaa Ala
150 160
Gly Gly Val Leu Val Ala Ser Xaa Leu Gln Xaa Phe Leu Xaa Xaa
170
Ser Tyr Arg Val Leu Xaa Xaa Leu Ala Gln Pro (SEQ ID NO:1)
wherein
Xaa at position 1 is Thr, Ser, Arg, Tyr or Gly;
Xaa at position 2 is Pro or Leu;
Xaa at position 3 is Leu, Arg, Tyr or Ser;
Xaa at position 13 is Phe, Ser, His, Thr or Pro;
Xaa at position 16 is Lys, Pro, Ser, Thr or His;
Xaa at position 17 is Cys, Ser, Gly, Ala, Ile, Tyr or Arg;
Xaa at position 18 is Leu, Thr, Pro, His, Ile or Cys;
Xaa at position 22 is Arg, Tyr, Ser, Thr or Ala;
Xaa at position 24 is Ile, Pro, Tyr or Leu;
Xaa at position 27 is Asp, or Gly;
Xaa at position 30 is Ala, Ile, Leu or Gly;
Xaa at position 34 is Lys or Ser;
Xaa at position 36 is Cys or Ser;
Xaa at position 42 is Cys or Ser;
Xaa at position 43 is His, Thr, Gly, Val, Lys, Trp, Ala,
Arg, Cys, or Leu;
Xaa at position 44 is Pro, Gly, Arg, Asp, Val, Ala, His,
Trp, Gln, or Thr;
Xaa at position 46 is Glu, Arg, Phe, Arg, Ile or Ala;
Xaa at position 47 is Leu or Thr;
Xaa at position 49 is Leu, Phe, Arg or Ser;
Xaa at position 50 is Leu, Ile, His, Pro or Tyr;
Xaa at position 54 is Leu or His;
Xaa at position 64 is Cys or Ser;
Xaa at position 67 is Gln, Lys, Leu or Cys;
Xaa at position 70 is Gln, Pro, Leu, Arg or Ser;
Xaa at position 74 is Cys or Ser;

541
Xaa at position 104 is Asp, Gly or Val;
Xaa at position 108 is Leu, Ala, Val, Arg, Trp, Gln or Gly;
Xaa at position 115 is Thr, His, Leu or Ala;
Xaa at position 120 is Gln, Gly, Arg, Lys or His
Xaa at position 123 is Glu, Arg, Phe or Thr
Xaa at position 144 is Phe, His, Arg, Pro, Leu, Gln or Glu;
Xaa at position 146 is Arg or Gln;
Xaa at position 147 is Arg or Gln;
Xaa at position 156 is His, Gly or Ser;
Xaa at position 159 is Ser, Arg, Thr, Tyr, Val or Gly;
Xaa at position 162 is Glu, Leu, Gly or Trp;
Xaa at position 163 is Val, Gly, Arg or Ala;
Xaa at position 169 is Arg, Ser, Leu, Arg or Cys;
Xaa at position 170 is His, Arg or Ser;
wherein optionally 1-11 amino acids from the N-terminus and
1-5 from the C-terminus can be deleted from said modified
human G-CSF amino acid sequence; and
wherein the N-terminus is joined to the C-terminus directly
or through a linker capable of joining the N-terminus to the
C-terminus and having new C- and M-termini at amino acids
38-39 62-63 123-124
39-40 63-64 124-125
40-41 64-65 125-126
41-42 65-66 126-127
42-43 66-67 128-129
43-44 67-68 128-129
45-46 68-69 129-130
48-49 69-70 130-131
49-50 70-71 131-132
52-53 71-72 132-133
53-54 91-92 133-134
54-55 92-93 134-135
55-56 93-94 135-136
56-57 94-95 136-137
57-58 95-96 137-138
58-59 96-97 138-139
59-60 97-98 139-140
60-61 98-99 140-141
61-62 99-100 141-142
or 142-143
respectively;

542
wherein R2 is a polypeptide comprising; a modified
human IL-3 amino acid sequence of the formula:
Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Thr Ser Trp Val Asn
1 5 10 15
Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
100 105
Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
110 115 120
Xaa Xaa Xaa Gln Gln Thr Thr Leu Ser Leu Ala Ile Phe
125 130 (SEQ ID NO:2)
wherein Xaa at position 17 is Ser, Lys, Gly, Asp, Met, Gln, or Arg;
Xaa at position 18 is Asn, His, Leu, Ile, Phe, Arg, or Gln;
Xaa at position 19 is Met, Phe, Ile, Arg, Gly, Ala, or Cys;
Xaa at position 20 is Ile, Cys, Gln, Glu, Arg, Pro, or Ala;

543
Xaa at position 21 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gln, Asn,
Thr, Ser or Val;
Xaa at position 22 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn, Gln,
Leu, Val or Gly;
Xaa at position 23 is Ile, Val, Ala, Gly, Trp, Lys, Phe,
Leu, Ser, or Arg;
Xaa at position 24 is Ile, Gly, Val, Arg, Ser, Phe, or Leu;
Xaa at position 25 is Thr, His, Gly, Gln, Arg, Pro, or Ala;
Xaa at position 26 is His, Thr, Phe, Gly, Arg, Ala, or Trp;
Xaa at position 27 is Leu, Gly, Arg, Thr, Ser, or Ala;
Xaa at position 28 is Lys, Arg, Leu, Gln, Gly, Pro, Val or Trp;
Xaa at position 29 is Gln, Asn, Leu, Pro, Arg, or Val;
Xaa at position 30 is Pro, His, Thr, Gly, Asp, Gln, Ser, Leu, or Lys
Xaa at position 31 is Pro, Asp, Gly, Ala, Arg, Leu, or Gln;
Xaa at position 32 is Leu, Val, Arg, Gln, Asn, Gly, Ala, or Glu;
Xaa at position 33 is Pro, Leu, Gln, Ala, Thr, or Glu;
Xaa at position 34 is Leu, Val, Gly, Ser, Lys, Glu, Gln, Thr,
Arg, Ala, Phe, Ile or Met;
Xaa at position 35 is Leu, Ala, Gly, Asn, Pro, Gln, or Val;
Xaa at position 36 is Asp, Leu, or Val;
Xaa at position 37 is Phe, Ser, Pro, Trp, or Ile;
Xaa at position 38 is Asn, or Ala;
Xaa at position 40 is Leu, Trp, or Arg;
Xaa at position 41 is Asn, Cys, Arg, Leu, His, Met, or Pro;
Xaa at position 42 is Gly, Asp, Ser, Cys, Asn, Lys, Thr, Leu,
Val, Glu, Phe, Tyr, Ile, Met or Ala;
Xaa at position 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys,
Gln, Arg, Thr, Gly or Ser;
Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp,
Glu, Asn, Gln, Ala or Pro;
Xaa at position 45 is Gln, Pro, Phe, Val, Met, Leu, Thr, Lys,
Trp, Asp, Asn, Arg, Ser, Ala, Ile, Glu or His;
Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gln,
Lys, His, Ala, Tyr, Ile, Val or Gly;
Xaa at position 47 is Ile, Gly, Val, Ser, Arg, Pro, or His;

544
Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, His, Phe, Glu,
Lys, Thr, Ala, Met, Val or Asn;
Xaa at position 49 is Met, Arg, Ala, Gly, Pro, Asn, His, or Asp;
Xaa at position 50 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser,
Ala, Ile, Val, His, Phe, Met or Gln;
Xaa at position 51 is Asn, Arg, Met, Pro, Ser, Thr, or His;
Xaa at position 52 is Asn, His, Arg, Leu, Gly, Ser, or Thr;
Xaa at position 53 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Met;
Xaa at position 54 is Arg, Asp, Ile, Ser, Val, Thr, Gln, Asn,
Lys, His, Ala or Leu;
Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gly;
Xaa at position 56 is Pro, Gly, Cys, Ser, Gln, Glu, Arg, His,
Thr, Ala, Tyr, Phe, Leu, Val or Lys;
Xaa at position 57 is Asn or Gly;
Xaa at position 58 is Leu, Ser, Asp, Arg, Gln, Val, or Cys;
Xaa at position 59 is Glu Tyr, His, Leu, Pro, or Arg;
Xaa at position 60 is Ala, Ser, Pro, Tyr, Asn, or Thr;
Xaa at position 61 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser;
Xaa at position 62 is Asn, His, Val, Arg, Pro, Thr, Asp, or Ile;
Xaa at position 63 is Arg, Tyr, Trp, Lys, Ser, His, Pro, or Val;
Xaa at position 64 is Ala, Asn, Pro, Ser, or Lys;
Xaa at position 65 is Val, Thr, Pro, His, Leu, Phe, or Ser;
Xaa at positlon 66 is Lys, Ile, Arg, Val, Asn, Glu, or Ser;
Xaa at position 67 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His;
Xaa at position 68 is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His;
Xaa at position 69 is Gln, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leu;
Xaa at position 70 is Asn, Leu, Val, Trp, Pro, or Ala;
Xaa at position 71 is Ala, Met, Leu, Pro, Arg, Glu, Thr, Gln,
Trp, or Asn;
Xaa at position 72 is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp;
Xaa at position 73 is Ala, Glu, Asp, Leu, Ser, Gly, Thr, or Arg;
Xaa at position 74 is Ile, Met, Thr, Pro, Arg, Gly, Ala;
Xaa at position 75 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser,
Gln, or Leu;
Xaa at position 76 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp;

545
Xaa at position 77 is Ile, Ser, Arg, Thr, or Leu;
Xaa at position 78 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg;
Xaa at position 79 is Lys, Thr, Asn, Met, Arg, Ile, Gly, or Asp;
Xaa at position 80 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg;
Xaa at position 81 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys;
Xaa at position 82 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn,
His, Thr, Ser, Ala, Tyr, Phe, Ile, Met or Val;
Xaa at position 83 is Pro, Ala, Thr, Trp, Arg, or Met;
Xaa at position 84 is Cys, Glu, Gly, Arg, Met, or Val;
Xaa at position 85 is Leu, Asn, Val, or Gln;
Xaa at position 86 is Pro, Cys, Arg, Ala, or Lys;
Xaa at position 87 is Leu, Ser, Trp, or Gly;
Xaa at position 88 is Ala, Lys, Arg, Val, or Trp;
Xaa at position 89 is Thr, Asp, Cys, Leu, Val, Glu, His, Asn, or Ser;
Xaa at position 90 is Ala, Pro, Ser, Thr, Gly, Asp, Ile, or Met;
Xaa at position 91 is Ala, Pro, Ser, Thr, Phe, Leu, Asp, or His;
Xaa at position 92 is Pro, Phe, Arg, Ser, Lys, His, Ala, Gly, Ile or
Leu;
Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, or Arg;
Xaa at position 94 is Arg, Ile, Ser, Glu, Leu, Val, Gln, Lys, His,
Ala, or Pro;
Xaa at position 95 is His, Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn,
Lys, Ser, Ala, Trp, Phe, Ile, or Tyr;
Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr;
Xaa at position 97 is Ile, Val, Lys, Ala, or Asn;
Xaa at position 98 is His, Ile, Asn, Leu, Asp, Ala, Thr,
Glu, Gln, Ser, Phe, Met, Val, Lys, Arg, Tyr or Pro;
Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gln,
Gly, Ser, Phe, or His;
Xaa at position 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Gln, or Pro;
Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Val,
Tyr, Glu, Asn, Ser, Ala, Gly, Ile, Leu, or Gln;
Xaa at position 102 is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro;
Xaa at position 103 is Asp, or Ser;
Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu,

546
Gln, Lys, Ala, Phe, or Gly;
Xaa at position 105 is Asn, Pro, Ala, Phe, Ser, Trp, Gln, Tyr,
Leu, Lys, Ile, Asp, or His;
Xaa at position 106 is Glu, Ser, Ala, Lys, Thr, Ile, Gly, or Pro;
Xaa at position 108 is Arg, Lys, Asp, Leu, Thr, Ile, Gln, His, Ser,
Ala or Pro;
Xaa at position 109 is Arg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly;
Xaa at position 110 is Lys, Ala, Asn, Thr, Leu, Arg, Gln, His, Glu,
Ser, or Trp;
Xaa at position 111 is Leu, Ile, Arg, Asp, or Met;
Xaa at position 112 is Thr, Val, Gln, Tyr, Glu, His, Ser, or Phe;
Xaa at position 113 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp,
Lys, Leu, Ile, Val or Asn;
Xaa at position 114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu;
Xaa at position 115 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr,
Trp, or Met;
Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu,
Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gln, or Ile;
Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro;
Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr;
Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg;
Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gln;
Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly;
Xaa at position 122 is Gln, Ser, Met, Trp, Arg, Phe, Pro, His,
Ile, Tyr, or Cys;
Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu;
wherein from 1 to 14 amino acids can optionally be deleted
from the N-terminus and/or from 1 to 15 amino acids can
optionally be deleted from the C-terminus of said modified
human interleukin-3 amino acid sequence; and wherein from 0
to 44 of the amino acids designated by Xaa are different
from the corresponding amino acids of native (1-133) human
interleukin-3; and

547
wherein the N-terminus is joined to the C-terminus directly
or through a linker (L2) capable of joining the N-terminus
to the C-terminus and having new C- and N-termini at amino
acids;
26-27 49-50 83-84
27-28 50-51 84-85
28-29 51-52 85-86
29-30 52-53 86-87
30-31 53-54 87-88
31-32 54-55 88-89
32-33 64-65 89-90
33-34 65-66 90-91
34-35 66-67 91-92
35-36 67-68 92-93
36-37 68-69 97-98
37-38 69-70 98-99
38-39 70-71 99-100
39-40 71-72 100-101
40-41 72-73 101-102
41-42 82-83 102-103
or 103-104
respectively;
wherein L1 is a linker capable of linking R1 to R2; and
said hematopoietic protein can optionally be
immediately preceded by (methionine-1), (alanine-1) or
(methionine-2, alanine-1).
6. A hematopoietic protein comprising; an amino acid
sequence of the formula:
R1-L1-R2, R2-L1-R1, R1-R2, or R2-R1
wherein R1 is a polypeptide comprising; a modified
human G-CSF amino acid sequence of the formula:
Xaa Xaa Xaa Gly Pro Ala Ser Ser Leu Pro Gln Ser Xaa

548
Leu Leu Xaa Xaa Xaa Glu Gln Val Xaa Lys Xaa Gln Gly Xaa Gly
Ala Xaa Leu Gln Glu Xaa Leu Xaa Ala Thr Tyr Lys Leu Xaa Xaa
Xaa Glu Xaa Xaa Val Xaa Xaa Gly His Ser Xaa Gly Ile Pro Trp
Ala Pro Leu Ser Ser Xaa Pro Ser Xaa Ala Leu Xaa Leu Ala Gly
Xaa Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu
100
Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu
110
Xaa Thr Leu Gln Xaa Asp Val Ala Asp Phe Ala Xaa Thr Ile Trp
120 130
Gln Gln Met Glu Xaa Xaa Gly Met Ala Pro Ala Leu Gln Pro Thr
140
Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Xaa Gln Xaa Xaa Ala
150 160
Gly Gly Val Leu Val Ala Ser Xaa Leu Gln Xaa Phe Leu Xaa Xaa
170
Ser Tyr Arg Val Leu Xaa Xaa Leu Ala Gln Pro (SEQ ID NO:1)
wherein
Xaa at position 1 is Thr, Ser, Arg, Tyr or Gly;
Xaa at position 2 is Pro or Leu;
Xaa at position 3 is Leu, Arg, Tyr or Ser;
Xaa at position 13 is Phe, Ser, His, Thr or Pro;
Xaa at position 16 is Lys, Pro, Ser, Thr or His;
Xaa at position 17 is Cys, Ser, Gly, Ala, Ile, Tyr or Arg;
Xaa at position 18 is Leu, Thr, Pro, Xis, Ile or Cys;
Xaa at position 22 is Arg, Tyr, Ser, Thr or Ala;
Xaa at position 24 is Ile, Pro, Tyr or Leu;
Xaa at position 27 is Asp, or Gly;
Xaa at position 30 is Ala, Ile, Leu or Gly;
Xaa at position 34 is Lys or Ser;
Xaa at position 36 is Cys or Ser;
Xaa at position 42 is Cys or Ser;
Xaa at position 43 is His, Thr, Gly, Val, Lys, Trp, Ala,
Arg, Cys, or Leu;

549
Xaa at position 44 is Pro, Gly, Arg, Asp, Val, Ala, His,
Trp, Gln, or Thr;
Xaa at position 46 is Glu, Arg, Phe, Arg, Ile or Ala;
Xaa at position 47 is Leu or Thr;
Xaa at position 49 is Leu, Phe, Arg or Ser;
Xaa at position 50 is Leu, Ile, His, Pro or Tyr;
Xaa at position 54 is Leu or His;
Xaa at position 64 is Cys or Ser;
Xaa at position 67 is Gln, Lys, Leu or Cys;
Xaa at position 70 is Gln, Pro, Leu, Arg or Ser;
Xaa at position 74 is Cys or Ser;
Xaa at position 104 is Asp, Gly or Val;
Xaa at position 108 is Leu, Ala, Val, Arg, Trp, Gln or Gly;
Xaa at position 115 is Thr, His, Leu or Ala;
Xaa at position 120 is Gln, Gly, Arg, Lys or His
Xaa at position 123 is Glu, Arg, Phe or Thr
Xaa at position 144 is Phe, His, Arg, Pro, Leu, Gln or Glu;
Xaa at position 146 is Arg or Gln;
Xaa at position 147 is Arg or Gln;
Xaa at position 156 is His, Gly or Ser;
Xaa at position 159 is Ser, Arg, Thr, Tyr, Val or Gly;
Xaa at position 162 is Glu, Leu, Gly or Trp;
Xaa at position 163 is Val, Gly, Arg or Ala;
Xaa at position 169 is Arg, Ser, Leu, Arg or Cys;
Xaa at position 170 is His, Arg or Ser;
wherein optionally 1-11 amino acids from the N-terminus and
1-5 from the C-terminus can be deleted from said modified
human G-CSF amino acid sequence; and
wherein the N-terminus is joined to the C-terminus directly
or through a linker capable of joining the N-terminus to the
C-terminus and having new C- and N-termini at amino acids;
38-39 62-63 123-124
39-40 63-64 124-125
40-41 64-65 125-126
41-42 65-66 126-127
42-43 66-67 128-129
43-44 67-68 128-129
45-46 68-69 129-130
48-49 69-70 130-131
49-50 70-71 131-132
52-53 71-72 132-133
53-54 91-92 133-134
54-55 92-93 134-135
55-56 93-94 135-136
56-57 94-95 136-137

550
57-58 95-96 137-138
58-59 96-97 138-139
59-60 97-98 139-140
60-61 98-99 140-141
61-62 99-100 141-142
or 142-143
respectively; and
R2 is a polypeptide comprising; a modified human IL-3
amino acid sequence of the formula:
Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Thr Ser Trp Val Asn
1 5 10 15
Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
100 105
Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
110 115 120
Xaa Xaa Xaa Gln Gln Thr Thr Leu Ser Leu Ala Ile Phe

551
125 130
wherein Xaa at position 17 is Ser, Lys, Gly, Asp, Met, Gln, or Arg;
Xaa at position 18 is Asn, His, Leu, Ile, Phe, Arg, or Gln;
Xaa at position 19 is Met, Phe, Ile, Arg, Gly, Ala, or Cys;
Xaa at position 20 is Ile, Cys, Gln, Glu, Arg, Pro, or Ala;
Xaa at position 21 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gln, Asn,
Thr, Ser or Val;
Xaa at position 22 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn, Gln,
Leu, Val or Gly;
Xaa at position 23 is Ile, Val, Ala, Gly, Trp, Lys, Phe,
Leu, Ser, or Arg;
Xaa at position 24 is Ile, Gly, Val, Arg, Ser, Phe. or Leu;
Xaa at position 25 is Thr, His, Gly, Gln, Arg, Pro, or Ala;
Xaa at position 26 is His, Thr, Phe, Gly, Arg, Ala, or Trp;
Xaa at position 27 is Leu, Gly, Arg, Thr, Ser, or Ala;
Xaa at position 28 is Lys, Arg, Leu, Gln, Gly, Pro, Val or Trp;
Xaa at position 29 is Gln, Asn, Leu, Pro, Arg, or Val;
Xaa at position 30 is Pro, His, Thr, Gly, Asp, Gln, Ser, Leu, or Lys;
Xaa at position 31 is Pro, Asp, Gly, Ala, Arg, Leu, or Gln;
Xaa at position 32 is Leu, Val, Arg, Gln, Asn, Gly, Ala, or Glu;
Xaa at position 33 is Pro, Leu, Gln, Ala, Thr, or Glu;
Xaa at position 34 is Leu, Val, Gly, Ser, Lys, Glu, Gln, Thr,
Arg, Ala, Phe, Ile or Met;
Xaa at position 35 is Leu, Ala, Gly, Asn, Pro, Gln, or Val;
Xaa at position 36 is Asp, Leu, or Val;
Xaa at position 37 is Phe, Ser, Pro, Trp, or Ile;
Xaa at position 38 is Asn, or Ala;
Xaa at position 40 is Leu, Trp, or Arg;
Xaa at position 41 is Asn, Cys, Arg, Leu, His, Met, or Pro;
Xaa at position 42 is Gly, Asp, Ser, Cys, Asn, Lys, Thr, Leu,
Val, Glu, Phe, Tyr, Ile, Met or Ala;
Xaa at position 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys,
Gln, Arg, Thr, Gly or Ser;
Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp,

552
Glu, Asn, Gln, Ala or Pro;
Xaa at position 45 is Gln, Pro, Phe, Val, Met, Leu, Thr, Lys,
Trp, Asp, Asn, Arg, Ser, Ala, Ile, Glu or His;
Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gln,
Lys, His, Ala, Tyr, Ile, Val or Gly;
Xaa at position 47 is Ile, Gly, Val, Ser, Arg, Pro, or His;
Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, His, Phe, Glu,
Lys, Thr, Ala, Met, Val or Asn;
Xaa at position 49 is Met, Arg, Ala, Gly, Pro, Asn, His, or Asp;
Xaa at position 50 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser,
Ala, Ile, Val, His, Phe, Met or Gln;
Xaa at position 51 is Asn, Arg, Met, Pro, Ser, Thr, or His;
Xaa at position 52 is Asn, His, Arg, Leu, Gly, Ser, or Thr;
Xaa at position 53 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Met;
Xaa at position 54 is Arg, Asp, Ile, Ser, Val, Thr, Gln, Asn,
Lys, His, Ala or Leu;
Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gly;
Xaa at position 56 is Pro, Gly, Cys, Ser, Gln, Glu, Arg, His,
Thr, Ala, Tyr, Phe, Leu, Val or Lys;
Xaa at position 57 is Asn or Gly;
Xaa at position 58 is Leu, Ser, Asp, Arg, Gln, Val, or Cys;
Xaa at position 59 is Glu Tyr, His, Leu, Pro, or Arg;
Xaa at position 60 is Ala, Ser, Pro, Tyr, Asn, or Thr;
Xaa at position 61 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser;
Xaa at position 62 is Asn, His, Val, Arg, Pro, Thr, Asp, or Ile;
Xaa at position 63 is Arg, Tyr, Trp, Lys, Ser, His, Pro, or Val;
Xaa at position 64 is Ala, Asn, Pro, Ser, or Lys;
Xaa at position 65 is Val, Thr, Pro, His, Leu, Phe, or Ser;
Xaa at position 66 is Lys, Ile, Arg, Val, Asn, Glu, or Ser;
Xaa at position 67 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His;
Xaa at position 68 is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His;
Xaa at position 69 is Gln, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leu;
Xaa at position 70 is Asn, Leu, Val, Trp, Pro, or Ala;
Xaa at position 71 is Ala, Met, Leu, Pro, Arg, Glu, Thr, Gln,
Trp, or Asn;

553
Xaa at position 72 is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp;
Xaa at position 73 is Ala, Glu, Asp, Leu, Ser, Gly, Thr, or Arg;
Xaa at position 74 is Ile, Met, Thr, Pro, Arg, Gly, Ala;
Xaa at position 75 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser,
Gln, or Leu;
Xaa at position 76 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp;
Xaa at position 77 is Ile, Ser, Arg, Thr, or Leu;
Xaa at position 78 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg;
Xaa at position 79 is Lys, Thr, Asn, Met, Arg, Ile, Gly, or Asp;
Xaa at position 80 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg;
Xaa at position 81 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys;
Xaa at position 82 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn,
His, Thr, Ser, Ala, Tyr, Phe, Ile, Met or Val;
Xaa at position 83 is Pro, Ala, Thr, Trp, Arg, or Met;
Xaa at position 84 is Cys, Glu, Gly, Arg, Met, or Val;
Xaa at position 85 is Leu, Asn, Val, or Gln;
Xaa at position 86 is Pro, Cys, Arg, Ala, or Lys;
Xaa at position 87 is Leu, Ser, Trp, or Gly;
Xaa at position 88 is Ala, Lys, Arg, Val, or Trp;
Xaa at position 89 is Thr, Asp, Cys, Leu, Val, Glu, His, Asn, or Ser;
Xaa at position 90 is Ala, Pro, Ser, Thr, Gly, Asp, Ile, or Met;
Xaa at position 91 is Ala, Pro, Ser, Thr, Phe, Leu, Asp, or His;
Xaa at position 92 is Pro, Phe, Arg, Ser, Lys, His, Ala, Gly, Ile or
Leu;
Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, or Arg;
Xaa at position 94 is Arg, Ile, Ser, Glu, Leu, Val, Gln, Lys, His,
Ala, or Pro;
Xaa at position 95 is His, Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn,
Lys, Ser, Ala, Trp, Phe, Ile, or Tyr;
Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr;
Xaa at position 97 is Ile, Val, Lys, Ala, or Asn;
Xaa at position 98 is His, Ile, Asn, Leu, Asp, Ala, Thr,
Glu, Gin, Ser, Phe, Met, Val, Lys, Arg, Tyr or Pro;
Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gln,
Gly, Ser, Phe, or His;

554
Xaa at position 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Gln, or Pro;
Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Val,
Tyr, Glu, Asn, Ser, Ala, Gly, Ile, Leu, or Gln;
Xaa at position 102 is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro;
Xaa at position 103 is Asp, or Ser;
Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu,
Gln, Lys, Ala, Phe, or Gly;
Xaa at position 105 is Asn, Pro, Ala, Phe, Ser, Trp, Gln, Tyr,
Leu, Lys, Ile, Asp, or His;
Xaa at position 106 is Glu, Ser, Ala, Lys, Thr, Ile, Gly, or Pro;
Xaa at position 108 is Arg, Lys, Asp, Leu, Thr, Ile, Gln, His, Ser,
Ala or Pro;
Xaa at position 109 is Arg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly;
Xaa at position 110 is Lys, Ala, Asn, Thr, Leu, Arg, Gln, His, Glu,
Ser, or Trp;
Xaa at position 111 is Leu, Ile, Arg, Asp, or Met;
Xaa at position 112 is Thr, Val, Gln, Tyr, Glu, His, Ser, or Phe;
Xaa at position 113 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp,
Lys, Leu, Ile, Val or Asn;
Xaa at position 114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu;
Xaa at position 115 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr,
Trp, or Met;
Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu,
Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gln, or Ile;
Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro;
Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr;
Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg;
Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gln;
Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly;
Xaa at position 122 is Gln, Ser, Met, Trp, Arg, Phe, Pro, His,
Ile, Tyr, or Cys;
Xaa at posi.tion 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu;
wherein from 1 to 14 amino acids can optionally be deleted
from the N-terminus and/or from 1 to 15 amino acids can

555
optionally be deleted from the C-terminus; and wherein from
1 to 44 of the amino acids designated by Xaa are different
from the corresponding amino acids of native (1-133) human
interleukin-3;
wherein L1 is a linker capable of linking R1 to R2; and
additionally said hematopoietic protein can be
immediately preceded by (methionine-1), (alanine-1) or
(methionine-2, alanine-1).
7. A hematopoietic protein comprising; an amino acid
sequence of the formula:
R1-L1-R2, R2-L1-R1, R1-R2, or R2-R1
wherein R1 is a polypeptide comprising; a modified
human G-CSF amino acid sequence of the formula:
1 10
Xaa Xaa Xaa Gly Pro Ala Ser Ser Leu Pro Gln Ser Xaa
Leu Leu Xaa Xaa Xaa Glu Gln Val Xaa Lys Xaa Gln Gly Xaa Gly
Ala Xaa Leu Gln Glu Xaa Leu Xaa Ala Thr Tyr Lys Leu Xaa Xaa
Xaa Glu Xaa Xaa Val Xaa Xaa Gly His Ser Xaa Gly Ile Pro Trp
Ala Pro Leu Ser Ser Xaa Pro Ser Xaa Ala Leu Xaa Leu Ala Gly
Xaa Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu
100
Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu
110
Xaa Thr Leu Gln Xaa Asp Val Ala Asp Phe Ala Xaa Thr Ile Trp

556
120 130
Gln Gln Met Glu Xaa Xaa Gly Met Ala Pro Ala Leu Gln Pro Thr
140
Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Xaa Gln Xaa Xaa Ala
150 160
Gly Gly Val Leu Val Ala Ser Xaa Leu Gln Xaa Phe Leu Xaa Xaa
170
Ser Tyr Arg Val Leu Xaa Xaa Leu Ala Gln Pro (SEQ ID NO:1)
wherein
Xaa at position 1 is Thr, Ser, Arg, Tyr or Gly;
Xaa at position 2 is Pro or Leu;
Xaa at position 3 is Leu, Arg, Tyr or Ser;
Xaa at position 13 is Phe, Ser, His, Thr or Pro;
Xaa at position 16 is Lys, Pro, Ser, Thr or His;
Xaa at position 17 is Cys, Ser, Gly, Ala, Ile, Tyr or Arg;
Xaa at position 18 is Leu, Thr, Pro, His, Ile or Cys;
Xaa at position 22 is Arg, Tyr, Ser, Thr or Ala;
Xaa at position 24 is Ile, Pro, Tyr or Leu;
Xaa at position 27 is Asp, or Gly;
Xaa at position 30 is Ala, Ile, Leu or Gly;
Xaa at position 34 is Lys or Ser;
Xaa at position 36 is Cys or Ser;
Xaa at position 42 is Cys or Ser;
Xaa at position 43 is His, Thr, Gly, Val, Lys, Trp, Ala,
Arg, Cys, or Leu;
Xaa at position 44 is Pro, Gly, Arg, Asp, Val, Ala, His,
Trp, Gln, or Thr;
Xaa at position 46 is Glu, Arg, Phe, Arg, Ile or Ala;
Xaa at position 47 is Leu or Thr;
Xaa at position 49 is Leu, Phe, Arg or Ser;
Xaa at position 50 is Leu, Ile, His, Pro or Tyr;
Xaa at position 54 is Leu or His;
Xaa at position 64 is Cys or Ser;
Xaa at position 67 is Gln, Lys, Leu or Cys;
Xaa at position 70 is Gln, Pro, Leu, Arg or Ser;
Xaa at position 74 is Cys or Ser;
Xaa at posltion 104 is Asp, Gly or Val;
Xaa at position 108 is Leu, Ala, Val, Arg, Trp, Gln or Gly;
Xaa at position 115 is Thr, His, Leu or Ala;
Xaa at position 120 is Gln, Gly, Arg, Lys or His
Xaa at position 123 is Glu, Arg, Phe or Thr
Xaa at position 144 is Phe, His, Arg, Pro, Leu, Gln or Glu;
Xaa at position 146 is Arg or Gln;
Xaa at position 147 is Arg or Gln;
Xaa at position 156 is His, Gly or Ser;
Xaa at position 159 is Ser, Arg, Thr, Tyr, Val or Gly;

557
Xaa at position 162 is Glu, Leu, Gly or Trp;
Xaa at position 163 is Val, Gly, Arg or Ala;
Xaa at position 169 is Arg, Ser, Leu, Arg or Cys;
Xaa at position 170 is His, Arg or Ser;
wherein optionally 1-11 amino acids from the N-terminus and
1-5 from the C-terminus can be deleted from said modified
human G-CSP amino acid sequence; and
wherein the N-terminus is joined to the C-terminus directly
or through a linker capable of joining the N-terminus to the
C-terminus and having new C- and N-termini at amino acids;
38-39 62-63 123-124
39-40 63-64 124-125
40-41 64-65 125-126
41-42 65-66 126-127
42-43 66-67 128-129
43-44 67-68 128-129
45-46 68-69 129-130
48-49 69-70 130-131
49-50 70-71 131-132
52-53 71-72 132-133
53-54 91-92 133-134
54-55 92-93 134-135
55-56 93-94 135-136
56-57 94-95 136-137
57-58 95-96 137-138
58-59 96-97 138-139
59-60 97-98 139-140
60-61 98-99 140-141
61-62 99-100 141-142
or 142-143
respectively; and
R2 is a polypeptide comprising; a modified human c-mpl
ligand amino acid sequence of the formula:
SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSer
1 5 10 15
HisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrPro
ValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGlu

558
ThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla
AlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGly
GlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnxaaxaaXaa
100 105 110
XaaGlyArgThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHis
115 120 125 130
LeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysVal
135 140 145 150
Arg (SEQ ID No:256)
153
wherein;
Xaa at position 112 is deleted or Leu, Ala, Val, Ile, Pro,
Phe, Trp, or Met;
Xaa at position 113 is deleted or Pro, Phe, Ala, Val, Leu,
Ile, Trp, or Met;
Xaa at position 114 is deleted or Pro, Phe, Ala, Val, Leu,
Ile, Trp, or Met;
Xaa at position 115 is deleted or Gln, Gly, Ser, Thr, Tyr,
or Asn; and
wherein the N-terminus is joined to the C-terminus directly
or through a linker (L2) capable of joining the N-terminus
to the C-terminus and having new C- and N-termini at amino
acids;
26-27 51-52 108-109
27-28 52-53 109-110
28-29 53-54 110-111
29-30 54-55 111-112
30-31 55-56 112-113
32-33 56-57 113-114
33-34 57-58 114-115
34-35 58-59 115-116

559
36-37 59-60 116-117
37-38 78-79 117-118
38-39 79-80 118-119
40-41 80-81 119-120
41-42 81-82 120-121
42-43 82-83 121-122
43-44 83-84 122-123
44-45 84-85 123-124
46-47 85-86 124-125
47-48 86-87 125-126
48-49 87-88 126-127
50-51 88-89 or 127-128;
wherein L1 is a linker capable of linking R1 to R2; and
additionally said hematopoietic protein can be
immediately preceded by (methionine-1), (alanine-1) or
(methionine-2, alanine-1).
8. A hematopoietic protein comprising; an amino acid
sequence of the formula:
R1-L1-R2, R2-L1-R1, R1-R2, or R2-R1
wherein R1 is a polypeptide comprising; a modified
human c-mpl ligand amino acid sequence of the formula:
SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSer
1 5 10 15
HisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrPro
ValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGlu
ThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla
AlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGly
GlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnXaaXaaXaa
100 105 110
XaaGlyArgThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHis

560
115 120 125 130
LeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysVal
135 140 145 150
Arg (SEQ ID NO: 256)
153
wherein;
Xaa at position 112 is deleted or Leu, Ala, Val, Ile, Pro,
Phe, Trp, or Met;
Xaa at position 113 is deleted or Pro, Phe, Ala, Val, Leu,
Ile, Trp, or Met;
Xaa at position 114 is deleted or Pro, Phe, Ala, Val, Leu,
Ile, Trp, or Met;
Xaa at position 115 is deleted or Gln, Gly, Ser, Thr, Tyr,
or Asn; and
wherein the N-terminus is joined to the C-terminus directly
or through a linker (L2) capaple of joining the N-terminus
to the C-terminus and having new C- and M-termini at amino
acids;
26-27 51-52 108-109
27-28 52-53 109-110
28-29 53-54 110-111
29-30 54-55 111-112
30-31 55-56 112-113
32-33 56-57 113-114
33-34 57-58 114-115
34-35 58-59 115-116
36-37 59-60 116-117
37-38 78-79 117-118
38-39 79-80 118-119
40-41 80-81 119-120
41-42 81-82 120-121
42-43 82-83 121-122
43-44 83-84 122-123
44-45 84-85 123-124
46-47 85-86 124-125
47-48 86-87 125-126
48-49 87-88 126-127

561
50-51 88-89 or 127-128;
wherein R2 is a polypeptide comprising; a modified
human IL-3 amino acid sequence of the formula:
Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Thr Ser Trp Val Asn
1 5 10 15
Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
100 105
Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
110 115 120
Xaa Xaa Xaa Gln Gln Thr Thr Leu Ser Leu Ala Ile Phe
125 130
wherein Xaa at position 17 is Ser, Lys, Gly, Asp, Met, Gln, or Arg;
Xaa at position 18 is Asn, His, Leu, Ile, Phe, Arg, or Gln;

562
Xaa at position 19 is Met, Phe, Ile, Arg, Gly, Ala, or Cys;
Xaa at position 20 is Ile, Cys, Gln, Glu, Arg, Pro, or Ala;
Xaa at position 21 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gln, Asn,
Thr, Ser or Val;
Xaa at position 22 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn, Gln,
Leu, Val or Gly;
Xaa at position 23 is Ile, Val, Ala, Gly, Trp, Lys, Phe,
Leu, Ser, or Arg;
Xaa at position 24 is Ile, Gly, Val, Arg, Ser, Phe, or Leu;
Xaa at position 25 is Thr, His, Gly, Gln, Arg, Pro, or Ala;
Xaa at position 26 is His, Thr, Phe, Gly, Arg, Ala, or Trp;
Xaa at position 27 is Leu, Gly, Arg, Thr, Ser, or Ala;
Xaa at position 28 is Lys, Arg, Leu, Gln, Gly, Pro, Val or Trp;
Xaa at position 29 is Gln, Asn, Leu, Pro, Arg, or Val;
Xaa at position 30 is Pro, His, Thr, Gly, Asp, Gln, Ser, Leu, or Lys;
Xaa at position 31 is Pro, Asp, Gly, Ala, Arg, Leu, or Gln;
Xaa at position 32 is Leu, Val, Arg, Gln, Asn, Gl , Ala, or Glu;
Xaa at position 33 is Pro, Leu, Gln, Ala, Thr, or Glu;
Xaa at position 34 is Leu, Val, Gly, Ser, Lys, Glu, Gln, Thr,
Arg, Ala, Phe, Ile or Met;
Xaa at position 35 is Leu, Ala, Gly, Asn, Pro, Gln, or Val;
Xaa at position 36 is Asp, Leu, or Val;
Xaa at position 37 is Phe, Ser, Pro, Trp, or Ile;
Xaa at position 38 is Asn, or Ala;
Xaa at position 40 is Leu, Trp, or Arg;
Xaa at position 41 is Asn, Cys, Arg, Leu, His, Met, or Pro;
Xaa at position 42 is Gly, Asp, Ser, Cys, Asn, Lys, Thr, Leu,
Val, Glu, Phe, Tyr, Ile, Met or Ala;
Xaa at position 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys,
Gln, Arg, Thr, Gly or Ser;
Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp,
Glu, Asn, Gln, Ala or Pro;
Xaa at position 45 is Gln, Pro, Phe, Val, Met, Leu, Thr, Lys,
Trp, Asp, Asn, Arg, Ser, Ala, Ile, Glu or His;
Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gln,

563
Lys, His, Ala, Tyr, Ile, Val or Gly;
Xaa at position 47 is Ile, Gly, Val, Ser, Arg, Pro, or His;
Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, His, Phe, Glu,
Lys, Thr, Ala, Met, Val or Asn;
Xaa at position 49 is Met, Arg, Ala, Gly, Pro, Asn, His, or Asp;
Xaa at position 50 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser,
Ala, Ile, Val, His, Phe, Met or Gln;
Xaa at position 51 is Asn, Arg, Met, Pro, Ser, Thr, or His;
Xaa at position 52 is Asn, His, Arg, Leu, Gly, Ser, or Thr;
Xaa at position 53 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Met;
Xaa at position 54 is Arg, Asp, Ile, Ser, Val, Thr, Gln, Asn,
Lys, His, Ala or Leu;
Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gly;
Xaa at position 56 is Pro, Gly, Cys, Ser, Gln, Glu, Arg, His,
Thr, Ala, Tyr, Phe, Leu, Val or Lys;
Xaa at position 57 is Asn or Gly;
Xaa at position 58 is Leu, Ser, Asp, Arg, Gln, Val, or Cys;
Xaa at position 59 is Glu Tyr, His, Leu, Pro, or Arg;
Xaa at position 60 is Ala, Ser, Pro, Tyr, Asn, or Thr;
Xaa at position 61 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser;
Xaa at position 62 is Asn, His, Val, Arg, Pro, Thr, Asp, or Ile;
Xaa at position 63 is Arg, Tyr, Trp, Lys, Ser, His, Pro, or Val;
Xaa at position 64 is Ala, Asn, Pro, Ser, or Lys;
Xaa at position 65 is Val, Thr, Pro, His, Leu, Phe, or Ser;
Xaa at position 66 is Lys, Ile, Arg, Val, Asn, Glu, or Ser;
Xaa at position 67 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His;
Xaa at position 68 is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His;
Xaa at position 69 is Gln, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leu;
Xaa at position 70 is Asn, Leu, Val, Trp, Pro, or Ala;
Xaa at position 71 is Ala, Met, Leu, Pro, Arg, Glu, Thr, Gln,
Trp, or Asn;
Xaa at position 72 is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp;
Xaa at position 73 is Ala, Glu, Asp, Leu, Ser, Gly, Thr, or Arg;
Xaa at position 74 is Ile, Met, Thr, Pro, Arg, Gly, Ala;
Xaa at position 75 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser,

564
Gln, or Leu;
Xaa at position 76 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp;
Xaa at position 77 is Ile, Ser, Arg, Thr, or Leu;
Xaa at position 78 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg;
Xaa at position 79 is Lys, Thr, Asn, Met, Arg, Ile, Gly, or Asp;
Xaa at position 80 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg;
Xaa at position 81 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys;
Xaa at position 82 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn,
His, Thr, Ser, Ala, Tyr, Phe, Ile, Met or Val;
Xaa at position 83 is Pro, Ala, Thr, Trp, Arg, or Met;
Xaa at position 84 is Cys, Glu, Gly, Arg, Met, or Val;
Xaa at position 85 is Leu, Asn, Val, or Gln;
Xaa at position 86 is Pro, Cys, Arg, Ala, or Lys;
Xaa at position 87 is Leu, Ser, Trp, or Gly;
Xaa at position 88 is Ala, Lys, Arg, Val, or Trp;
Xaa at position 89 is Thr, Asp, Cys, Leu, Val, Glu, His, Asn, or Ser;
Xaa at position 90 is Ala, Pro, Ser, Thr, Gly, Asp, Ile, or Met;
Xaa at position 91 is Ala, Pro, Ser, Thr, Phe, Leu, Asp, or His;
Xaa at position 92 is Pro, Phe, Arg, Ser, Lys, His, Ala, Gly, Ile or
Leu;
Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, or Arg;
Xaa at position 94 is Arg, Ile, Ser, Glu, Leu, Val, Gln, Lys, His,
Ala, or Pro;
Xaa at position 95 is His, Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn,
Lys, Ser, Ala, Trp, Phe, Ile, or Tyr;
Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr;
Xaa at position 97 is Ile, Val, Lys, Ala, or Asn;
Xaa at position 98 is His, Ile, Asn, Leu, Asp, Ala, Thr,
Glu, Gln, Ser, Phe, Met, Val, Lys, Arg, Tyr or Pro;
Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gln,
Gly, Ser, Phe, or His;
Xaa at position 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Gln, or Pro;
Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Val,
Tyr, Glu, Asn, Ser, Ala, Gly, Ile, Leu, or Gln;
Xaa at position 102 is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro;

565
Xaa at position 103 is Asp, or Ser;
Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu,
Gln, Lys, Ala, Phe, or Gly;
Xaa at position 105 is Asn, Pro, Ala, Phe, Ser, Trp, Gln, Tyr,
Leu, Lys, Ile, Asp, or His;
Xaa at position 106 is Glu, Ser, Ala, Lys, Thr, Ile, Gly, or Pro;
Xaa at position 108 is Arg, Lys, Asp, Leu, Thr, Ile, Gln, His, Ser,
Ala or Pro;
Xaa at position 109 is Arg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly;
Xaa at position 110 is Lys, Ala, Asn, Thr, Leu, Arg, Gln, His, Glu,
Ser, or Trp;
Xaa at position 111 is Leu, Ile, Arg, Asp, or Met;
Xaa at position 112 is Thr, Val, Gln, Tyr, Glu, His, Ser, or Phe;
Xaa at position 113 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp,
Lys, Leu, Ile, Val or Asn;
Xaa at position 114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu;
Xaa at position 115 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr,
Trp, or Met;
Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu,
Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gln, or Ile;
Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro;
Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr;
Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg;
Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Gln;
Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly;
Xaa at position 122 is Gln, Ser, Met, Trp, Arg, Phe, Pro, His,
Ile, Tyr, or Cys;
Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu;
wherein from 1 to 14 amino acids can optionally be deleted
from the N-terminus and/or from 1 to 15 amino acids can
optionally be deleted from the C-terminus of said modified
human interleukin-3 amino acid sequence; and wherein from 1
to 44 of the amino acids designated by xaa are different

566
from the corresponding amino acids of native (1-133) human
interleukin-3;
wherein L1 is a linker capable of linking R1 to R2; and
said hematopoietic protein can optionally be
immediately preceded by (methionine-1), (alanine-1) or
(methionine-2, alanine-1).
9. The hematopoeitic protein of claim 6 or 8 wherein R2 is
selected from the group consisting of;
Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys
Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Ala Glu
Asp Val Asp Ile Leu Met Glu Arg Asn Leu Arg Leu Pro Asn Leu
Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly
Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala
Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp
Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu
Glu Gln Ala Gln Glu Gln Gln (SEQ ID NO:225);
Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys
Arg Pro Pro Asn Pro Leu Leu Asp Pro Asn Asn Leu Asn Ser Glu
Asp Met Asp Ile Leu Met Glu Arg Asn Leu Arg Thr Pro Asn Leu
Leu Ala Phe Val Arg Ala Val Lys His Leu Glu Asn Ala Ser Gly
Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala
Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp
Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu
Glu Gln Ala Gln Glu Gln Gln (SEQ ID NO:226);
Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys
Val Pro Pro Ala Pro Leu Leu Asp Ser Asn Asn Leu Asn Ser Glu

567
Asp Met Asp Ile Leu Met Glu Arg Asn Leu Arg Leu Pro Asn Leu
Leu Ala Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly
Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala
Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp
Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu
Glu Gln Ala Gln Glu Gln Gln (SEQ ID NO:227); and
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln (SEQ ID NO:228).
10. A hematopoietic protein comprising; an amino acid
sequence of the formula:
R1-L1-R2, R2-L1-R1, R1-R2, or R2-R1
wherein R1 is a polypeptide comprising; a modified
human c-mpl ligand amino acid sequence of the formula:
SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSer
1 5 10 15
HisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrPro
ValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGlu
ThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla
AlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGly

568
GlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnXaaXaaXaa
100 105 110
XaaGlyArgThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHis
115 120 125 130
LeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysVal
135 140 145 150
Arg (SEQ ID MO:256)
153
wherein;
xaa at position 112 is deleted or Leu, Ala, Val, Ile, Pro,
Phe, Trp, or Met;
Xaa at position 113 is deleted or Pro, Phe, Ala, Val, Leu,
Ile, Trp, or Met;
Xaa at position 114 is deleted or Pro, Phe, Ala, Val, Leu,
Ile, Trp, or Met;
Xaa at position 115 is deleted or Gln, Gly, Ser, Thr, Tyr,
or Asn; and
wherein the N-terminus is joined to the C-terminus directly
or through a linker (L2) capable of joining the N-terminus
to the C-terminus and having new C- and N-termini at amino
acids;
26-27 51-52 108-109
27-28 52-53 109-110
28-29 53-54 110-111
29-30 54-55 111-112
30-31 55-56 112-113
32-33 56-57 113-114
33-34 57-58 114-115
34-35 58-59 115-116
36-37 59-60 116-117
37-38 78-79 117-118
38-39 79-80 118-119
40-41 80-81 119-120
41-42 81-82 120-121
42-43 82-83 121-122

569
43-44 83-84 122-123
44-45 84-85 123-124
46-47 85-86 124-125
47-48 86-87 125-126
48-49 87-88 126-127
50-51 88-89 or 127-128
respectively;
wherein R2 is G-CSF or G-CSF Ser17;
wherein L1 is a linker capable of linking R1 to R2; and
said hematopoietic protein can optionally be
immediately preceded by (methionine-1), (alanine-1) or
(methionine-2, alanine-1).
11. The hematopoietic protein as recited in claim 1,
2, 3, 4, 5, 6, 7, 8, or 10 wherein said linker (L2) is
selected from the group consisting of;
GlyGlyGlySer (SEQ ID MO:12);
GlyGlyGlySerGlyGlyGlySer (SEQ ID NO:242);
GlyGlyGlySerGlyGlyGlySerGlyGlyGlySer (SEQ ID No:243);
SerGlyGlySerGlyGlySer (SEQ ID No:244);
GluPheGlyAsnMetAla (SEQ ID NO:245);
GluPheGlyGlyAsnMetAla (SEQ ID NO:246);
GluPheGlyGlyAsnGlyGlyAsnMetAla (SEQ ID NO:247); and
GlyGlySerAspMetAlaGly (SEQ ID NO:248).
12. The hematopoietic protein as recited in claim 9
wherein said linker (L2) is selected from the group
consisting of;
GlyGlyGlySer (SEQ ID NO:12);
GlyGlyGlySerGlyGlyGlySer (SEQ ID NO:242);
GlyGlyGlySerGlyGlyGlySerGlyGlyGlySer (SEQ ID NO:243);
SerGlyGlySerGlyGlySer (SEQ ID No:244);
GluPheGlyAsnMetAla (SEQ ID NO:245);

570
GluPheGlyGlyAsnMetAla (SEQ ID NO:246);
GluPheGlyGlyAsnGlyGlyAsnMetAla (SEQ ID No:247); and
GlyGlySerAspMetAlaGly (SEQ ID NO:248).
13. The hematopoietic protein as recited in claim 1
wherein said protein is selected from the group consisting
of;
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Tyr Lys Leu Cys
His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro
Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala
Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly
Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr
Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile
Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro
Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu
Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly
Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val
Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys
Ala Thr (SEQ ID NO:166);
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Tyr Lys Leu Cys
His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro
Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala
Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly
Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr
Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile
Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro
Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg

571
Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu
Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly
Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val
Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys
Ala Thr (SEQ ID NO:167);
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Pro Glu Leu Gly
Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala ASp Phe Ala Thr
Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu
Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln
Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe
Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser
Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu
Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys
Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu
Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys
Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His
Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly
Ile Ser (SEQ ID NO:168);
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Pro Glu Leu Gly
Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr
Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu
Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln
Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe
Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser
Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu
Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys
Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu
Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys
Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His
Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly
Ile Ser (SEQ ID NO:169);

572
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Met Ala Pro Ala
Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe
Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser
Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro
Ser Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu
Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu
Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val
Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser
Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu
His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu
Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu
Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu
Leu Gly (SEQ ID NO:170);
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Met Ala Pro Ala
Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe
Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser
Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro
Ser Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu
Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu
Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val
Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser
Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu
His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu
Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu
Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu
Leu Gly (SEQ ID NO:171);
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu

573
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Thr Gln Gly Ala
Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val
Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg
Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly Ser Gly Gly Ser
Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val Arg Lys Ile Gln
Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys
Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly
Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln
Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr
Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly
Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr
Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu
Gln Pro (SEQ ID NO:172);
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Thr Gln Gly Ala
Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val
Leu Val Ala Ser HiS Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg
Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly Ser Gly Gly Ser
Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val Arg Lys Ile Gln
Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys
Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly
Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln
Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr
Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly
Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr
Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu
Gln Pro (SEQ ID NO:173);
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro

574
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Ser Ala Phe Gln
Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe
Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser
Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu
Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys
Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu
Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys
Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His
Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly
Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp
Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu
Gly Met Ala Pro Ala Leu Gln Pro Thr Gln Gly Ala Met Pro Ala
Phe Ala (SEQ ID NO:177);
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Ser Ala Phe Gln
Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe
Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser
Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu
Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys
Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu
Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys
Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His
Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly
Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp
Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu
Gly Met Ala Pro Ala Leu Gln Pro Thr Gln Gly Ala Met Pro Ala
Phe Ala (SEQ ID NO:175);
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Tyr Lys Leu Cys
His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro
Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala
Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly
Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr

575
Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile
Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro
Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu
Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Thr Pro Leu
Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys Ser Leu
Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu
Lys Leu Cys Ala Thr (SEQ ID NO:176);
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile HiS His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Tyr Lys Leu Cys
His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro
Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala
Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly
Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr
Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile
Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro
Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu
Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Thr Pro Leu
Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys Ser Leu
Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu
Lys Leu Cys Ala Thr (SEQ ID NO:177);
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Pro Glu Leu Gly
Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr
Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu
Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln
Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe
Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Thr
Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys
Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu
Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu

576
Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu
Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser
Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala
Leu Glu Gly Ile Ser (SEQ ID NO:179);
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Met Ala Pro Ala
Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe
Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser
Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro
Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu
Lys Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala
Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu
Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro
Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu
Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln
Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr
Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln
Met Glu Glu Leu Gly (SEQ ID NO:181);
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Thr Gln Gly Ala
Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val
Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg
Val Leu Arg His Leu Ala Gln Pro Thr Pro Leu Gly Pro Ala Ser
Ser Leu Pro Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val Arg
Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys Ala
Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His
Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln
Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu
Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro
Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp
Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala
Pro Ala Leu Gln Pro (SEQ ID NO:182);

577
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Glu Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Thr Gln Gly Ala
Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val
Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg
Val Leu Arg His Leu Ala Gln Pro Thr Pro Leu Gly Pro Ala Ser
Ser Leu Pro Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val Arg
Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys Ala
Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His
Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln
Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu
Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro
Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp
Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala
Pro Ala Leu Gln Pro (SEQ ID NO:183);
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Ser Ala Phe Gln
Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe
Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Thr
Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys
Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu
Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu
Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu
Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser
Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala
Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu
Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met
Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro Thr Gln Gly Ala
Met Pro Ala Phe Ala (SEQ ID NO:184);
MetAlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAla
ProLeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsn
LeuArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSer
GlyIleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro

578
SerArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThr
PheTyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaTyrLysLeuCysHisProGluGluLeuValLeuLeu
GlyHisSerLeuGlyIleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGln
LeuAlaGlyCysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGln
AlaLeuGluGlyIleSerProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspVal
AlaAspPheAlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAlaProAlaLeu
GlnProThrGlnGlyAlaMetProAlaPheAlaSerAlaPheGlnArgArgAlaGlyGly
ValLeuValAlaSerHisLeuGlnSerPheLeuGluValSerTyrArgValLeuArgHis
LeuAlaGlnProGlyGlyGlySerAspMetAlaThrProLeuGlyProAlaSerSerLeu
ProGlnSerPheLeuLeuLysSerLeuGluGlnValArgLysIleGlnGlyAspGlyAla
AlaLeuGlnGluLysLeuCysAlaThr (SEQ ID NO:194);
MetAlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAla
ProLeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsn
LeuArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSer
GlyIleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro
SerArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThr
PheTyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaProGluLeuGlyProThrLeuAspThrLeuGlnLeu
AspValAlaAspPheAlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAlaPro
AlaLeuGlnProThrGlnGlyAlaMetProAlaPheAlaSerAlaPheGlnArgArgAla
GlyGlyValLeuValAlaSerHisLeuGlnSerPheLeuGluValSerTyrArgValLeu
ArgHisLeuAlaGlnProGlyGlyGlySerAspMetAlaThrProLeuGlyProAlaSer
SerLeuProGlnSerPheLeuLeuLysSerLeuGluGlnValArgLysIleGlnGlyAsp
GlyAlaAlaLeuGlnGluLysLeuCysAlaThrTyrLysLeuCysHisProGluGluLeu
ValLeuLeuGlyHisSerLeuGlyIleProTrpAlaProLeuSerSerCysProSerGln
AlaLeuGlnLeuAlaGlyCysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGly
LeuLeuGlnAlaLeuGluGlyIleSer (SEQ ID NO:195);
MetAlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAla
ProLeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsn
LeuArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSer
GlyIleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro
SerArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThr
PheTyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaSerAlaPheGlnArgArgAlaGlyGlyValLeuVal
AlaSerHisLeuGlnSerPheLeuGluValSerTyrArgValLeuArgHisLeuAlaGln
ProGlyGlyGlySerAspMetAlaThrProLeuGlyProAlaSerSerLeuProGlnSer
PheLeuLeuLysSerLeuGluGlnValArgLysIleGlnGlyAspGlyAlaAlaLeuGln
GluLysLeuCysAlaThrTyrLysLeuCysHisProGluGluLeuValLeuLeuGlyHis
SerLeuGlyIleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGlnLeuAla
GlyCysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGlnAlaLeu
GluGlyIleSerProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspValAlaAsp
PheAlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAlaProAlaLeuGlnPro
ThrGlnGlyAlaMetProAlaPheAla (SEQ ID NO:196);

579
MetAlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAla
ProLeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsn
LeuArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSer
GlyIleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro
SerArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThr
PheTyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaMetAlaProAlaLeuGlnProThrGlnGlyAlaMet
ProAlaPheAlaSerAlaPheGlnArgArgAlaGlyGlyValLeuValAlaSerHisLeu
GlnSerPheLeuGluValSerTyrArgValLeuArgHisLeuAlaGlnProGlyGlyGly
SerAspMetAlaThrProLeuGlyProAlaSerSerLeuProGlnSerPheLeuLeuLys
SerLeuGluGlnValArgLysIleGlnGlyAspGlyAlaAlaLeuGlnGluLysLeuCys
AlaThrTyrLysLeuCysHisProGluGluLeuValLeuLeuGlyHisSerLeuGlyIle
ProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGlnLeuAlaGlyCysLeuSer
GlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGlnAlaLeuGluGlyIleSer
ProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspValAlaAspPheAlaThrThr
IleTrpGlnGlnMetGluGluLeuGly (SEQ ID NO:197);
MetAlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAla
ProLeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsn
LeuArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSer
GlyIleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro
SerArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThr
PheTyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaThrGlnGlyAlaMetProAlaPheAlaSerAlaPhe
GlnArgArgAlaGlyGlyValLeuValAlaSerHisLeuGlnSerPheLeuGluValSer
TyrArgValLeuArgHisLeuAlaGlnProGlyGlyGlySerAspMetAlaThrProLeu
GlyProAlaSerSerLeuProGlnSerPheLeuLeuLysSerLeuGluGlnValArgLys
IleGlnGlyAspGlyAlaAlaLeuGlnGluLysLeuCysAlaThrTyrLysLeuCysHis
ProGluGluLeuValLeuLeuGlyHisSerLeuGlyIleProTrpAlaProLeuSerSer
CysProSerGlnAlaLeuGlnLeuAlaGlyCysLeuSerGlnLeuHisSerGlyLeuPhe
LeuTyrGlnGlyLeuLeuGlnAlaLeuGluGlyIleSerProGluLeuGlyProThrLeu
AspThrLeuGlnLeuAspValAlaAspPheAlaThrThrIleTrpGlnGlnMetGluGlu
LeuGlyMetAlaProAlaLeuGlnPro (SEQ ID NO:198);
Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys
Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu
Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu
Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly
Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala
Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp
Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu
Glu Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Gly Pro Thr Cys Leu
Ser Ser Leu Leu Gly Gln Leu Ser Gly Gln Val Arg Leu Leu Leu
Gly Ala Leu Gln Ser Leu Leu Gly Thr Gln Leu Pro Pro Gln Gly

580
Arg Thr Thr Ala His Lys Asp Pro Asn Ala Ile Phe Leu Ser Phe
Gln His Leu Leu Arg Gly Lys Val Arg Phe Leu Met Leu Val Gly
Gly Ser Thr Leu Cys Val Arg Glu Phe Gly Gly Asn Met Ala Ser
Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser Lys Leu Leu
Arg Asp Ser His Val Leu His Ser Arg Leu Ser Gln Cys Pro Glu
Val His Pro Leu Pro Thr Pro Val Leu Leu Pro Ala Val Asp Phe
Ser Leu Gly Glu Trp Lys Thr Gln Met Glu Glu Thr Lys Ala Gln
Asp Ile Leu Gly Ala Val Thr Leu Leu Leu Glu Gly Val Met Ala
Ala Arg Gly Gln Leu (SEQ ID NO:209);
Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys
Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu
Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu
Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly
Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala
Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp
Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu
Glu Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Gly Thr Gln Leu Pro
Pro Gln Gly Arg Thr Thr Ala His Lys Asp Pro Asn Ala Ile Phe
Leu Ser Phe Gln His Leu Leu Arg Gly Lys Val Arg Phe Leu Met
Leu Val Gly Gly Ser Thr Leu Cys Val Arg Glu Phe Gly Gly Asn
Met Ala Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg Val Leu Ser
Lys Leu Leu Arg Asp Ser His Val Leu His Ser Arg Leu Ser Gln
Cys Pro Glu Val His Pro Leu Pro Thr Pro Val Leu Leu Pro Ala
Val Asp Phe Ser Leu Gly Glu Trp Lys Thr Gln Met Glu Glu Thr
Lys Ala Gln Asp Ile Leu Gly Ala Val Thr Leu Leu Leu Glu Gly
Val Met Ala Ala Arg Gly Gln Leu Gly Pro Thr Cys Leu Ser Ser
Leu Leu Gly Gln Leu Ser Gly Gln Val Arg Leu Leu Leu Gly Ala
Leu Gln Ser Leu Leu (SEQ ID NO:210);
Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys
Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu
Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu
Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly
Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala
Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp
Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu
Glu Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Gly Arg Thr Thr Ala
His Lys Asp Pro Asn Ala Ile Phe Leu Ser Phe Gln His Leu Leu
Arg Gly Lys Val Arg Phe Leu Met Leu Val Gly Gly Ser Thr Leu
Cys Val Arg Glu Phe Gly Gly Asn Met Ala Ser Pro Ala Pro Pro
Ala Cys Asp Leu Arg Val Leu Ser Lys Leu Leu Arg Asp Ser His
Val Leu His Ser Arg Leu Ser Gln Cys Pro Glu Val His Pro Leu
Pro Thr Pro Val Leu Leu Pro Ala Val Asp Phe Ser Leu Gly Glu
Trp Lys Thr Gln Met Glu Glu Thr Lys Ala Gln Asp Ile Leu Gly
Ala Val Thr Leu Leu Leu Glu Gly Val Met Ala Ala Arg Gly Gln

581
Leu Gly Pro Thr Cys Leu Ser Ser Leu Leu Gly Gln Leu Ser Gly
Gln Val Arg Leu Leu Leu Gly Ala Leu Gln Ser Leu Leu Gly Thr
Gln Leu Pro Pro Gln (SEQ ID NO:211);
Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys
Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu
Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu
Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly
Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala
Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp
Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu
Glu Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala His Lys Asp Pro
Asn Ala Ile Phe Leu Ser Phe Gln His Leu Leu Arg Gly Lys Val
Arg Phe Leu Met Leu Val Gly Gly Ser Thr Leu Cys Val Arg Glu
Phe Gly Gly Asn Met Ala Ser Pro Ala Pro Pro Ala Cys Asp Leu
Arg Val Leu Ser Lys Leu Leu Arg Asp Ser His Val Leu His Ser
Arg Leu Ser Gln Cys Pro Glu Val His Pro Leu Pro Thr Pro Val
Leu Leu Pro Ala Val Asp Phe Ser Leu Gly Glu Trp Lys Thr Gln
Met Glu Glu Thr Lys Ala Gln Asp Ile Leu Gly Ala Val Thr Leu
Leu Leu Glu Gly Val Met Ala Ala Arg Gly Gln Leu Gly Pro Thr
Cys Leu Ser Ser Leu Leu Gly Gln Leu Ser Gly Gln Val Arg Leu
Leu Leu Gly Ala Leu Gln Ser Leu Leu Gly Thr Gln Leu Pro Pro
Gln Gly Arg Thr Thr (SEQ ID NO:212);
Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met
Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala
Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg
Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg
His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gln Glu Phe Arg Glu
Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala Gln Glu Gln
Gln Gly Gly Gly Ser Asn Cys Ser Ile Met Ile Asp Glu Ile Ile
His His Leu Lys Arg Pro Pro Ala Pro Leu Tyr Val Glu Gly Gly
Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn
Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala
Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu
Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly
Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln val
Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys
Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly
His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser
Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly
Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser
Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala
Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met
Ala Pro Ala Leu Gln Pro ( SEQ ID NO: 186);

582
Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys
Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile
Lys Ala Gly Asp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr
Leu Val Thr Leu Glu Gln Ala Gln Glu Gln Gln Gly Gly Gly Ser
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Tyr Val Glu Gly Gly
Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn
Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala
Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu
Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly
Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val
Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys
Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly
His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser
Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly
Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser
Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala
Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met
Ala Pro Ala Leu Gln Pro (SEQ ID NO:187);
Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gln
Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln
Ala Gln Glu Gln Gln Gly Gly Gly Ser Asn Cys Ser Ile Met Ile
Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu
Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met Asp
Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val
Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn
Leu Gln Pro Cys Leu Pro Ser Ala Thr Ala Tyr Val Glu Gly Gly
Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn
Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala
Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu
Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly
Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val
Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys
Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly
His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser
Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly
Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser
Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala
Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met
Ala Pro Ala Leu Gln Pro (SEQ ID NO:189);
Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met
Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala
Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg
Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg

583
His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gln Glu Phe Arg Glu
Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala Gln Glu Gln
Gln Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Asn Cys
Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro
Ala Pro Leu Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro
Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu
Ser His Lys Ser Pro Asn Met Ala Thr Gln Gly Ala Met Pro Ala
Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val Leu Val Ala
Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg
His Leu Ala Gln Pro Ser Gly Gly Ser Gly Gly Ser Gln Ser Phe
Leu Leu Lys Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly
Ala Ala Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His
Pro Glu Glu Leu Val l,eu Leu Gly His Ser Leu Gly Ile Pro Trp
Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly
Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu
Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu
Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp
Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro (SEQ
ID NO:190);
Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys
Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile
Lys Ala Gly Asp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr
Leu Val Thr Leu Glu Gln Ala Gln Glu Gln Gln Gly Gly Gly Ser
Gly Gly Gly Ser Gly Gly Gly Ser Asn Cys Ser Ile Met Ile Asp
Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp
Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met Asp Arg
Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys
Asn Leu Glu Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro
Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu
Ser His Lys Ser Pro Asn Met Ala Thr Gln Gly Ala Met Pro Ala
Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val Leu Val Ala
Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg
His Leu Ala Gln Pro Ser Gly Gly Ser Gly Gly Ser Gln Ser Phe
Leu Leu Lys Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly
Ala Ala Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His
Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp
Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly
Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu
Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu
Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp
Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro;
(SEQ ID NO:191)
MetAlaAsnCysSerAsnMetIleAspGluIleIleThrHisLeuLysGlnProProLeu
ProLeuLeuAspPheAsnAsnLeuAsnGlyGluAspGlnAspIleLeuMetAspAsnAsn
LeuArgArgProAsnLeuGluAlaPheAsnArgAlaValLysSerLeuGlnAsnAlaSer
AlaIleGluSerIleLeuLysAsnLeuLeuProCysLeuProLeuAlaThrAlaAlaPro
ThrArgHisProIleHisIleLysAspGlyAspTrpAsnGluPheArgArgLysLeuThr
PheTyrLeuLysThrLeuGluAsnAlaGlnAlaGlnGlnTyrValGluGlyGlyGlyGly

584
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaThrGlnGlyAlaMetProAlaPheAlaSerAlaPhe
GlnArgArgAlaGlyGlyValLeuValAlaSerHisLeuGlnSerPheLeuGluValSer
TyrArgValLeuArgHisLeuAlaGlnProSerGlyGlySerGlyGlySerGlnSerPhe
LeuLeuLysSerLeuGluGlnValArgLysIleGlnGlyAspGlyAlaAlaLeuGlnGlu
LysLeuCysAlaThrTyrLysLeuCysHisProGluGluLeuValLeuLeuGlyHisSer
LeuGlyIleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGlnLeuAlaGly
CysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGlnAlaLeuGlu
GlyIleSerProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspValAlaAspPhe
AlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAlaProAlaLeuGlnPro;
(SEQ ID NO:199)
MetAlaAsnCysSerAsnMetIleAspGluIleIleThrHisLeuLysGlnProProLeu
ProLeuLeuAspPheAsnAsnLeuAsnGlyGluAspGlnAspIleLeuMetGluAsnAsn
LeuArgArgProAsnLeuGluAlaPheAsnArgAlaValLysSerLeuGlnAsnAlaSer
AlaIleGluSerIleLeuLysAsnLeuLeuProCysLeuProLeuAlaThrAlaAlaPro
ThrArgHisProIleIleIleArgAspGlyAspTrpAsnGluPheArgArgLysLeuThr
PheTyrLeuLysThrLeuGluAsnAlaGlnAlaGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaThrGlnGlyAlaMetProAlaPheAlaSerAlaPhe
GlnArgArgAlaGlyGlyValLeuValAlaSerHisLeuGlnSerPheLeuGluValSer
TyrArgValLeuArgHisLeuAlaGlnProThrProLeuGlyProAlaSerSerLeuPro
GlnSerPheLeuLeuLysSerLeuGluGlnValArgLysIleGlnGlyAspGlyAlaAla
LeuGlnGluLysLeuCysAlaThrTyrLysLeuCysHisProGluGluLeuValLeuLeu
GlyHisSerLeuGlyIleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGln
LeuAlaGlyCysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGln
AlaLeuGluGlyIleSerProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspVal
AlaAspPheAlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAlaProAlaLeu
GlnPro (SEQ ID NO:200);
MetAlaAsnCysSerAsnMetIleAspGluIleIleThrHisLeuLysGlnProProLeu
ProLeuLeuAspPheAsnAsnLeuAsnGlyGluAspGlnAspIleLeuMetGluAsnAsn
LeuArgArgProAsnLeuGluAlaPheAsnArgAlaValLysSerLeuGlnAsnAlaSer
AlaIleGluSerIleLeuLysAsnLeuLeuProCysLeuProLeuAlaThrAlaAlaPro
ThrArgHisProIleIleIleArgAspGlyAspTrpAsnGluPheArgArgLysLeuThr
PheTyrLeuLysThrLeuGluAsnAlaGlnAlaGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaThrGlnGlyAlaMetProAlaPheAlaSerAlaPhe
GlnArgArgAlaGlyGlyValLeuValAlaSerHisLeuGlnSerPheLeuGluValSer
TyrArgValLeuArgHisLeuAlaGlnProSerGlyGlySerGlyGlySerGlnSerPhe
LeuLeuLysSerLeuGluGlnValArgLysIleGlnGlyAspGlyAlaAlaLeuGlnGlu
LysLeuCysAlaThrTyrLysLeuCysHisProGluGluLeuValLeuLeuGlyHisSer
LeuGlyIleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGlnLeuAlaGly
CysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGlnAlaLeuGlu
GlyIleSerProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspValAlaAspPhe
AlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAlaProAlaLeuGlnPro;
(SEQ ID NO:201)
MetAlaAsnCysSerAsnMetIleAspGluIleIleThrHisLeuLysGlnProProLeu

585
ProLeuLeuAspPheAsnAsnLeuAsnGlyGluAspGlnAspIleLeuMetAspAsnAsn
LeuArgArgProAsnLeuGluAlaPheAsnArgAlaValLysSerLeuGlnAsnAlaSer
AlaIleGluSerIleLeuLysAsnLeuLeuProCysLeuProLeuAlaThrAlaAlaPro
ThrArgHisProIleHisIleLysAspGlyAspTrpAsnGluPheArgArgLysLeuThr
PheTyrLeuLysThrLeuGluAsnAlaGlnAlaGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaThrGlnGlyAlaMetProAlaPheAlaSerAlaPhe
GlnArgArgAlaGlyGlyValLeuValAlaSerHisLeuGlnSerPheLeuGluValSer
TyrArgValLeuArgHisLeuAlaGlnProThrProLeuGlyProAlaSerSerLeuPro
GlnSerPheLeuLeuLysSerLeuGluGlnValArgLysIleGlnGlyAspGlyAlaAla
LeuGlnGluLysLeuCysAlaThrTyrLysLeuCysHisProGluGluLeuValLeuLeu
GlyHisSerLeuGlyIleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGln
LeuAlaGlyCysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGln
AlaLeuGluGlyIleSerProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspVal
AlaAspPheAlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAlaProAlaLeu
GlnPro (SEQ ID NO:202);
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGly
GlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGln
GlyArgThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeu
ArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPhe
GlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeu
ArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuPro
ThrProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGlu
GluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla
AlaArgGlyGlnLeu (SEQ ID NO:221);
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGlyThrGlnLeuProProGlnGlyArgThrThrAlaHisLys
AspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArgPheLeu
MetLeuValGlyGlySerThrLeuCysValArgGluPheGlyAsnMetAlaSerProAla
ProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHisValLeuHis
SerArgLeuSerGlnCysProGluValHisProLeuProThrProValLeuLeuProAla
ValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAlaGlnAspIle
LeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGlnLeuGlyPro
ThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeuLeuGlyAla
LeuGlnSerLeuLeu (SEQ ID No:222);

586
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGly
GlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGln
GlyArgThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeu
ArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPhe
GlyGlyAsnGlyGlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeu
SerLysLeuLeuArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluVal
HisProLeuProThrProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLys
ThrGlnMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGlu
GlyValMetAlaAlaArgGlyGlnLeu (SEQ ID No:223;
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGlyThrGlnLeuProProGlnGlyArgThrThrAlaHisLys
AspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArgPheLeu
MetLeuValGlyGlySerThrLeuCysValArgGluPheGlyGlyAsnGlyGlyAsnMet
AlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSer
HisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProVal
LeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLys
AlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGly
GlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeu
LeuLeuGlyAlaLeuGlnSerLeuLeu (SEQ ID NO:234);
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGlyArgThrThrAlaHisLysAspProAsnAlaIlePheLeu
SerPheGlnHisLeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThr
LeuCysValArgGluPheGlyGlyAsnGlyGlyAsnMetAlaSerProAlaProProAla
CysAspLeuArgValLeuSerLysLeuLeuArgAspSerHisValLeuHisSerArgLeu
SerGlnCysProGluValHisProLeuProThrProValLeuLeuProAlaValAspPhe
SerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAlaGlnAspIleLeuGlyAla
ValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGlnLeuGlyProThrCysLeu

587
SerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSer
LeuLeuGlyThrGlnLeuProProGln (SEQ ID NO:235);
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHis
LeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArg
GluPheGlyGlyAsnGlyGlyAsnMetAlaSerProAlaProProAlaCysAspLeuArg
ValLeuSerLysLeuLeuArgAspSerHisValLeuHisSerArgLeuSerGlnCysPro
GluValHisProLeuProThrProValLeuLeuProAlaValAspPheSerLeuGlyGlu
TrpLysThrGlnMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeu
LeuGluGlyValMetAlaAlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeu
GlyGlnLeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThr
GlnLeuProProGlnGlyArgThrThr (SEQ ID No:236);
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArg
GlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGly
GlyAsnGlyGlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSer
LysLeuLeuArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluValHis
ProLeuProThrProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThr
GlnMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGly
ValMetAlaAlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeu
SerGlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuPro
ProGlnGlyArgThrThrAlaHisLys (SEQ ID No:237);
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysVal
ArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGlyGlyAsnGly
GlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeu
ArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuPro
ThrProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGlu

588
GluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla
AlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGln
ValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGly
ArgThrThrAlaHisLysAspProAsn (SEQ ID NO:238); and
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArg
GlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGly
GlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeu
ArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuPro
ThrProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGlu
GluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla
AlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGln
ValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnGlyArgThrThrAla
HisLys (SEQ ID NO:239).
14. The hematopoietic protein of claim 1, 2, 3, 4, 5, 6, 7,
8, 10 or 11 wherein said colony stimulating factor is selected
from the group consisting of GM-CSF, G-CSF, G-CSF Ser17, c-mpl
ligand (TPO), M-CSF, erythropoietin (EPO), IL-1, IL-4, IL-2, IL-3,
IL-5, IL 6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15,
LIF, flt3/flk2 ligand, human growth hormone, B-cell growth factor,
B-cell differentiation factor, eosinophil differentiation factor
and stem cell factor (SCF).
15. The hematopoietic protein of claim 14 wherein
said colony stimulating factor is selected from the group
consisting of G-CSF, G-CSF Ser17 and c-mpl ligand (TPO).
16. A nucleic acid molecule encoding said hematopoietic
protein of claim 1.
17. A nucleic acid molecule encoding said hematopoietic
protein of claim 2.

589
18. A nucleic acid molecule encoding said hematopoietic
protein of claim 3.
19. A nucleic acid molecule encoding said hematopoietic
protein of claim 4.
20. A nucleic acid molecule encoding said hematopoietic
protein of claim 5.
21. A nucleic acid molecule encoding said hematopoietic
protein of claim 6.
22. A nucleic acid molecule encoding said hematopoietic
protein of claim 7.
23. A nucleic acid molecule encoding said hematopoietic
protein of claim 8.
24. A nucleic acid molecule encoding said hematopoietic
protein of claim 9.
25. A nucleic acid molecule encoding said hematopoietic
protein of claim 10.
26. A nucleic acid molecule encoding said hematopoietic
protein of claim 11.
27. A nucleic acid molecule encoding said hematopoietic
protein of claim 12.
28. A nucleic acid molecule encoding said hematopoietic
protein of claim 13.
29. A nucleic acid molecule encoding said hematopoietic
protein of claim 14.

590
30. A nucleic acid molecule encoding said hematopoietic
protein of claim 15.
31. The nucleic acid molecule according to claim 27
selected from group consisting of;
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTT
401 ACAAGCTGTG CCACCCCGAG GAGCTGGTGC TGCTCGGACA CTCTCTGGGC
451 ATCCCCTGGG CTCCCCTGAG CTCCTGCCCC AGCCAGGCCC TGCAGCTGGC
501 AGGCTGCTTG AGCCAACTCC ATAGCGGCCT TTTCCTCTAC CAGGGGCTCC
551 TGCAGGCCCT GGAAGGGATA TCCCCCGAGT TGGGTCCCAC CTTGGACACA
601 CTGCAGCTGG ACGTCGCCGA CTTTGCCACC ACCATCTGGC AGCAGATGGA
651 AGAACTGGGA ATGGCCCCTG CCCTGCAGCC CACCCAGGGT GCCATGCCGG
701 CCTTCGCCTC TGCTTTCCAG CGCCGGGCAG GAGGGGTCCT GGTTGCTAGC
751 CATCTGCAGA GCTTCCTGGA GGTGTCGTAC CGCGTTCTAC GCCACCTTGC
801 GCAGCCCTCT GGCGGCTCTG GCGGCTCTCA GAGCTTCCTG CTCAAGTCTT
851 TAGAGCAAGT GAGAAAGATC CAGGGCGATG GCGCAGCGCT CCAGGAGAAG
901 CTGTGTGCCA CCTAATAA (SEQ ID NO:94);
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTTACAAG
451 CTGTGCCACC CCGAGGAGCT GGTGCTGCTC GGACACTCTC TGGGCATCCC
501 CTGGGCTCCC CTGAGCTCCT GCCCCAGCCA GGCCCTGCAG CTGGCAGGCT
551 GCTTGAGCCA ACTCCATAGC GGCCTTTTCC TCTACCAGGG GCTCCTGCAG
601 GCCCTGGAAG GGATATCCCC CGAGTTGGGT CCCACCTTGG ACACACTGCA
651 GCTGGACGTC GCCGACTTTG CCACCACCAT CTGGCAGCAG ATGGAAGAAC
701 TGGGAATGGC CCCTGCCCTG CAGCCCACCC AGGGTGCCAT GCCGGCCTTC
751 GCCTCTGCTT TCCAGCGCCG GGCAGGAGGG GTCCTGGTTG CTAGCCATCT
801 GCAGAGCTTC CTGGAGGTGT CGTACCGCGT TCTACGCCAC CTTGCGCAGC
851 CCTCTGGCGG CTCTGGCGGC TCTCAGAGCT TCCTGCTCAA GTCTTTAGAG
901 CAAGTGAGAA AGATCCAGGG CGATGGCGCA GCGCTCCAGG AGAAGCTGTG
951 TGCCACCTAA TAA (SEQ ID NO:95);

591
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTC
401 CCGAGTTGGG TCCCACCTTG GACACACTGC AGCTGGACGT CGCCGACTTT
451 GCCACCACCA TCTGGCAGCA GATGGAAGAA CTGGGAATGG CCCCTGCCCT
501 GCAGCCCACC CAGGGTGCCA TGCCGGCCTT CGCCTCTGCT TTCCAGCGCC
551 GGGCAGGAGG GGTCCTGGTT GCTAGCCATC TGCAGAGCTT CCTGGAGGTG
601 TCGTACCGCG TTCTACGCCA CCTTGCGCAG CCCTCTGGCG GCTCTGGCGG
651 CTCTCAGAGC TTCCTGCTCA AGTCTTTAGA GCAAGTGAGA AAGATCCAGG
701 GCGATGGCGC AGCGCTCCAG GAGAAGCTGT GTGCCACCTA CAAGCTGTGC
751 CACCCCGAGG AGCTGGTGCT GCTCGGACAC TCTCTGGGCA TCCCCTGGGC
801 TCCCCTGAGC TCCTGCCCCA GCCAGGCCCT GCAGCTGGCA GGCTGCTTGA
851 GCCAA~TCCA TAGCGGCCTT TTCCTCTACC AGGGGCTCCT GCAGGCCCTG
901 GAAGGGATAT CCTAATAA (SEQ ID NO:96);
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTCCCGAG
451 TTGGGTCCCA CCTTGGACAC ACTGCAGCTG GACGTCGCCG ACTTTGCCAC
501 CACCATCTGG CAGCAGATGG AAGAACTGGG AATGGCCCCT GCCCTGCAGC
551 CCACCCAGGG TGCCATGCCG GCCTTCGCCT CTGCTTTCCA GCGCCGGGCA
601 GGAGGGGTCC TGGTTGCTAG CCATCTGCAG AGCTTCCTGG AGGTGTCGTA
651 CCGCGTTCTA CGCCACCTTG CGCAGCCCTC TGGCGGCTCT GGCGGCTCTC
701 AGAGCTTCCT GCTCAAGTCT TTAGAGCAAG TGAGAAAGAT CCAGGGCGAT
751 GGCGCAGCGC TCCAGGAGAA GCTGTGTGCC ACCTACAAGC TGTGCCACCC
801 CGAGGAGCTG GTGCTGCTCG GACACTCTCT GGGCATCCCC TGGGCTCCCC
851 TGAGCTCCTG CCCCAGCCAG GCCCTGCAGC TGGCAGGCTG CTTGAGCCAA
901 CTCCATAGCG GCCTTTTCCT CTACCAGGGG CTCCTGCAGG CCCTGGAAGG
951 GATATCCTAA TAA (SEQ ID NO:97);
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTA

592
401 TGGCCCCTGC CCTGCAGCCC ACCCAGGGTG CCATGCCGGC CTTCGCCTCT
451 GCTTTCCAGC GCCGGGCAGG AGGGGTCCTG GTTGCTAGCC ATCTGCAGAG
501 CTTCCTGGAG GTGTCGTACC GCGTTCTACG CCACCTTGCG CAGCCCTCTG
551 GCGGCTCTGG CGGCTCTCAG AGCTTCCTGC TCAAGTCTTT AGAGCAAGTG
601 AGAAAGATCC AGGGCGATGG CGCAGCGCTC CAGGAGAAGC TGTGTGCCAC
651 CTACAAGCTG TGCCACCCCG AGGAGCTGGT GCTGCTCGGA CACTCTCTGG
701 GCATCCCCTG GGCTCCCCTG AGCTCCTGCC CCAGCCAGGC CCTGCAGCTG
751 GCAGGCTGCT TGAGCCAACT CCATAGCGGC CTTTTCCTCT ACCAGGGGCT
801 CCTGCAGGCC CTGGAAGGGA TATCCCCCGA GTTGGGTCCC ACCTTGGACA
851 CACTGCAGCT GGACGTCGCC GACTTTGCCA CCACCATCTG GCAGCAGATG
901 GAAGAACTGG GATAATAA (SEQ ID NO:98);
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTATGGCC
451 CCTGCCCTGC AGCCCACCCA GGGTGCCATG CCGGCCTTCG CCTCTGCTTT
501 CCAGCGCCGG GCAGGAGGGG TCCTGGTTGC TAGCCATCTG CAGAGCTTCC
551 TGGAGGTGTC GTACCGCGTT CTACGCCACC TTGCGCAGCC CTCTGGCGGC
601 TCTGGCGGCT CTCAGAGCTT CCTGCTCAAG TCTTTAGAGC AAGTGAGAAA
651 GATCCAGGGC GATGGCGCAG CGCTCCAGGA GAAGCTGTGT GCCACCTACA
701 AGCTGTGCCA CCCCGAGGAG CTGGTGCTGC TCGGACACTC TCTGGGCATC
751 CCCTGGGCTC CCCTGAGCTC CTGCCCCAGC CAGGCCCTGC AGCTGGCAGG
801 CTGCTTGAGC CAACTCCATA GCGGCCTTTT CCTCTACCAG GGGCTCCTGC
851 AGGCCCTGGA AGGGATATCC CCCGAGTTGG GTCCCACCTT GGACACACTG
901 CAGCTGGACG TCGCCGACTT TGCCACCACC ATCTGGCAGC AGATGGAAGA
951 ACTGGGATAA TAA (SEQ ID NO:99);
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTA
401 CCCAGGGTGC CATGCCGGCC TTCGCCTCTG CTTTCCAGCG CCGGGCAGGA
451 GGGGTCCTGG TTGCTAGCCA TCTGCAGAGC TTCCTGGAGG TGTCGTACCG
501 CGTTCTACGC CACCTTGCGC AGCCCTCTGG CGGCTCTGGC GGCTCTCAGA
551 GCTTCCTGCT CAAGTCTTTA GAGCAAGTGA GAAAGATCCA GGGCGATGGC
601 GCAGCGCTCC AGGAGAAGCT GTGTGCCACC TACAAGCTGT GCCACCCCGA
651 GGAGCTGGTG CTGCTCGGAC ACTCTCTGGG CATCCCCTGG GCTCCCCTGA
701 GCTCCTGCCC CAGCCAGGCC CTGCAGCTGG CAGGCTGCTT GAGCCAACTC
751 CATAGCGGCC TTTTCCTCTA CCAGGGGCTC CTGCAGGCCC TGGAAGGGAT
801 ATCCCCCGAG TTGGGTCCCA CCTTGGACAC ACTGCAGCTG GACGTCGCCG

593
851 ACTTTGCCAC CACCATCTGG CAGCAGATGG AAGAACTGGG AATGGCCCCT
901 GCCCTGCAGC CCTAATAA (SEQ ID NO:100);
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTACCCAG
451 GGTGCCATGC CGGCCTTCGC CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT
501 CCTGGTTGCT AGCCATCTGC AGAGCTTCCT GGAGGTGTCG TACCGCGTTC
551 TACGCCACCT TGCGCAGCCC TCTGGCGGCT CTGGCGGCTC TCAGAGCTTC
601 CTGCTCAAGT CTTTAGAGCA AGTGAGAAAG ATCCAGGGCG ATGGCGCAGC
651 GCTCCAGGAG AAGCTGTGTG CCACCTACAA GCTGTGCCAC CCCGAGGAGC
701 TGGTGCTGCT CGGACACTCT CTGGGCATCC CCTGGGCTCC CCTGAGCTCC
751 TGCCCCAGCC AGGCCCTGCA GCTGGCAGGC TGCTTGAGCC AACTCCATAG
801 CGGCCTTTTC CTCTACCAGG GGCTCCTGCA GGCCCTGGAA GGGATATCCC
851 CCGAGTTGGG TCCCACCTTG GACACACTGC AGCTGGACGT CGCCGACTTT
901 GCCACCACCA TCTGGCAGCA GATGGAAGAA CTGGGAATGG CCCCTGCCCT
951 GCAGCCCTAA TAA (SEQ ID NO:101);
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTT
401 CTGCTTTCCA GCGCCGGGCA GGAGGGGTCC TGGTTGCTAG CCATCTGCAG
451 AGCTTCCTGG AGGTGTCGTA CCGCGTTCTA CGCCACCTTG CGCAGCCCTC
501 TGGCGGCTCT GGCGGCTCTC AGAGCTTCCT GCTCAAGTCT TTAGAGCAAG
551 TGAGAAAGAT CCAGGGCGAT GGCGCAGCGC TCCAGGAGAA GCTGTGTGCC
601 ACCTACAAGC TGTGCCACCC CGAGGAGCTG GTGCTGCTCG GACACTCTCT
651 GGGCATCCCC TGGGCTCCCC TGAGCTCCTG CCCCAGCCAG GCCCTGCAGC
701 TGGCAGGCTG CTTGAGCCAA CTCCATAGCG GCCTTTTCCT CTACCAGGGG
751 CTCCTGCAGG CCCTGGAAGG GATATCCCCC GAGTTGGGTC CCACCTTGGA
801 CACACTGCAG CTGGACGTCG CCGACTTTGC CACCACCATC TGGCAGCAGA
851 TGGAAGAACT GGGAATGGCC CCTGCCCTGC AGCCCACCCA GGGTGCCATG
901 CCGGCCTTCG CCTAATAA (SEQ ID NO:102);
pMON25191
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA

594
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTCCCGAG
451 TTGGGTCCCA CCTTGGACAC ACTGCAGCTG GACGTCGCCG ACTTTGCCAC
501 CACCATCTGG CAGCAGATGG AAGAACTGGG AATGGCCCCT GCCCTGCAGC
551 CCACCCAGGG TGCCATGCCG GCCTTCGCCT CTGCTTTCCA GCGCCGGGCA
601 GGAGGGGTCC TGGTTGCTAG CCATCTGCAG AGCTTCCTGG AGGTGTCGTA
651 CCGCGTTCTA CGCCACCTTG CGCAGCCCAC ACCATTGGGC CCTGCCAGCT
701 CCCTGCCCCA GAGCTTCCTG CTCAAGTCTT TAGAGCAAGT GAGAAAGATC
751 CAGGGCGATG GCGCAGCGCT CCAGGAGAAG CTGTGTGCCA CCTACAAGCT
801 GTGCCACCCC GAGGAGCTGG TGCTGCTCGG ACACTCTCTG GGCATCCCCT
851 GGGCTCCCCT GAGCTCCTGC CCCAGCCAGG CCCTGCAGCT GGCAGGCTGC
901 TTGAGCCAAC TCCATAGCGG CCTTTTCCTC TACCAGGGGC TCCTGCAGGC
951 CCTGGAAGGG ATATCCTAAT AA (SEQ ID NO:107);
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTTCTGCT
451 TTCCAGCGCC GGGCAGGAGG GGTCCTGGTT GCTAGCCATC TGCAGAGCTT
501 CCTGGAGGTG TCGTACCGCG TTCTACGCCA CCTTGCGCAG CCCTCTGGCG
551 GCTCTGGCGG CTCTCAGAGC TTCCTGCTCA AGTCTTTAGA GCAAGTGAGA
601 AAGATCCAGG GCGATGGCGC AGCGCTCCAG GAGAAGCTGT GTGCCACCTA
651 CAAGCTGTGC CACCCCGAGG AGCTGGTGCT GCTCGGACAC TCTCTGGGCA
701 TCCCCTGGGC TCCCCTGAGC TCCTGCCCCA GCCAGGCCCT GCAGCTGGCA
751 GGCTGCTTGA GCCAACTCCA TAGCGGCCTT TTCCTCTACC AGGGGCTCCT
801 GCAGGCCCTG GAAGGGATAT CCCCCGAGTT GGGTCCCACC TTGGACACAC
851 TGCAGCTGGA CGTCGCCGAC TTTGCCACCA CCATCTGGCA GCAGATGGAA
901 GAACTGGGAA TGGCCCCTGC CCTGCAGCCC ACCCAGGGTG CCATGCCGGC
951 CTTCGCCTAA TAA (SEQ ID NO:103);
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTT
401 ACAAGCTGTG CCACCCCGAG GAGCTGGTGC TGCTCGGACA CTCTCTGGGC
451 ATCCCCTGGG CTCCCCTGAG CTCCTGCCCC AGCCAGGCCC TGCAGCTGGC
501 AGGCTGCTTG AGCCAACTCC ATAGCGGCCT TTTCCTCTAC CAGGGGCTCC

595
551 TGCAGGCCCT GGAAGGGATA TCCCCCGAGT TGGGTCCCAC CTTGGACACA
601 CTGCAGCTGG ACGTCGCCGA CTTTGCCACC ACCATCTGGC AGCAGATGGA
651 AGAACTGGGA ATGGCCCCTG CCCTGCAGCC CACCCAGGGT GCCATGCCGG
701 CCTTCGCCTC TGCTTTCCAG CGCCGGGCAG GAGGGGTCCT GGTTGCTAGC
751 CATCTGCAGA GCTTCCTGGA GGTGTCGTAC CGCGTTCTAC GCCACCTTGC
801 GCAGCCCACA CCATTGGGCC CTGCCAGCTC CCTGCCCCAG AGCTTCCTGC
851 TCAAGTCTTT AGAGCAAGTG AGAAAGATCC AGGGCGATGG CGCAGCGCTC
901 CAGGAGAAGC TGTGTGCCAC CTAATAA (SEQ ID NO:104);
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTTACAAG
451 CTGTGCCACC CCGAGGAGCT GGTGCTGCTC GGACACTCTC TGGGCATCCC
501 CTGGGCTCCC CTGAGCTCCT GCCCCAGCCA GGCCCTGCAG CTGGCAGGCT
551 GCTTGAGCCA ACTCCATAGC GGCCTTTTCC TCTACCAGGG GCTCCTGCAG
601 GCCCTGGAAG GGATATCCCC CGAGTTGGGT CCCACCTTGG ACACACTGCA
651 GCTGGACGTC GCCGACTTTG CCACCACCAT CTGGCAGCAG ATGGAAGAAC
701 TGGGAATGGC CCCTGCCCTG CAGCCCACCC AGGGTGCCAT GCCGGCCTTC
751 GCCTCTGCTT TCCAGCGCCG GGCAGGAGGG GTCCTGGTTG CTAGCCATCT
801 GCAGAGCTTC CTGGAGGTGT CGTACCGCGT TCTACGCCAC CTTGCGCAGC
851 CCACACCATT GGGCCCTGCC AGCTCCCTGC CCCAGAGCTT CCTGCTCAAG
901 TCTTTAGAGC AAGTGAGAAA GATCCAGGGC GATGGCGCAG CGCTCCAGGA
951 GAAGCTGTGT GCCACCTAAT AA (SEQ ID NO:105);
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTATGGCC
451 CCTGCCCTGC AGCCCACCCA GGGTGCCATG CCGGCCTTCG CCTCTGCTTT
501 CCAGCGCCGG GCAGGAGGGG TCCTGGTTGC TAGCCATCTG CAGAGCTTCC
551 TGGAGGTGTC GTACCGCGTT CTACGCCACC TTGCGCAGCC CACACCATTG
601 GGCCCTGCCA GCTCCCTGCC CCAGAGCTTC CTGCTCAAGT CTTTAGAGCA
651 AGTGAGAAAG ATCCAGGGCG ATGGCGCAGC GCTCCAGGAG AAGCTGTGTG
701 CCACCTACAA GCTGTGCCAC CCCGAGGAGC TGGTGCTGCT CGGACACTCT
751 CTGGGCATCC CCTGGGCTCC CCTGAGCTCC TGCCCCAGCC AGGCCCTGCA
801 GCTGGCAGGC TGCTTGAGCC AACTCCATAG CGGCCTTTTC CTCTACCAGG
851 GGCTCCTGCA GGCCCTGGAA GGGATATCCC CCGAGTTGGG TCCCACCTTG
901 GACACACTGC AGCTGGACGT CGCCGACTTT GCCACCACCA TCTGGCAGCA
951 GATGGAAGAA CTGGGATAAT AA (SEQ ID NO:109);

596
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTA
401 CCCAGGGTGC CATGCCGGCC TTCGCCTCTG CTTTCCAGCG CCGGGCAGGA
451 GGGGTCCTGG TTGCTAGCCA TCTGCAGAGC TTCCTGGAGG TGTCGTACCG
501 CGTTCTACGC CACCTTGCGC AGCCCACACC ATTGGGCCCT GCCAGCTCCC
551 TGCCCCAGAG CTTCCTGCTC AAGTCTTTAG AGCAAGTGAG AAAGATCCAG
601 GGCGATGGCG CAGCGCTCCA GGAGAAGCTG TGTGCCACCT ACAAGCTGTG
651 CCACCCCGAG GAGCTGGTGC TGCTCGGACA CTCTCTGGGC ATCCCCTGGG
701 CTCCCCTGAG CTCCTGCCCC AGCCAGGCCC TGCAGCTGGC AGGCTGCTTG
751 AGCCAACTCC ATAGCGGCCT TTTCCTCTAC CAGGGGCTCC TGCAGGCCCT
801 GGAAGGGATA TCCCCCGAGT TGGGTCCCAC CTTGGACACA CTGCAGCTGG
851 ACGTCGCCGA CTTTGCCACC ACCATCTGGC AGCAGATGGA AGAACTGGGA
901 ATGGCCCCTG CCCTGCAGCC CTAATAA (SEQ ID NO:110);
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTACCCAG
451 GGTGCCATGC CGGCCTTCGC CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT
501 CCTGGTTGCT AGCCATCTGC AGAGCTTCCT GGAGGTGTCG TACCGCGTTC
551 TACGCCACCT TGCGCAGCCC ACACCATTGG GCCCTGCCAG CTCCCTGCCC
601 CAGAGCTTCC TGCTCAAGTC TTTAGAGCAA GTGAGAAAGA TCCAGGGCGA
651 TGGCGCAGCG CTCCAGGAGA AGCTGTGTGC CACCTACAAG CTGTGCCACC
701 CCGAGGAGCT GGTGCTGCTC GGACACTCTC TGGGCATCCC CTGGGCTCCC
751 CTGAGCTCCT GCCCCAGCCA GGCCCTGCAG CTGGCAGGCT GCTTGAGCCA
801 ACTCCATAGC GGCCTTTTCC TCTACCAGGG GCTCCTGCAG GCCCTGGAAG
851 GGATATCCCC CGAGTTGGGT CCCACCTTGG ACACACTGCA GCTGGACGTC
901 GCCGACTTTG CCACCACCAT CTGGCAGCAG ATGGAAGAAC TGGGAATGGC
951 CCCTGCCCTG CAGCCCTAAT AA (SEQ ID NO:111);
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG

597
CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTT
CTGCTTTCCA GCGCCGGGCA GGAGGGGTCC TGGTTGCTAG CCATCTGCAG
AGCTTCCTGG AGGTGTCGTA CCGCGTTCTA CGCCACCTTG CGCAGCCCAC
ACCATTGGGC CCTGCCAGCT CCCTGCCCCA GAGCTTCCTG CTCAAGTCTT
TAGAGCAAGT GAGAAAGATC CAGGGCGATG GCGCAGCGCT CCAGGAGAAG
CTGTGTGCCA CCTACAAGCT GTGCCACCCC GAGGAGCTGG TGCTGCTCGG
ACACTCTCTG GGCATCCCCT GGGCTCCCCT GAGCTCCTGC CCCAGCCAGG
CCCTGCAGCT GGCAGGCTGC TTGAGCCAAC TCCATAGCGG CCTTTTCCTC
TACCAGGGGC TCCTGCAGGC CCTGGAAGGG ATATCCCCCG AGTTGGGTCC
CACCTTGGAC ACACTGCAGC TGGACGTCGC CGACTTTGCC ACCACCATCT
GGCAGCAGAT GGAAGAACTG GGAATGGCCC CTGCCCTGCA GCCCACCCAG
GGTGCCATGC CGGCCTTCGC CTAATAA (SEQ ID NO:112);
ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
CTATCCTGAT GGATCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GTCTTACAAG
CTGTGCCACC CCGAGGAGCT GGTGCTGCTC GGACACTCTC TGGGCATCCC
CTGGGCTCCC CTGAGCTCCT GCCCCAGCCA GGCCCTGCAG CTGGCAGGCT
GCTTGAGCCA ACTCCATAGC GGCCTTTTCC TCTACCAGGG GCTCCTGCAG
GCCCTGGAAG GGATATCCCC CGAGTTGGGT CCCACCTTGG ACACACTGCA
GCTGGACGTC GCCGACTTTG CCACCACCAT CTGGCAGCAG ATGGAAGAAC
TGGGAATGGC CCCTGCCCTG CAGCCCACCC AGGGTGCCAT GCCGGCCTTC
GCCTCTGCTT TCCAGCGCCG GGCAGGAGGG GTCCTGGTTG CTAGCCATCT
GCAGAGCTTC CTGGAGGTGT CGTACCGCGT TCTACGCCAC CTTGCGCAGC
CCGGCGGCGG CTCTGACATG GCTACACCAT TAGGCCCTGC CAGCTCCCTG
CCCCAGAGCT TCCTGCTCAA GTCTTTAGAG CAAGTGAGGA AGATCCAGGG
CGATGGCGCA GCGCTCCAGG AGAAGCTGTG TGCCACCTAA TAA (SEQ ID
NO:155);
ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
CTATCCTGAT GGATCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GTCTCCCGAG
TTGGGTCCCA CCTTGGACAC ACTGCAGCTG GACGTCGCCG ACTTTGCCAC
CACCATCTGG CAGCAGATGG AAGAACTGGG AATGGCCCCT GCCCTGCAGC
CCACCCAGGG TGCCATGCCG GCCTTCGCCT CTGCTTTCCA GCGCCGGGCA
GGAGGGGTCC TGGTTGCTAG CCATCTGCAG AGCTTCCTGG AGGTGTCGTA
CCGCGTTCTA CGCCACCTTG CGCAGCCCGG CGGCGGCTCT GACATGGCTA
CACCATTAGG CCCTGCCAGC TCCCTGCCCC AGAGCTTCCT GCTCAAGTCT

598
751 TTAGAGCAAG TGAGGAAGAT CCAGGGCGAT GGCGCAGCGC TCCAGGAGAA
801 GCTGTGTGCC ACCTACAAGC TGTGCCACCC CGAGGAGCTG GTGCTGCTCG
851 GACACTCTCT GGGCATCCCC TGGGCTCCCC TGAGCTCCTG CCCCAGCCAG
901 GCCCTGCAGC TGGCAGGCTG CTTGAGCCAA CTCCATAGCG GCCTTTTCCT
951 CTACCAGGGG CTCCTGCAGG CCCTGGAAGG GATATCCTAA TAA (SEQ ID
NO:156);
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGATCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GTCTTCTGCT
451 TTCCAGCGCC GGGCAGGAGG GGTCCTGGTT GCTAGCCATC TGCAGAGCTT
501 CCTGGAGGTG TCGTACCGCG TTCTACGCCA CCTTGCGCAG CCCGGCGGCG
551 GCTCTGACAT GGCTACACCA TTAGGCCCTG CCAGCTCCCT GCCCCAGAGC
601 TTCCTGCTCA AGTCTTTAGA GCAAGTGAGG AAGATCCAGG GCGATGGCGC
651 AGCGCTCCAG GAGAAGCTGT GTGCCACCTA CAAGCTGTGC CACCCCGAGG
701 AGCTGGTGCT GCTCGGACAC TCTCTGGGCA TCCCCTGGGC TCCCCTGAGC
751 TCCTGCCCCA GCCAGGCCCT GCAGCTGGCA GGCTGCTTGA GCCAACTCCA
801 TAGCGGCCTT TTCCTCTACC AGGGGCTCCT GCAGGCCCTG GAAGGGATAT
851 CCCCCGAGTT GGGTCCCACC TTGGACACAC TGCAGCTGGA CGTCGCCGAC
901 TTTGCCACCA CCATCTGGCA GCAGATGGAA GAACTGGGAA TGGCCCCTGC
951 CCTGCAGCCC ACCCAGGGTG CCATGCCGGC CTTCGCCTAA TAA; (SEQ
ID NO:157)
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGATCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GTCTATGGCC
451 CCTGCCCTGC AGCCCACCCA GGGTGCCATG CCGGCCTTCG CCTCTGCTTT
501 CCAGCGCCGG GCAGGAGGGG TCCTGGTTGC TAGCCATCTG CAGAGCTTCC
551 TGGAGGTGTC GTACCGCGTT CTACGCCACC TTGCGCAGCC CGGCGGCGGC
601 TCTGACATGG CTACACCATT AGGCCCTGCC AGCTCCCTGC CCCAGAGCTT
651 CCTGCTCAAG TCTTTAGAGC AAGTGAGGAA GATCCAGGGC GATGGCGCAG
701 CGCTCCAGGA GAAGCTGTGT GCCACCTACA AGCTGTGCCA CCCCGAGGAG
751 CTGGTGCTGC TCGGACACTC TCTGGGCATC CCCTGGGCTC CCCTGAGCTC
801 CTGCCCCAGC CAGGCCCTGC AGCTGGCAGG CTGCTTGAGC CAACTCCATA
851 GCGGCCTTTT CCTCTACCAG GGGCTCCTGC AGGCCCTGGA AGGGATATCC
901 CCCGAGTTGG GTCCCACCTT GGACACACTG CAGCTGGACG TCGCCGACTT
951 TGCCACCACC ATCTGGCAGC AGATGGAAGA ACTGGGATAA TAA; (SEQ
ID NO:158)

599
ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
CTATCCTGAT GGATCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GTCTACCCAG
GGTGCCATGC CGGCCTTCGC CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT
CCTGGTTGCT AGCCATCTGC AGAGCTTCCT GGAGGTGTCG TACCGCGTTC
TACGCCACCT TGCGCAGCCC GGCGGCGGCT CTGACATGGC TACACCATTA
GGCCCTGCCA GCTCCCTGCC CCAGAGCTTC CTGCTCAAGT CTTTAGAGCA
AGTGAGGAAG ATCCAGGGCG ATGGCGCAGC GCTCCAGGAG AAGCTGTGTG
CCACCTACAA GCTGTGCCAC CCCGAGGAGC TGGTGCTGCT CGGACACTCT
CTGGGCATCC CCTGGGCTCC CCTGAGCTCC TGCCCCAGCC AGGCCCTGCA
GCTGGCAGGC TGCTTGAGCC AACTCCATAG CGGCCTTTTC CTCTACCAGG
GGCTCCTGCA GGCCCTGGAA GGGATATCCC CCGAGTTGGG TCCCACCTTG
GACACACTGC AGCTGGACGT CGCCGACTTT GCCACCACCA TCTGGCAGCA
GATGGAAGAA CTGGGAATGG CCCCTGCCCT GCAGCCCTAA TAA; (SEQ
ID NO:159)
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGA
CAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAG
GGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTC
CGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTC
GGCGGCAACATGGCGTCTCCGGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTG
CTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTG
CCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATG
GAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATG
GCAGCACGGGGACAACTG (SEQ ID NO:124);
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAG
GATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTG

600
ATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAACATGGCGTCTCCG
GCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTT
CACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCT
GCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGAC
ATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGA
CCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGG
GCCCTGCAGAGCCTCCTT (SEQ ID No:125);
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTG
AGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACC
CTCTGCGTCAGGGAATTCGGCGGCAACATGGCGTCTCCGGCGCCGCCTGCTTGTGACCTC
CGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGC
CCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGA
GAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTT
CTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTC
CTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGA
ACCCAGCTTCCTCCACAG (SEQ ID NO:126);
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACAC
CTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGG
GAATTCGGCGGCAACATGGCGTCTCCGGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGT
AAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCAC
CCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACC
CAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGA
GTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTT
TCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCT
CCACAGGGCAGGACCACA (SEQ ID NO:127);
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT

601
CATAAATCTCCAAACATGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGA
GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC
GGCAACATGGCGTCTCCGGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTT
CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCT
ACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAG
GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA
GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAG
GTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGC
AGGACCACAGCTCACAAG (SEQ ID NO:128);
ATGGCTAACT GCTCTAACAT GATCGATGAA ATCATCACCC ACCTGAAGCA
GCCACCGCTG CCGCTGCTGG ACTTCAACAA CCTCAATGGT GAAGACCAAG
ATATCCTAAT GGACAATAAC CTTCGTCGTC CAAACCTCGA GGCATTCAAC
CGTGCTGTCA AGTCTCTGCA GAATGCATCA GCAATTGAGA GCATTCTTAA
AAATCTCCTG CCATGTCTGC CGCTAGCCAC GGCCGCACCC ACGCGACATC
CAATCCATAT CAAGGACGGT GACTGGAATG AATTCCGTCG TAAACTGACC
TTCTATCTGA AAACCTTGGA GAACGCGCAG GCTCAACAGT ACGTAGAGGG
CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTACCCAG
GGTGCCATGC CGGCCTTCGC CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT
CCTGGTTGCT AGCCATCTGC AGAGCTTCCT GGAGGTGTCG TACCGCGTTC
TACGCCACCT TGCGCAGCCC TCTGGCGGCT CTGGCGGCTC TCAGAGCTTC
CTGCTCAAGT CTTTAGAGCA AGTGAGAAAG ATCCAGGGCG ATGGCGCAGC
GCTCCAGGAG AAGCTGTGTG CCACCTACAA GCTGTGCCAC CCCGAGGAGC
TGGTGCTGCT CGGACACTCT CTGGGCATCC CCTGGGCTCC CCTGAGCTCC
TGCCCCAGCC AGGCCCTGCA GCTGGCAGGC TGCTTGAGCC AACTCCATAG
CGGCCTTTTC CTCTACCAGG GGCTCCTGCA GGCCCTGGAA GGGATATCCC
CCGAGTTGGG TCCCACCTTG GACACACTGC AGCTGGACGT CGCCGACTTT
GCCACCACCA TCTGGCAGCA GATGGAAGAA CTGGGAATGG CCCCTGCCCT
GCAGCCCTAA TAA (SEQ ID NO:114);
ATGGCTAACT GCTCTAACAT GATCGATGAA ATCATCACCC ACCTGAAGCA
GCCACCGCTG CCGCTGCTGG ACTTCAACAA CCTCAATGGT GAAGACCAAG
ATATCCTGAT GGAAAATAAC CTTCGTCGTC CAAACCTCGA GGCATTCAAC
CGTGCTGTCA AGTCTCTGCA GAATGCATCA GCAATTGAGA GCATTCTTAA
AAATCTCCTG CCATGTCTGC CCCTGGCCAC GGCCGCACCC ACGCGACATC
CAATCATCAT CCGTGACGGT GACTGGAATG AATTCCGTCG TAAACTGACC
TTCTATCTGA AAACCTTGGA GAACGCGCAG GCTCAACAGT ACGTAGAGGG
CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTACCCAG
GGTGCCATGC CGGCCTTCGC CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT
CCTGGTTGCT AGCCATCTGC AGAGCTTCCT GGAGGTGTCG TACCGCGTTC
TACGCCACCT TGCGCAGCCC ACACCATTGG GCCCTGCCAG CTCCCTGCCC
CAGAGCTTCC TGCTCAAGTC TTTAGAGCAA GTGAGAAAGA TCCAGGGCGA
TGGCGCAGCG CTCCAGGAGA AGCTGTGTGC CACCTACAAG CTGTGCCACC
CCGAGGAGCT GGTGCTGCTC GGACACTCTC TGGGCATCCC CTGGGCTCCC
CTGAGCTCCT GCCCCAGCCA GGCCCTGCAG CTGGCAGGCT GCTTGAGCCA
ACTCCATAGC GGCCTTTTCC TCTACCAGGG GCTCCTGCAG GCCCTGGAAG
GGATATCCCC CGAGTTGGGT CCCACCTTGG ACACACTGCA GCTGGACGTC

602
GCCGACTTTG CCACCACCAT CTGGCAGCAG ATGGAAGAAC TGGGAATGGC
CCCTGCCCTG CAGCCCTAAT AA (SEQ ID NO:115);
ATGGCTAACT GCTCTAACAT GATCGATGAA ATCATCACCC ACCTGAAGCA
GCCACCGCTG CCGCTGCTGG ACTTCAACAA CCTCAATGGT GAAGACCAAG
ATATCCTGAT GGAAAATAAC CTTCGTCGTC CAAACCTCGA GGCATTCAAC
CGTGCTGTCA AGTCTCTGCA GAATGCATCA GCAATTGAGA GCATTCTTAA
AAATCTCCTG CCATGTCTGC CCCTGGCCAC GGCCGCACCC ACGCGACATC
CAATCATCAT CCGTGACGGT GACTGGAATG AATTCCGTCG TAAACTGACC
TTCTATCTGA AAACCTTGGA GAACGCGCAG GCTCAACAGT ACGTAGAGGG
CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTACCCAG
GGTGCCATGC CGGCCTTCGC CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT
CCTGGTTGCT AGCCATCTGC AGAGCTTCCT GGAGGTGTCG TACCGCGTTC
TACGCCACCT TGCGCAGCCC TCTGGCGGCT CTGGCGGCTC TCAGAGCTTC
CTGCTCAAGT CTTTAGAGCA AGTGAGAAAG ATCCAGGGCG ATGGCGCAGC
GCTCCAGGAG AAGCTGTGTG CCACCTACAA GCTGTGCCAC CCCGAGGAGC
TGGTGCTGCT CGGACACTCT CTGGGCATCC CCTGGGCTCC CCTGAGCTCC
TGCCCCAGCC AGGCCCTGCA GCTGGCAGGC TGCTTGAGCC AACTCCATAG
CGGCCTTTTC CTCTACCAGG GGCTCCTGCA GGCCCTGGAA GGGATATCCC
CCGAGTTGGG TCCCACCTTG GACACACTGC AGCTGGACGT CGCCGACTTT
GCCACCACCA TCTGGCAGCA GATGGAAGAA CTGGGAATGG CCCCTGCCCT
GCAGCCCTAA TAA (SEQ ID NO:116);
ATGGCTAACT GCTCTAACAT GATCGATGAA ATCATCACCC ACCTGAAGCA
GCCACCGCTG CCGCTGCTGG ACTTCAACAA CCTCAATGGT GAAGACCAAG
ATATCCTAAT GGACAATAAC CTTCGTCGTC CAAACCTCGA GGCATTCAAC
CGTGCTGTCA AGTCTCTGCA GAATGCATCA GCAATTGAGA GCATTCTTAA
AAATCTCCTG CCATGTCTGC CGCTAGCCAC GGCCGCACCC ACGCGACATC
CAATCCATAT CAAGGACGGT GACTGGAATG AATTCCGTCG TAAACTGACC
TTCTATCTGA AAACCTTGGA GAACGCGCAG GCTCAACAGT ACGTAGAGGG
CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTACCCAG
GGTGCCATGC CGGCCTTCGC CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT
CCTGGTTGCT AGCCATCTGC AGAGCTTCCT GGAGGTGTCG TACCGCGTTC
TACGCCACCT TGCGCAGCCC ACACCATTGG GCCCTGCCAG CTCCCTGCCC
CAGAGCTTCC TGCTCAAGTC TTTAGAGCAA GTGAGAAAGA TCCAGGGCGA
TGGCGCAGCG CTCCAGGAGA AGCTGTGTGC CACCTACAAG CTGTGCCACC
CCGAGGAGCT GGTGCTGCTC GGACACTCTC TGGGCATCCC CTGGGCTCCC
CTGAGCTCCT GCCCCAGCCA GGCCCTGCAG CTGGCAGGCT GCTTGAGCCA
ACTCCATAGC GGCCTTTTCC TCTACCAGGG GCTCCTGCAG GCCCTGGAAG
GGATATCCCC CGAGTTGGGT CCCACCTTGG ACACACTGCA GCTGGACGTC
GCCGACTTTG CCACCACCAT CTGGCAGCAG ATGGAAGAAC TGGGAATGGC
CCCTGCCCTG CAGCCCTAAT AA (SEQ ID NO:117);
ATGGCTCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCCTGAT
GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA

603
AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG TAATCTCCAA
CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC CAATCATCAT
CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG TTCTATCTGG
TTACCCTTGA GCAAGCGCAG GAACAACAGG GTGGTGGCTC TAACTGCTCT
ATAATGATCG ATGAAATTAT ACATCACTTA AAGAGACCAC CTGCACCTTT
GTACGTAGAG GGCGGTGGAG GCTCCCCGGG TGAACCGTCT GGTCCAATCT
CTACTATCAA CCCGTCTCCT CCGTCTAAAG AATCTCATAA ATCTCCAAAC
ATGGCTACCC AGGGTGCCAT GCCGGCCTTC GCCTCTGCTT TCCAGCGCCG
GGCAGGAGGG GTCCTGGTTG CTAGCCATCT GCAGAGCTTC CTGGAGGTGT
CGTACCGCGT TCTACGCCAC CTTGCGCAGC CCTCTGGCGG CTCTGGCGGC
TCTCAGAGCT TCCTGCTCAA GTCTTTAGAG CAAGTGAGAA AGATCCAGGG
CGATGGCGCA GCGCTCCAGG AGAAGCTGTG TGCCACCTAC AAGCTGTGCC
ACCCCGAGGA GCTGGTGCTG CTCGGACACT CTCTGGGCAT CCCCTGGGCT
CCCCTGAGCT CCTGCCCCAG CCAGGCCCTG CAGCTGGCAG GCTGCTTGAG
CCAACTCCAT AGCGGCCTTT TCCTCTACCA GGGGCTCCTG CAGGCCCTGG
AAGGGATATC CCCCGAGTTG GGTCCCACCT TGGACACACT GCAGCTGGAC
GTCGCCGACT TTGCCACCAC CATCTGGCAG CAGATGGAAG AACTGGGAAT
GGCCCCTGCC CTGCAGCCCT AATAA (SEQ ID NO:86);
ATGGCTAATG CATCAGGTAT TGAGGCAATT CTTCGTAATC TCCAACCATG
TCTGCCCTCT GCCACGGCCG CACCCTCTCG ACATCCAATC ATCATCAAGG
CAGGTGACTG GCAAGAATTC CGGGAAAAAC TGACGTTCTA TCTGGTTACC
CTTGAGCAAG CGCAGGAACA ACAGGGTGGT GGCTCTAACT GCTCTATAAT
GATCGATGAA ATTATACATC ACTTAAAGAG ACCACCTGCA CCTTTGCTGG
ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCCTGAT GGACCGAAAC
CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA AGAACTTAGA
ATACGTAGAG GGCGGTGGAG GCTCCCCGGG TGAACCGTCT GGTCCAATCT
CTACTATCAA CCCGTCTCCT CCGTCTAAAG AATCTCATAA ATCTCCAAAC
ATGGCTACCC AGGGTGCCAT GCCGGCCTTC GCCTCTGCTT TCCAGCGCCG
GGCAGGAGGG GTCCTGGTTG CTAGCCATCT GCAGAGCTTC CTGGAGGTGT
CGTACCGCGT TCTACGCCAC CTTGCGCAGC CCTCTGGCGG CTCTGGCGGC
TCTCAGAGCT TCCTGCTCAA GTCTTTAGAG CAAGTGAGAA AGATCCAGGG
CGATGGCGCA GCGCTCCAGG AGAAGCTGTG TGCCACCTAC AAGCTGTGCC
ACCCCGAGGA GCTGGTGCTG CTCGGACACT CTCTGGGCAT CCCCTGGGCT
CCCCTGAGCT CCTGCCCCAG CCAGGCCCTG CAGCTGGCAG GCTGCTTGAG
CCAACTCCAT AGCGGCCTTT TCCTCTACCA GGGGCTCCTG CAGGCCCTGG
AAGGGATATC CCCCGAGTTG GGTCCCACCT TGGACACACT GCAGCTGGAC
GTCGCCGACT TTGCCACCAC CATCTGGCAG CAGATGGAAG AACTGGGAAT
GGCCCCTGCC CTGCAGCCCT AATAA (SEQ ID NO:87);
ATGGCTGCAC CCTCTCGACA TCCAATCATC ATCAAGGCAG GTGACTGGCA
AGAATTCCGG GAAAAACTGA CGTTCTATCT GGTTACCCTT GAGCAAGCGC
AGGAACAACA GGGTGGTGGC TCTAACTGCT CTATAATGAT CGATGAAATT
ATACATCACT TAAAGAGACC ACCTGCACCT TTGCTGGACC CGAACAACCT
CAATGACGAA GACGTCTCTA TCCTGATGGA CCGAAACCTT CGACTTCCAA
ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGCATCAGGT
ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC
CTACGTAGAG GGCGGTGGAG GCTCCCCGGG TGAACCGTCT GGTCCAATCT
CTACTATCAA CCCGTCTCCT CCGTCTAAAG AATCTCATAA ATCTCCAAAC
ATGGCTACCC AGGGTGCCAT GCCGGCCTTC GCCTCTGCTT TCCAGCGCCG

604
501 GGCAGGAGGG GTCCTGGTTG CTAGCCATCT GCAGAGCTTC CTGGAGGTGT
551 CGTACCGCGT TCTACGCCAC CTTGCGCAGC CCTCTGGCGG CTCTGGCGGC
601 TCTCAGAGCT TCCTGCTCAA GTCTTTAGAG CAAGTGAGAA AGATCCAGGG
651 CGATGGCGCA GCGCTCCAGG AGAAGCTGTG TGCCACCTAC AAGCTGTGCC
701 ACCCCGAGGA GCTGGTGCTG CTCGGACACT CTCTGGGCAT CCCCTGGGCT
751 CCCCTGAGCT CCTGCCCCAG CCAGGCCCTG CAGCTGGCAG GCTGCTTGAG
801 CCAACTCCAT AGCGGCCTTT TCCTCTACCA GGGGCTCCTG CAGGCCCTGG
851 AAGGGATATC CCCCGAGTTG GGTCCCACCT TGGACACACT GCAGCTGGAC
901 GTCGCCGACT TTGCCACCAC CATCTGGCAG CAGATGGAAG AACTGGGAAT
951 GGCCCCTGCC CTGCAGCCCT AATAA (SEQ ID No:88);
1 ATGGCTCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCCTGAT
51 GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA
101 AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG TAATCTCCAA
151 CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC CAATCATCAT
201 CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG TTCTATCTGG
251 TTACCCTTGA GCAAGCGCAG GAACAACAGG GTGGTGGCTC TGGCGGTGGC
301 AGCGGCGGCG GTTCTAACTG CTCTATAATG ATCGATGAAA TTATACATCA
351 CTTAAAGAGA CCACCTGCAC CTTTGTACGT AGAGGGCGGT GGAGGCTCCC
401 CGGGTGAACC GTCTGGTCCA ATCTCTACTA TCAACCCGTC TCCTCCGTCT
451 AAAGAATCTC ATAAATCTCC AAACATGGCT ACCCAGGGTG CCATGCCGGC
501 CTTCGCCTCT GCTTTCCAGC GCCGGGCAGG AGGGGTCCTG GTTGCTAGCC
551 ATCTGCAGAG CTTCCTGGAG GTGTCGTACC GCGTTCTACG CCACCTTGCG
601 CAGCCCTCTG GCGGCTCTGG CGGCTCTCAG AGCTTCCTGC TCAAGTCTTT
651 AGAGCAAGTG AGAAAGATCC AGGGCGATGG CGCAGCGCTC CAGGAGAAGC
701 TGTGTGCCAC CTACAAGCTG TGCCACCCCG AGGAGCTGGT GCTGCTCGGA
751 CACTCTCTGG GCATCCCCTG GGCTCCCCTG AGCTCCTGCC CCAGCCAGGC
801 CCTGCAGCTG GCAGGCTGCT TGAGCCAACT CCATAGCGGC CTTTTCCTCT
851 ACCAGGGGCT CCTGCAGGCC CTGGAAGGGA TATCCCCCGA GTTGGGTCCC
901 ACCTTGGACA CACTGCAGCT GGACGTCGCC GACTTTGCCA CCACCATCTG
951 GCAGCAGATG GAAGAACTGG GAATGGCCCC TGCCCTGCAG CCCTAATAA
(SEQ ID NO:90);
1 ATGGCTAATG CATCAGGTAT TGAGGCAATT CTTCGTAATC TCCAACCATG
51 TCTGCCCTCT GCCACGGCCG CACCCTCTCG ACATCCAATC ATCATCAAGG
101 CAGGTGACTG GCAAGAATTC CGGGAAAAAC TGACGTTCTA TCTGGTTACC
151 CTTGAGCAAG CGCAGGAACA ACAGGGTGGT GGCTCTGGCG GTGGCAGCGG
201 CGGCGGTTCT AACTGCTCTA TAATGATCGA TGAAATTATA CATCACTTAA
251 AGAGACCACC TGCACCTTTG CTGGACCCGA ACAACCTCAA TGACGAAGAC
301 GTCTCTATCC TGATGGACCG AAACCTTCGA CTTCCAAACC TGGAGAGCTT
351 CGTAAGGGCT GTCAAGAACT TAGAATACGT AGAGGGCGGT GGAGGCTCCC
401 CGGGTGAACC GTCTGGTCCA ATCTCTACTA TCAACCCGTC TCCTCCGTCT
451 AAAGAATCTC ATAAATCTCC AAACATGGCT ACCCAGGGTG CCATGCCGGC
501 CTTCGCCTCT GCTTTCCAGC GCCGGGCAGG AGGGGTCCTG GTTGCTAGCC
551 ATCTGCAGAG CTTCCTGGAG GTGTCGTACC GCGTTCTACG CCACCTTGCG
601 CAGCCCTCTG GCGGCTCTGG CGGCTCTCAG AGCTTCCTGC TCAAGTCTTT
651 AGAGCAAGTG AGAAAGATCC AGGGCGATGG CGCAGCGCTC CAGGAGAAGC
701 TGTGTGCCAC CTACAAGCTG TGCCACCCCG AGGAGCTGGT GCTGCTCGGA
751 CACTCTCTGG GCATCCCCTG GGCTCCCCTG AGCTCCTGCC CCAGCCAGGC
801 CCTGCAGCTG GCAGGCTGCT TGAGCCAACT CCATAGCGGC CTTTTCCTCT

605
ACCAGGGGCT CCTGCAGGCC CTGGAAGGGA TATCCCCCGA GTTGGGTCCC
ACCTTGGACA CACTGCAGCT GGACGTCGCC GACTTTGCCA CCACCATCTG
GCAGCAGATG GAAGAACTGG GAATGGCCCC TGCCCTGCAG CCCTAATAA
(SEQ ID NO:91);
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGA
CAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAG
GGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTC
CGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTC
GGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTT
CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCT
ACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAG
GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA
GCACGGGGACAACTG (SEQ ID NO:136);
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAG
GATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTG
ATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCAACATGGCGTCTCCCGCT
CCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCAC
AGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCT
GTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATT
CTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCC
ACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCC
CTGCAGAGCCTCCTT (SEQ ID NO:137);
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGA
CAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAG
GGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTC
CGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTC

606
GGCGGCAACGGCGGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTC
AGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTT
CACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAA
ACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAG
GGAGTGATGGCAGCACGGGGACAACTG (SEQ ID NO:148);
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAG
GATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTG
ATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAACGGCGGCAACATG
GCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCC
CATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTC
CTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAG
GCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGA
CAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTC
CTCCTTGGGGCCCTGCAGAGCCTCCTT (SEQ ID NO:149);
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTG
AGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACC
CTCTGCGTCAGGGAATTCGGCGGCAACGGCGGCAACATGGCGTCCCCAGCGCCGCCTGCT
TGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTG
AGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTT
AGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCA
GTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTC
TCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGC
CTCCTTGGAACCCAGCTTCCTCCACAG (SEQ ID NO:150);
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACAC
CTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGG

607
GAATTCGGCGGCAACGGCGGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGA
GTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCA
GAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAA
TGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTG
CTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTG
GGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACC
CAGCTTCCTCCACAGGGCAGGACCACA (SEQ ID NO:151);
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGA
GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC
GGCAACGGCGGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGT
AAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCAC
CCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACC
CAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGA
GTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTT
TCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCT
CCACAGGGCAGGACCACAGCTCACAAG (SEQ ID NO:152);
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTG
CGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAACGGC
GGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTT
CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCT
ACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAG
GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA
GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAG
GTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGC
AGGACCACAGCTCACAAGGATCCCAAT (SEQ ID NO:153); and
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT

608
CATAAATCTCCAAACATGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGA
GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC
GGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTT
CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCT
ACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAG
GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA
GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAG
GTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGGGCAGGACCACAGCT
CACAAG (SEQ ID NO:154).
32. A method of producing a hematopoietic protein
comprising: growing under suitable nutrient conditions, a
host cell transformed or transfected with a replicable
vector comprising a nucleic acid molecule of claim 16, 17,
18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 in a
manner allowing expression of said hematopoietic protein and
recovering said hematopoietic protein.
33. A pharmaceutical composition comprising; the
hematopoietic protein according to claim 1, 2, 3, 4, 5, 6,
7, 8, 10, 11, 12, 13 or 14 and a pharmaceutically acceptable
carrier.
34. A method of stimulating the production of
hematopoietic cells in a patient comprising the step of;
administering an effective amount of the hematopoietic
protein as recited in claim 1, 2, 3, 4, 5, 6, 7, 8, 10, 11,
12, 13 or 14 to said patient.
35. A method of stimulating the production of hematopoietic
cells in a patient comprising the step of; administering an
effective amount of the hematopoietic protein as recited in claim
9 to said patient.
36. A method for selective ex vivo expansion of stem cells,
comprising the steps of;
a) separating stem cells from other cells;

609
(b) culturing said separated stem cells with a selected
culture medium comprising; the hematopoietic protein of claim 1,
2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13 or 14; and
(c) harvesting said cultured cells.
37. A method for selective ex vivo expansion of stem cells,
comprising the steps of;
(a) separating stem cells from other cells;
(b) culturing said separated stem cells with a selected
culture medium comprising; the hematopoietic protein of claim 9;
and
(c) harvesting said cultured cells.
38. A method for treatment of a patient having a
hematopoietic disorder, comprising the steps of;
(a) removing stem cells;
(b) separating stem cells from other cells;
(c) culturing said separated stem cells with a selected
culture medium comprising; the hematopoietic protein of
claim 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13 or 14;
(d) harvesting said cultured cells; and
(e) transplanting said cultured cells into said
patient.
39. A method for treatment of a patient having a
hematopoietic disorder, comprising the steps of;
(a) removing stem cells;
(b) separating stem cells from other cells;
(c) culturing said separated stem cells with a selected
culture medium comprising; the hematopoietic protein of
claim 9;
(d) harvesting said cultured cells; and
(e) transplanting said cultured cells into said
patient.

610
40. A method of human gene therapy, comprising the
steps of;
(a) removing stem cells from a patient;
(b) separating said stem cells from other cells;
(c) culturing said separated stem cells with a
selected culture medium comprising; the hematopoietic
protein of claim 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13 or
14;
(d) introducing DNA into said cultured cells;
(e) harvesting said transduced cells; and
(f) transplanting said transduced cells into said
patient.
41. A method of human gene therapy, comprising the
steps of;
(a) removing stem cells from a patient;
(b) separating said stem cells from other cells;
(c) culturing said separated stem cells with a
selected culture medium comprising; the hematopoietic
protein of claim 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13 or
14;
(d) introducing DNA into said cultured cells;
(e) harvesting said transduced cells; and
(f) transplanting said transduced cells into said
patient.

Description

Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.

.. . . -. .: - .= -..CA 02234061 1998-04-06
.' .
.
DEMANDES OU BR~V{~TS VOLUM~N~JX
~A PRÉSBYTE PARTIE~ DE CEl~E D13VIANDE OU CE ~REVET
COMPRE~ ) PLUS D'UN TOME.
CECI EST LE TOME / --DE ~Z_
NOTE: Pour les tomes additicnels, veuillez c~ntacte~ le Bureau canadien ~es
brevets
z~3Y~k/ - -
JUNIBO APPLICATIONS/PA~ENTS - .
l~HIS SECTION ~3F ~HE APPLICATION/PATENT CONTAINS MORE
THAN ONE VOLUME
T~IS IS VOI UME ¦ OF ~ -
.
NO~: F~r additi~na1 ~rDiUmes please cs:~ntact~~e Canad~an Patent C)ff~ce
. .
.

CA 02234061 1998-04-06
W O 9711~985 1 PCT~US96/15774
MULTI-FUNCTIONA~ HEMATOPOIETIC RECEPTOR AGONISTS
The present application claims priority under 35 USC
119(e) of United States provisional application Serial No.
5 60/004,834 ~iled October 05, 1995.
.
Field of the Invention
The present invention relates to multi-functional
hematopoietic receptor agonists.
Backaround of the Invention
Colony stimulating factors (CSFs) which stimulate the
differentiation and/or proliferation of bone marrow cells
have generated much interest because of their therapeutic
potential for restoring depressed levels of hematopoietic
stem cell-derived cells. CS~s in both human and murine
systems have been identified and distinguished according to
their activities. For example, granulocyte-CSF (G-CSF) and
macrophage-CSF (M-CSF) stimulate the in vitro formation of
neutrophilic granulocyte and macrophage colonies,
respectively, while GM-CSF and interleukin-3 (IL-3) have
broader activities and stimulate the ~ormation of both
macrophage, neutrophilic and eosinophilic granulocyte
colonies. IL-3 also stimulates the formation of mast,
megakaryocyte and pure and mixed erythroid colonies.
U.S. 4,877,729 and U.S. 4,959,455 disclose human IL-3
and gibbon IL-3 cDNAs and the protein sequences for which
they code. The hIL-3 disclosed has serine rather than
proline at position 8 in the protein sequence.
International Patent Application (PCT~ WO 88/00598
discloses gibbon- and human-like IL-3. The hIL-3 contains a
Ser8 -> Pro8 replacement. Suggestions are made to replace
Cys by Ser, thereby breaking the disulfide bridge, and to
replace one or more amino acids at the glycosylation sites.

CA 02234061 1998-04-06
W O 97/12985 2 PCT/US96/15774
U.S. 4,810,643 discloses the DNA sea!uence encoding
human G-CSF.
WO 91/02754 discloses a fusion protein comprised of GM-
CSF and IL-3 which has increased biological activity
compared to GM-CSF or IL-3 alone. Also disclosed are
nonglycosylated IL-3 and GM-CSF analog proteins as
components of the multi-functional hematopoietic receptor
agonist.
WO 92/04455 discloses fusion proteins composed of IL-3
fused to a lymphokine selected from the group consisting of
IL-3, IL-6, I~-7, IL-9, IL-ll, EPO and G-CSF.
WO 95/21197 and WO 95/21254 disclose fusion proteins
capable of broad multi-functional hematopoietic properties.
GB 2,285,446 relates to the c-mpl ligand
(thrombopoietin) and various forms of thrombopoietin which
are shown to influence the replication, dif~erentiation and
maturation of megakaryocytes and megakaryocytes progenitors
which may be used for the treatment of thrombocytopenia.
EP 675,201 Al relates to the c-mpl ligand
~Megakaryocyte growth and development factor (MGDF), allelic
variations of c-mpl ligand and c-mpl ligand attached to
water soluble polymers such as polyethylene glycol.
WO 95/21920 provides the murine and human c-mpl ligand
and polypeptide fragments thereof. The proteins are useful
for in vivo and ex vivo therapy for stimulating platelet
production.
~e~rr~naement of Protein Seauences
In evolution, rearranyements of DMA sequences serve an
important role in generating a diversity of protein
structure and function. Gene duplication and exon shuffling
provide an important mechanism to rapidly generate diversity
and thereby provide organisms with a competitive advantage,
especially since the basal mutation rate is low (Doolittle,
.

CA 0223406l l998-04-06
W O 97/12985 3 PCTrUS96/15774
Protein Science 1:191-200, 1992).
The development of recombinant DNA methods has made it
possible to study the effects o~ sequence transposition on
protein folding, structure and function. The approach used
in creating new sequences resembles that of naturally
occurring pairs of proteins that are related by linear
reorganization of their amino acid sequences (Cunningham, et
al., Proc. Natl . Acad . Sci . U. S.A. 76:3218-3222, 1979;
Teather & Erfle, J. Bacteriol. 172: 3837-3841, 1990;
St-~lmm;ng et al., Eur. J. Bioc~em. 204: 13-19, 1992i
Yamiuchi and Minamikawa, FEBS Lett . 260: 127-130, 1991;
MacGregor et al., FEBS Lett. 378:263-266~. The ~irst in
vitro application of this type o~ rearrangement to proteins
was described by Goldenberg and Creighton (~. Mol . Biol .
15 165:407-413, 1983). A new N-terminus is selected at an
internal site (breakpoint) of the original sequence, the new
sequence having the same order o~ amino acids as the
original from the breakpoint until it reaches an amino acid
that is at or near the original C-terminus. At this point
20 the new sequence is joined, either directly or through an
additional portion of sequence (linker), to an amino acid
that is at or near the original N-terminus, and the new
sequence continues with the same sequence as the original
until it reaches a point that is at or near the amino acid
25 that was N-terminal to the breakpoint site o~ the original
sequence, this residue forming the new C-terminus o~ the
chaln .
This approach has been applied to proteins which range
in size from 58 to 462 amino acids (Goldenberg & Creighton,
30 J. Mol. Biol. 1~;5:407-413, 1983; Li & Coffino, Mol. Cell.
Biol. 13:2377-2383, 1993). The proteins examined have
represented a broad range of structural classes, including
proteins that contain predominantly a-helix (interleukin-4;
Kreitman et al., cytokine 7:311-318, lg95), ,B-sheet
35 (interleukin-l; Horlick et al., Protein Eng. 5:427-431,
.

CA 02234061 1998-04-06
W O 97/12985 PCTrUS96/1~774
1992), or mixtures of the two (yeast phosphoribosyl
anthranilate isomerase; Luger et al., Science ~43:206-210,
1989). Broad categories o~ protein function are represented
in these sequence reorganization studies:
Enzymes
T4 lysozyme Zhang et al., Biochemistry
32:12311-12318, 1993; Zhang et
al., Nature Struct. Biol. 1:434-438
~1995)
dihydro~olate Buchwalder et al., Biochemistry
reductase 31:1621-1630, 1994; Protasova et
al., Prot. Eng. 7:1373-1377, 1995)
ribonuclease Tl Mullins et al., ~. Am. Chem. Soc.
116:5529-5533, 1994; Garrett et al.,
Protein Science 5:204-211, 1996)
Bacillus ~-glucanse Hahn et al., Proc. Natl. Acad. Sci.
U.S.A. 91:10417-10421, 1994)
aspartate Yang & Schachman, Proc. Matl. Acad.
transcarbamoylase sci. U.S.A. 90:11980-11984, 1993)
phosphoribosyl Luger et al., Science 243:206-210
anthranilate (1989; Luger et al., Prot. Eng.
isomerase 3:249-258, 1990)
pepsin/pepsinogen Lin et al., Protein Science 4:159-
166, 1995)
glyceraldehyde-3- Vignais et al., Protein Science
phosphate dehydro- 4:994-1000, 1995)

CA 02234061 1998-04-06
W O 97/12985 PCTrUS96/lS774
genase
ornithine Li & Co~ino, Mol. Cell. Biol.
decarboxylase 13:2377-2383, 1993)
yeast Ritco-Vonsovici et al., Biochemistry
phosphoglycerate 34:165g3-16551, 1995)
dehydrogenase
Enzyme Inhibitor
basic pancreatic Goldenberg & Creighton, J. Mol.
trypsin inhibitor Biol. 165: 407-413, 1983)
Cytokines
interleukin-l~ Horlick et al., Protein Eng. 5:427-
431, 1992)
interleukin-4 Kreitman et al., Cytokine 7: 311-
318, 1995)
Tyrosine ginase
Recognition Domain
a-spectrin SH3 Viguera, et al., J.
domain Mol. Biol. 247: 670-681, 1995)
Transmembrane
Protein
omp A Koebnik & Kramer, ~. Mol. Biol.
250:617-626, 1995)
.~
3 5 Chimeric Protein

CA 02234061 1998-04-06
W O 97/1298~ PCT~US96/~5774
interleukin-4- Kreitman et al., Proc. Matl. Acad.
Pseudomonas sci . u. S.A. 91:6889-6893, 1994).
exotoxin
The results of these studies have been highly variable.
In many cases substantially lower activity, solubility or
thermodynamic stability were observed tE. coli dihydrofolate
reductase, aspartate transcarbamoylase, phosphoribosyl
anthranilate isomerase, glyceraldehyde-3-phosphate
dehydrogenase, ornithine decarboxylase, omp A, yeast
phosphoglycerate dehydrogenase). In other cases, the
sequence rearranged protein appeared to have many nearly
identical properties as its natural counterpart (basic
pancreatic trypsin inhibitor, T4 lysozyme, ribonuclease Tl,
Bacillus ~-glucanase, interleukin-l~, a-spectrin SH3 domain,
pepsinogen, interleukin-4). In exceptional cases, an
unexpected improvement over some properties of the natural
sequence w~s observed, e.g., the solubility and refolding
rate for rearranged a-spectrin SH3 domain sequences, and the
receptor affinity and anti-tumor activity of transposed
interleukin-4-Pseudomonas exotoxin fusion molecule (Kreitman
et al., Proc. Matl. Acad. Sci. U.S.~. 91:6889-6893, 1994;
Kreitman et al., Cancer Res. 55:3357-3363, 1995) .
The primary motivation for these types of studies has
been to study the role of short-range and long-range
interactions in protein folding and stability. Sequence
rearrangements of this type convert a subset of interactions
that are long-range in the original sequence into short-
range interactions in the new sequence, and vice versa. The
fact that many of these sequence rearrangements are able to
attain a conformation with at least some activity is
persuasive evidence that protein folding occurs by multiple
folding pathways tViguera, et al., J. Mol. Biol. 247:670-
681, 1995). In the case of the SH3 domain of a-spectrin,
choosing new termini at locations that corresponded to ~-

CA 0223406l l998-04-06
W O 97/12985 7 PCT~US96/15774
hairpin turns resulted in proteins with slightly less
stability, but which were nevertheless able to fold.
The positions o~ the internal breakpoints used in the
~ studies cited here are found exclusively on the surface of
proteins, and are distributed throughout the linear
sequence without any obvious bias towards the ends or the
middle (the variation in the relative distance from the
original N-terminus to the breakpoint is ca. 10 to 80% of
the total se~uence length). The linkers connecting the
original N- and C-termini in these studies have ranged from
0 to 9 residues. In one case (Yang & Schachman, Proc. Natl.
Acad . Sci . U. S.A. 90:11980-11984, 1993), a portion of
sequence has been deleted from the original C-terminal
segment, and the connection made from the truncated C-
terminus to the original M-terminus. Flexible hydrophilic
residues such as Gly and Ser are frequently used in the
linkers. Viguera, et al.(~. Mol . Biol . 247: 670-681, 1995)
compared joining the original N- and C- termini with 3- or
4-residue linkers; the 3-residue linker was less
thermodynamically stable. Protasova et al. (Protein Eng.
7:1373-1377, 1994) used 3- or 5-residue linkers in
connecting the original N-termini of E. coli dihydrofolate
reductase; only the 3-residue linker produced protein in
good yield.

CA 02234061 1998-04-06
W O 97/12985 8 PCT~US96/15774
Sllmm~rv of the Invention
Novel hematopoietic proteins o~ this invention are
represented by the formulas:
R1-L1-R2, R2-Ll-Rll Rl-R2~ or R2-R1
wherein R1 and R2 are independently selected from the
group consisting o~;
(I) A polypeptide comprising; a modified human G-CSF
amino acid sequence of the formula:
15 1 10
Xaa Xaa Xaa Gly Pro Ala Ser Ser Leu Pro Gln Ser Xaa
Leu Leu Xaa Xaa Xaa Glu Gln Val Xaa Lys Xaa Gln Gly Xaa Gly
Ala Xaa Leu Gln Glu Xaa Leu Xaa Ala Thr Tyr Lys Leu Xaa Xaa
Xaa Glu Xaa Xaa Val Xaa Xaa Gly His Ser Xaa Gly Ile Pro Trp
Ala Pro Leu Ser Ser Xaa Pro Ser Xaa Ala Leu Xaa Leu Ala Gly
Xaa Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu
90 100
Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu
110
Xaa Thr Leu Gln Xaa Asp Val Ala Asp Phe Ala Xaa Thr Ile Trp
120 130
Gln Gln Met Glu Xaa Xaa Gly Met Ala Pro Ala Leu Gln Pro Thr
140
Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Xaa Gln Xaa Xaa Ala
150 160
Gly Gly Val Leu Val Ala Ser Xaa Leu Gln Xaa Phe Leu Xaa Xaa

CA 02234061 1998-04-06
W O 97/1298~ 9 PCT~US96/15774
170
Ser Tyr Arg Val Leu Xaa Xaa Leu Ala Gln Pro (SEQ ID NO:l)
ein
Xaa at position 1 is Thr, Ser, Arg, Tyr or Gly;
Xaa at position 2 is Pro or Leu;
~ Xaa at position 3 is Leu, Arg, Tyr or Ser;
Xaa at position 13 is Phe, Ser, His, Thr or Pro;
Xaa at position 16 is Lys, Pro, Ser, Thr or His;
Xaa at position 17 is Cys, Ser, Gly, Ala, Ile, Tyr or Arg;
Xaa at position 18 is Leu, Thr, Pro, His, Ile or Cys;
Xaa at position 22 is Arg, Tyr, Ser, Thr or Ala;
Xaa at position 24 is Ile, Pro, Tyr or Leu;
Xaa at position 27 is Asp, or Gly;
Xaa at position 30 is Ala, Ile, Leu or Gly;
Xaa at position 34 is Lys or Ser;
Xaa at position 36 is Cys or Ser;
Xaa at position 42 is Cys or Ser;
Xaa at position 43 is His, Thr, Gly, Val, Lys, Trp, Ala,
Arg, Cys, or Leu;
Xaa at position 44 is Pro, Gly, Arg, Asp, Val, Ala, His,
Trp, Gln, or Thr;
Xaa at position 46 is Glu, Arg, Phe, Arg, Ile or Ala;
Xaa at position 47 is Leu or Thr;
Xaa at position 49 is Leu, Phe, Arg or Ser;
Xaa at position 50 is Leu, Ile, His, Pro or Tyr;
Xaa at position 54 is Leu or His;
Xaa at position 64 is Cys or Ser;
Xaa at position 67 is Gln, Lys, Leu or Cys;
Xaa at position 70 is Gln, Pro, Leu, Arg or Ser;
Xaa at position 74 is Cys or Ser;
Xaa at position 104 is Asp, Gly or Val;
Xaa at position 108 is Leu, Ala, Val, Arg, Trp, Gln or Gly;
Xaa at position 115 is Thr, His, Leu or Ala;
Xaa at position 120 is Gln, Gly, Arg, Lys or His
Xaa at position 123 is Glu, Arg, Phe or Thr
Xaa at position 144 is Phe, His, Arg, Pro, Leu, Gln or Glu;
Xaa at position 146 is Arg or Gln;
Xaa at position 147 is Arg or Gln;
Xaa at position 156 is His, Gly or Ser;
Xaa at position 159 is Ser, Arg, Thr, Tyr, Val or Gly;
Xaa at position 162 is Glu, Leu, Gly or Trp;
Xaa at position 163 is Val, Gly, Arg or Ala;
Xaa at position 16~ is Arg, Ser, Leu, Arg or Cys;
Xaa at position 170 is His, Arg or Ser;
wherein optionally 1-11 amino acids ~rom the N-terminus and
1-5 ~rom the C-terminus can be deleted; and

CA 02234061 1998-04-06
W O 97/12985 PCT~US96115774
wherein the N-terminus is joined to the C-terminus directly
or through a linker capable of joining the N-terminus to the
C-terminus and having new C- and N-termini at amino acids;
38-3g 62-63 123-124
39-40 63-64 124-125
40-41 64-65 125-126
41-42 65-66 126-127
42-43 66-67 128-129
43-44 67-68 128-129
45-46 68-69 129-130
48-49 69-70 130-131
49-50 70-71 131-132
52-53 71-72 132-133
53-54 91-92 133-134
54-55 92-93 134-135
55-56 93-94 135-136
56-57 94-95 136-137
57-58 95-96 137-138
58-59 96-97 138-139
59-60 97-98 139-140
60-61 98-99 140-141
61-62 99-100 141-142
or 142-143;
(II) A polypeptide comprising; a modi~ied hIL-3 amino
acid sequence of the ~ormula:
Ala Pro Met Thr Gln Thr Thr Ser Leu Lys Thr Ser Trp Val Asn
1 5 10 15
Cys Xaa Xaa Xaa Xaa Xaa xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
- 60
-

CA 0223406l l998-04-06
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Xaa Xaa Xaa Xaa X~a Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
-
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
100 105
Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
110 115 120
Xaa Xaa Xaa Gln Gln Thr Thr Leu Ser Leu Ala Ile Phe
125 130 ~SEQ ID NO:2);
wherein Xaa at position 17 is Ser, Lys, Gly, Asp, Met, Gln, or Arg;
Xaa at position 18 is Asn, His, Leu, Ile, Phe, Arg, or Gln;
Xaa at position 19 is Met, Phe, Ile, Arg, Gly, Ala, or Cys;
Xaa at position 20 is Ile, Cys, Gln, Glu, Arg, Pro, or Ala;
Xaa at positlon 21 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gln, Asn,
Thr, Ser or Val;
Xaa at position 22 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn, Gln,
Leu, Val or Gly;
Xaa at position 23 is Ile, Val, Ala, Gly, Trp, Lys, Phe,
Leu, Ser, or Arg;
Xaa at position 24 is Ile, Gly, Val, Arg, Ser, Phe, or Leu;
Xaa at position 25 is Thr, His, Gly, Gln, Arg, Pro, or Ala;
Xaa at position 26 is His, Thr, Phe, Gly, Arg, Ala, or Trp;
Xaa at position 27 is Leu, Gly, Arg, Thr, Ser, or Ala;
Xaa at position 28 is Lys, Arg, Leu, Gln, Gly, Pro, Val or Trp;
Xaa at position 29 is Gln, Asn, Leu, Pro, Arg, or Val;
Xaa at position 30 is Pro, His, Thr, Gly, Asp, Gln, Ser, Leu, or Lys;
Xaa at position 31 is Pro, Asp, Gly, Ala, Arg, Leu, or Gln;
Xaa at position 32 is Leu, Val, Arg, Gln, Asn, Gly, Ala, or Glu;
i

CA 02234061 1998-04-06
W O 97/12985 12 PCT~US96/f5774
Xaa at position 33 is Pro, Leu, Gln, Ala, Thr, or Glu;
Xaa at position 34 is Leu, Val, Gly, Ser, Lys, Glu, Gln, Thr,
Arg, Ala, Phe, Ile or Met;
Xaa at position 35 is Leu, Ala, Gly, Asn, Pro, Gln, or Val;
Xaa at position 36 is Asp, Leu, or Val;
Xaa at position 37 is Phe, Ser, Pro, Trp, or Ile;
Xaa at position 38 is Asn, or Ala;
Xaa at position 40 is Leu, Trp, or Arg;
Xaa at position 41 is Asn, Cys, Arg, Leu, His, Met, or Pro;~O Xaa at position 42 is Gly, Asp, Ser, Cys, Asn, Lys, Thr, Leu,
Val, Glu, Phe, Tyr, Ile, Met or Ala;
Xaa at position 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys,
Gln, Arg, Thr, Gly or Ser;
Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp,
Glu, Asn, Gln, Ala or Pro;
Xaa at position 45 is Gln, Pro, Phe, Val, Met, Leu, Thr, Lys,
Trp, Asp, Asn, Arg, Ser, Ala, Ile, Glu or His;
Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gln,
Lys, His, Ala, Tyr, Ile, Val or Gly;
Xaa at position 47 is Ile, Gly, Val, Ser, Arg, Pro, or His;
Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, Hi~, Phe, Glu,
Lys, Thr, Ala, Met, Val or Asn;
Xaa at position 4~ is Met, Arg, Ala, Gly, Pro, Asn, His, or Asp;
Xaa at position 50 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser,
Ala, Ile, Val, His, Phe, Met or Gln;
Xaa at position 5l is Asn, Arg, Met, Pro, Ser, Thr, or His;
Xaa at position 52 is Asn, His, Arg, Leu, Gly, Ser, or Thr;
Xaa at position 53 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Met;
Xaa at position 54 is Arg, Asp, Ile, Ser, Val, Thr, Gln, Asn,
Lys, His, Ala or Leu;
Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gly;
Xaa at position 56 i8 Pro, Gly, Cys, Ser, Gln, Glu, Arg, His,
Thr, Ala, Tyr, Phe, Leu, Val or Lys;
Xaa at position 57 is Asn or Gly;
Xaa at position 58 is Leu, Ser, Asp, Arg, Gln, Val, or Cys;

CA 0223406l l998-04-06
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Xaa at position 53 is Glu Tyr, His, Leu, Pro, or Arg;
Xaa at position 60 is Ala, Ser, Pro, Tyr, Asn, or Thr;
Xaa at position 61 is Phe, Asn, Glu, Pro, Lys, Arg, or Ser;
Xaa at position 62 is Asn, His, Val, Arg, Pro, Thr, Asp, or Ile;
Xaa at position 63 is Arg, Tyr, Trp, Lys, Ser, His, Pro, or Val;
Xaa at poslt~on 64 is Ala, Asn, Pro, Ser, or Lys;
Xaa at position 65 is Val, Thr, Pro, His, Leu, Phe, or Ser;
Xaa at position 66 is Lys, Ile, Arg, Val, Asn, Glu, or Ser;
Xaa at position 67 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His;
0 Xaa at position 68 is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His;
Xaa at position 69 is Gln, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leu;
Xaa at position 70 is Asn, Leu, Val, Trp, Pro, or Ala;
Xaa at position 71 is Ala, Met, Leu, Pro, Arg, Glu, Thr, Gln,
Trp, or Asn;
Xaa at position 72 is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp;
Xaa at position 73 is Ala, Glu, Asp, Leu, Ser, Gly, Thr, or Arg;
Xaa at position 74 is Ile, Met, Thr, Pro, Arg, Gly, Ala;
Xaa at position 75 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser,
Gln, or Leu;
Xaa at position 76 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp;
Xaa at position 77 is Ile, Ser, Arg, Thr, or Leu;
Xaa at position 78 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg;
Xaa at position 79 is Lys, Thr, Asn, Met, Arg, Ile, Gly, or Asp;
Xaa at position 80 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg;
Xaa at position 81 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys;
Xaa at position 82 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn,
His, Thr, Ser, Ala, Tyr, Phe, Ile, Met or Val;
Xaa at position 83 is Pro, Ala, Thr, Trp, Arg, or Met;
Xaa at position 84 is Cys, Glu, Gly, Arg, Met, or Val;
Xaa at position 85 is Leu, Asn, Val, or Gln;
Xaa at position 86 is Pro, Cys, Arg, Ala, or Lys;
Xaa at position 87 is Leu, Ser, Trp, or Gly;
Xaa at position 88 is Ala, Lys, Arg, Val, or Trp;
Xaa at position 89 is Thr, Asp, Cys, Leu, Val, Glu, His, Asn, or Ser;
Xaa at position 90 i5 Ala, Pro, Ser, Thr, Gly, Asp, Ile, or Met;

CA 0223406l l998-04-06
W O 97/12985 14 PCT~US96/15774
Xaa at position 91 is Ala, Pro, Ser, Thr, Phe, Leu, Asp, or His;
Xaa at position 92 is Pro, Phe, Arg, Ser, Lys, His, Ala, Gly, Ile or
Leu;
Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, or Argi
Xaa at position 94 i8 Arg, Ile, Ser, Glu, Leu, Val, Gln, Lys, His,
Ala, or Pro;
Xaa at position 95 is His, Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn,
Lys, Ser, Ala, Trp, Phe, Ile, or Tyr;
Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr;
0 Xaa at position 97 is Ile, Val, Lys, Ala, or Asn;
Xaa at position 98 is His, Ile, Asn, Leu, Asp, Ala, Thr,
Glu, Gln, Ser, Phe, Met, Val, Lys, Arg, Tyr or Pro;
Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gln,
Gly, Ser, Phe, or His;
Xaa at position 100 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Gln, or Pro;
Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Val,
Tyr, Glu, Asn, Ser, Ala, Gly, Ile, Leu, or Gln;
Xaa at position 102 is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro;
Xaa at position 103 is Asp, or Ser;
Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu,
Gln, Ly~, Ala, Phe, or Gly;
Xaa at position 105 is Asn, Pro, Ala, Phe, Ser, Trp, Gln, Tyr,
Leu, Lys, Ile, Asp, or His;
Xaa at position 106 is Glu, Ser, Ala, Lys, Thr, Ile, Gly, or Pro;
Xaa at position 108 is Arg, Lys, Asp, Leu, Thr, Ile, Gln, His, Ser,
Ala or Pro;
Xaa at position 109 is Arg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly;
Xaa at position 110 is Lys, Ala, Asn, Thr, Leu, Arg, Gln, His, Glu,
Ser, or Trp;
Xaa at position 111 is Leu, Ile, Arg, Asp, or Met;
Xaa at position 112 is Thr, Val, Gln, Tyr, Glu, His, Ser, or Phe;
Xaa at position 113 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp,
Lys, Leu, Ile, Val or Asn;
Xaa at position 114 i5 Tyr, Cys, His, Ser, Trp, Arg, or Leu;
Xaa at position 115 is Leu, Asn, Val, Pro, Arg, Ala, His, Thr,

CA 0223406l l998-04-06
W O 97/12985 15 PCT~US96/15774
Trp, or Met;
Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu,
Arg, T~p, Ser, Asn, His, Ala, Tyr, Phe, Gln, or Ile;
Xaa at position 117 is Thr, Ser, Asn, Ile, Trp, Lys, or Pro;
Xaa at position 118 is Leu, Ser, Pro, Ala, Glu, Cy~, Asp, or Tyr;
Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg;
Xaa at position 120 is Asn, Ala, Pro, Leu, His, Val, or Glni
Xaa at po~ition 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly;
Xaa at position 122 is Gln, Ser, Met, Trp, Arg, Phe, Pro, His,
Ile, Tyr, or Cys;
Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leu;
wherein optionally from 1 to 14 amino acids can be deleted
from the M-terminus and/or f-om 1 to 15 amino acids can be
deleted from the C-ter~inus; and wherein from 0 to 44 of the
amino acids designated by Xaa are di~~erent from the
corresponding amino acids of native (1-133) human
interleukin-3; and
wherein the N-terminus is joined to the C-terminus directly
or through a linker (L2) capable of joining the M-terminus
to the C-terminus and having new C- and N-termini at amino
acids;
26-27 49-50 83-84
27-28 50-51 84-85
28-29 51-52 85-86
29-30 52-53 86-87
30-31 53-54 87-88
31-32 54-55 88-89
32-33 64-65 89-90
33-3~ 65-66 90-91
34-35 66-67 91-92
35-36 67-68 92-93
36-37 68-69 97-98
37-38 69-70 98-99
38-39 70-71 99-100
39-40 71-72 100-101
40-41 72-73 101-102
41-42 82-83 102-103
or 103-104;

CA 0223406l 1998-04-06
WO 97112985 16 PCTnJS96/15774
or
(III) A polypeptide comprising; a modified human c-mpl
ligand amino aci~ sequence o~ the formula:
SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSer
1 5 10 15
10 HisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrPro
20 25 30 35
ValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGlu
40 45 50 55
ThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla
60 65 70 75
AlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGly
80 85 90 95
GlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGln~XaaXaa
100 105 110
XaaGlyArgThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHis
115 120 125 13 0
LeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysVal
135 140 145 150
ArgArgAlaProProThrThrAlaValProSerArgThrSerLeuValLeuThrLeu
155 160 165 - 170
AsnGluLeuProAsnArgThrSerGlyLeuLeUGluThrAsnPheThrAlaSerAla
35 175 180 185 190

CA 0223406l l998-04-06
W O 97/12985 17 PCT~US96/15774
ArgThrThrGlyserGlyLeuLeuLysTrpGlnGlnGlypheArgAlaLysIlepro
195 200 205
; GlyLeuLeuAsnGlnThrSerArgSerLeuAspGlnIleProGlyTyrLeuAsnArg 210 215 220 225
IleHisGlu~euLeuAsnGlyThrArgGlyLeuPheProGlyProSerArgArgThr
230 235 240 245
LeuGlyAlaProAspIleSerSerGlyThrSerAspThrGlySerLeuProProAsn
250 255 260 265
LeuGlnProGlyTyrSerProSerProThrHisProProThrGlyGlnTyrThrLeu
270 275 280 285
PheProLeuProProThrLeuProThrProValValGlnLeuHisProLeuLeuPro
290 295 300
AspProSerAlaProThrProThrProThrSerProLeuLeuAsnThrSerTyrThr
20 305 310 315 320
HisSerGlnAsnLeuSerGlnGluGly (SEQ ID NO: 3)
325 330 332
153
wherein;
Xaa at position 112 is deleted or Leu, Ala, Val, Ile, Pro,
Phe, Trp, or Met;
30- Xaa at position 113 is deleted or Pro, Phe, Ala, Val, Leu,
Ile, Trp, or Met;
Xaa at position 114 is deleted or Pro, Phe, Ala, Val, Leu,
Ile, Trp, or Met;
Xaa at position 115 iS deleted or Gln, Gly, Ser, Thr, Tyr,
3 5 or Asn; and

CA 0223406l l998-04-06
W O 97112985 PCTfUS96/15774
18
wherein the N-terminus is joined to the C-terminus directly
or through a linker tL2) capable o~ joining the N-terminus
to the C-terminus and having new C- and N-termini at amino
acids;
26-27 51-52 108-109
27-28 52-53 109-110
28-29 53-54 110-111
29-30 54-55 111-112
30-31 55-56 112-113
32-33 56-57 113-114
33-34 57-58 114-115
34-35 58-59 115-116
36-37 59-60 116-117
37-38 78-79 117-118
38-39 79-80 118-119
40-41 80-81 119-120
41-42 81-82 120-121
42-43 82-83 121-122
43-44 83-84 122-123
44-45 84-85 123-124
46-47 85-86 124-125
47-48 86-87 125-126
48-49 87-88 126-127
50-51 88-89 or 127-128;
or
10(IV) A polypeptide comprising; a modified hIL-3 amino
acid sequence o~ the ~ormula:
Ala Pro ~et Thr Gln Thr Thr Ser Leu Lys Thr ~er Trp Val Asn
151 5 10 15
Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa

CA 02234061 1998-04-06
W O 97112985 PCTfUS96/15774
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
50 55 60
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
65 70 75
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
0 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
100 105
Xaa Phe Xa~ Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
110 115 120
Xaa Xaa Xaa Gln Gln Thr Thr Leu Ser Leu Ala Ile Phe
125 130 (SEQ ID NO:2)
wherein Xaa at position 17 is Ser, Lys, Gly, Asp, Met, Gln, or Arg;
Xaa at position 18 is Asn, His, Leu, Ile, Phe, Arg, or Gln;
Xaa at position l9 is Met, Phe, Ile, Arg, Gly, Ala, or Cys;
Xaa at position 20 is Ile, Cys, Gln, Glu, Arg, Pro, or Ala;
Xaa at position 21 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gln, Asn,
Thr, Ser or Val;~5 Xaa at position 22 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn, Gln,
Leu, Val or Gly;
Xaa at position 23 is Ile, Val, Ala, Gly, Trp, Lys, Phe,
Leu, Ser, or Arg;
Xaa at position 2~ is Ile, Gly, Val, Arg, Ser, Phe, or Leu;
3Q Xaa at position 25 is Thr, His, Gly, Gln, Arg, Pro, or Ala;
Xaa at position 26 is His, Thr, Phe, Gly, Arg, Ala, or Trp;
Xaa at position 27 is Leu, Gly, Arg, Thr, Ser, or Ala;
Xaa at position 28 is Lys, Arg, Leu, Gln, Gly, Pro, Val or Trp;
Xaa at position 29 is Gln, Asn, Leu, Pro, Arg, or Val;
3~ Xaa at position 30 is Pro, His, Thr, Gly, Asp, Gln, Ser, Leu, or Lys;

CA 0223406l l998-04-06
WO 97/12985 PCT/US96/15774
Xaa at position 31 is Pro, Asp, Gly, Ala, Arg, Leu, or Gln;
Xaa at position 32 is Leu, Val, Arg, Gln, Asn, Gly, Ala, or Glu;
Xaa at position 33 is Pro, Leu, Gln, Ala, Thr, or Glu;
Xaa at posit~on 34 is Leu, Val, Gly, Ser, Lys, Glu, Gln, Thr,
Arg, Ala, Phe, Ile or Met;
Xaa at position 35 is Leu, Ala, Gly, Asn, Pro, Gln, or Val;
Xaa at position 36 is Asp, Leu, or Val;
Xaa at position 37 is Phe, Ser, Pro, Trp, or Ile;
Xaa at position 38 is Asn, or Ala;
0 Xaa at position a~o is Leu, Trp, or Arg;
Xaa at position 41 is Asn, Cys, Arg, Leu, His, Met, or Pro;
Xaa at position 4:2 is Gly, Asp, Ser, Cys, Asn, Lys, Thr, Leu,
Val, Glu, Phe, Tyr, Ile, Met or Ala;
Xaa at position 43 is Glu, Asn, Tyr, Leu, Phe, Asp, Ala, Cys,
Gln, Arg, Thr, Gly or Ser;
Xaa at position 44 is Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp,
Glu, Asn, Gln, Ala or Pro;
Xaa at position 45 is Gln, Pro, Phe, Val, Met, Leu, Thr, Lys,
Trp, Asp, Asn, Arg, Ser, Ala, Ile, Glu or His;
20 Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gln,
Lys, His, Ala, 'ryr, Ile, Val or Gly;
Xaa at position 47 is Ile, Gly, Val, Ser, Arg, Pro, or His;
Xaa at position 48 is Leu, Ser, Cys, Arg, Ile, His, Phe, Glu,
Lys, Thr, Ala, Met, Val or Asn;
25 Xaa at position 49 is Met, Arg, Ala, Gly, Pro, Asn, His, or Asp;
Xaa at position 50 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser,
Ala, Ile, Val, His, Phe, Met or Gln;
Xaa at position 51 is Asn, Arg, Met, Pro, Ser, Thr, or His;
Xaa at position 52 is Asn, His, Arg, Leu, Gly, Ser, or Thr;
30 Xaa at position 53 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Met;
Xaa at position 54 is Arg, Asp, Ile, Ser, Val, Thr, Gln, Asn,
Lys, His, Ala or Leu;
Xaa at position 55 is Arg, Thr, Val, Ser, Leu, or Gly;
Xaa at position 56 is Pro, Gly, Cys, Ser, Gln, Glu, Arg, His,
Thr, Ala, Tyr, Phe, Leu, Val or Lys;
_

CA 02234061 1998-04-06
W O 97/12985 21 PCTnJS96/15774
Xaa at position 57 is Asn or Gly;
Xaa at position 58 is Leu, Ser, Asp, Arg, Gln, Val, or Cys;
Xaa at position 59 is Glu Tyr, His, Leu, Pro, or Arg;
~ Xaa at position 60 is Ala, Ser, Pro, Tyr, Asn, or Thr;
Xaa at position 61 is Phe, Asn, Glu, Pro, hys, Arg, or Ser;
Xaa at position 62 is Asn, His, Val, Arg, Pro, Thr, Asp, or Ile;
Xaa at position 63 is Arg, Tyr, Trp, Lys, Ser, His, Pro, or Val;
Xaa at position 64 is Ala, Asn, Pro, Ser, or Lys;
Xaa at position 65 is Val, Thr, Pro, His, Leu, Phe, or Ser;
Xaa at position 66 is Lys, Ile, Arg, Val, Asn, Glu, or Ser;
Xaa at position 67 is Ser, Ala, Phe, Val, Gly, Asn, Ile, Pro, or His;
Xaa at position 68 is Leu, Val, Trp, Ser, Ile, Phe, Thr, or His;
Xaa at position 69 is Gln, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leu;
Xaa at position 70 is Asn, Leu, Val, Trp, Pro, or Ala;
Xaa at position 71 is Ala, Met, Leu, Pro, Arg, Glu, Thr, Gln,
Trp, or Asn;
Xaa at position 72 is Ser, Glu, Met, Ala, His, Asn, Arg, or Asp;
Xaa at position 73 is Ala, Glu, Asp, Leu, Ser, Gly, Thr, or Arg;
Xaa at position 74 is Ile, Met, Thr, Pro, Arg, Gly, Ala;
Xaa at position 75 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser,
Gln, or Leu;
Xaa at position 76 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp;
Xaa at position 77 is Ile, Ser, Arg, Thr, or Leu;
Xaa at position 78 is Leu, Ala, Ser, Glu, Phe, Gly, or Arg;
Xaa at position 79 is Lys, Thr, Asn, Met, Arg, Ile, Gly, or Asp;
Xaa at position 80 is Asn, Trp, Val, Gly, Thr, Leu, Glu, or Arg;
Xaa at position 81 is Leu, Gln, Gly, Ala, Trp, Arg, Val, or Lys;
Xaa at position 82 is Leu, Gln, Lys, Trp, Arg, Asp, Glu, Asn,
His, Thr, Ser, Ala, Tyr, Phe, Ile, Met or Val;
Xaa at position 83 is Pro, Ala, Thr, Trp, Arg, or Met;
Xaa at position 84 is Cys, Glu, Gly, Arg, Met, or Val;
Xaa at position 85 is Leu, Asn, Val, or Gln;
Xaa at position 86 is Pro, Cys, Arg, Ala, or Lys;
Xaa at position 87 is Leu, Ser, Trp, or Gly;
Xaa at position 88 is Ala, Lys, Arg, Val, or Trp;

CA 02234061 1998-04-06
W O 97/12985 22 PCT~US96/15774
Xaa at position 89 is Thr, A~p, Cys, Leu, Val, Glu, His, Asn, or Ser;
Xaa at position 90 is Ala, Pro, Ser, Thr, Gly, Asp, Ile, or Met;
Xaa at positlon 9l is Ala, Pro, Ser, Thr, Phe, Leu, Asp, or His;
Xaa at position 92 i5 Pro, Phe, Arg, Ser, Lys, His, Ala, Gly, Ile or
Leu;
Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leu, or Arg;
Xaa at position 94 is Arg, Ile, Ser, Glu, Leu, Val, Gln, Lys, His,
Ala, or Pro;
Xaa at position 95 is His, Gln, Pro, Arg, Val, Leu, Gly, Thr, Asn,
Lys, Ser, Ala, Trp, Phe, Ile, or Tyr;
Xaa at position 96 is Pro, Lys, Tyr, Gly, Ile, or Thr;
Xaa at position 97 is Ile, Val, Lys, Ala, or Asn;
Xaa at position 98 is His, Ile, Asn, Leu, Asp, Ala, Thr,
Glu, Gln, Ser, Phe, Met, Val, Lys, Arg, Tyr or Pro;
Xaa at position 99 is Ile, Leu, Arg, Asp, Val, Pro, Gln,
Gly, Ser, Phe, or His;
Xaa at position lO0 is Lys, Tyr, Leu, His, Arg, Ile, Ser, Gln, or Pro;
Xaa at posit:cn lQl is Asp, Pro, Met, Lys, His, Thr, Val,
Tyr, Glu, Asn, Ser, Ala, Gly, Ile, Leu, or Gln;
Xaa at position 102 is Gly, Leu, Glu, Lys, Ser, Tyr, or Pro;
Xaa at position 103 is Asp, or Ser;
Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu,
Gln, Lys, Ala, Phe, or Gly;
Xaa at position 105 is Asn, Pro, Ala, Phe, Ser, Trp, Gln, Tyr,
Leu, Lys, Ile, Asp, or His;
Xaa at position 106 is Glu, Ser, Ala, Lys, Thr, Ile, Gly, or Pro;
Xaa at position 108 is Arg, Lys, Asp, Leu, Thr, Ile, Gln, His, Ser,
Ala or Pro;
Xaa at position lO9 is Arg, Thr, Pro, Glu, Tyr, Leu, Ser, or Gly;
Xaa at position llO is Lys, Ala, Asn, Thr, Leu, Arg, Gln, His, Glu,
Ser, or Trp;
Xaa at position lll is Leu, Ile, Arg, Asp, or Met;
Xaa at position 112 is Thr, Val, Gln, Tyr, Glu, His, Ser, or Phe;
Xaa at position 113 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp,
Lys, Leu, Ile, Val or Asn;

CA 0223406l l998-04-06
W O 97/12985 23 PCTAJS96/15774
Xaa at position 114 is Tyr, Cys, His, Ser, Trp, Arg, or Leu;
Xaa at position 115 i8 Leu, Asn, Val, Pro, Arg, Ala, His, Thr,
Trp, or Met;
Xaa at position 116 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu,
Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gln, or Ile;
Xaa at po~ition 117 is Thr, Ser, A-~n, Ile, Trp, Lys, or Pro;
Xaa at position 118 is heu, Ser, Pro, Ala, Glu, Cys, Asp, or Tyr;
Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, or Arg;
Xaa at po~it on 120 is Asn, Ala, Pro, Leu, His, Val, or Gln;
0 Xaa at position 121 is Ala, Ser, Ile, Asn, Pro, Lys, Asp, or Gly;
Xaa at position 122 is Gln, Ser, Met, Trp, Arg, Phe, Pro, His,
Ile, Tyr, or Cys;
Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr, or Leui
wherein optionally from 1 to 14 amino acids can be deleted
from the N-terminus and/or from 1 to 15 amino acids can be
deleted ~rom the C-terminus; and wherein from 1 to 44 of the
amino acids designated by Xaa are different from the
corresponding amino acids of native (1-1333 human
interleukin-3
or
(V) a colony stimulating factor;
and wherein Ll is a linker capable of linking Rl to R2;
with the proviso that at least Rl or R2 is selected
from the polypeptide of formula (I) , (II), or (III); and~0
said hematopoietic protein can optionally be
immediately preceded by (methionine-l), (alanine~l) or
(methionine~2, alanine-l).
The more preferred breakpoints at which new C-
terminus and N-terminus can be made in the polypeptide (I)

CA 02234061 1998-04-06
W O 97112985 24 PCT~US96/15774
above are; 38-39, 39-40, 40-41, 41-42, 48-49, 53-54, 54-55,
55-56, 56-57, 57-58, 58-59, 59-60, 60-61, 61-62, 62-63, 64-
65, 65-66, 66-67, 67-68, 68-69, 69-70, 96-97, 125-126, 126-
127, 127-128, 128-129, 129-130, 130-131, 131-132, 132-133,
133-134, 134-13~, 135-136, 136-137, 137-138, 138-139, 13g-
140, 140-141 and 141-142.
The most preferred breakpoints at which new C-terminus
and N-terminus can be made in the polypeptide (I) above are;
38-39, 48-49, 96-97, 125-126, 132-133 and 141-142.
The more preferred breakpoints at which new C-terminus
and N-terminus can be made in the polypeptide (II) above
are; 28-29, 29-30, 30-31, 31-32, 32-33, 33-34, 34-35, 35-36,
36-37, 37-3&, 38-39, 39-40, 66-67, 67-68, 68-69, 69-70, 70-
71, 84-85, 85-86, 86-87, 87-88, 88-89, 89-90, 90-91, 98-99,
99-100, 100-101 and 101-102.
The most preferred breakpoints at which new C-terminus
and N-terminus can be made in the polypeptide (II) above
are; 34-35, 69-70 and 90-91.
The more preferred breakpoints at which new C-terminus
and N-terminus can be made in the polypeptide (III) above
or the amino acid sequence of (SEQ ID NO:256) are; 80-81,
81-82, 82-83, 83-84, 84-85, 85-86, 86-87, 108-109, 109-110,
110-111, 111-112, 112-113, 113-114, 114-115, 115-116, 116-
117, 117-118, 118-119, 119-120, 120-121, 121-122, 122-123,
123-124, 124-125, 125-126 and 126-127.
The most preferred breakpoints at which new C-terminu~
and N-terminus can be made in the polypeptide (III) above
or the amino acid sequen~e o~ (SEQ ID Mo:256) are; 81-82,
108-109, 115-116, 119-120, 122-123 and 125-126.

CA 02234061 1998-04-06
W O 97/12985 25 PCTAJS96/15774
The multi~unctional receptor agonist o~ the present
invention can also be represented by the following formula:
(Tl)a-(Ll)b-Xl-~L)C-X2-(L2)d-(T2)e
xl-(L)c-x2-(L)_yl_(L)c-y2
in which:
Xl i5 a peptide comprising an amino acid sequence
corresponding to the sequence of residues n~l through J of
the original protein having amino acids residues numbered
sequentially 1 through J with an amino terminus at residue
l;
L is an optional linker;
x2 is a peptide comprising an amino acid sequence of
residues 1 through n of the original protein;
yl is a peptide comprising an amino acid sequence
corresponding to the sequence of residues n=l through K of
the original protein having amino acids residues numbered
sequentially 1 through K with an amino terminus at residue
l;
y2 is a peptide comprising an amino acid sequence o~
residues 1 through n of the original protein;
Ll and L2 are optional peptide spacers:
n is an integer ranging from 1 to J-l;
b, c, and d are each independently 0 or 1;
a and e are either 0 or 1, provided that both a and e
cannot both be 0; and
Tl and T2 are proteins.
Additionally, the present invention relates to
recombinant expression vectors comprising nucleotide
sequences encoding the multi-functional hematopoietic
receptor agonists, related microbial expression systems, and
processes for making the multi-functional hematopoietic

CA 02234061 1998-04-06
W O 97/12985 26 PCT~US96/15774
receptor agonists. The invention also relates to
pharmaceutical compositions containing the multi-functional
hematopoietic receptor agonists, and methods ~or using the
multi-functional hematopoietic receptor agonists.
In addition to the use of the multi-~unctional
hematopoietic receptor agonists of the present invention in
vivo, it is envisioned that in vitro uses would include the
ability to stimulate bone marrow and blood cell activation
and growth be~ore infusion into patients.
_

CA 02234061 1998-04-06
W O 97/1298~ 27 PCTrUS96/15774
Br-ef Descri~tion of the Fiall~es
Figure 1 schematically illustrates the se~uence
rearrangement of a protein. The N-terminus (N) and the C-
terminus (C) of the native protein are joined through a
linker, or joined directly. The protein is opened at a
breakpoint creating a new N-terminus (new N) and a new C-
terminus (new-C) resulting in a protein with a new linear
amino acid sequence. A rearranged molecule may be
synthesized de novo as linear molecule and not go through
the steps of joining the original N-terminus and the C-
terminus and opening of the protein at the breakpoint.
Figure 2 shows a schematic of Method I, for creating
new proteins in which the original N-terminus and C-terminus
of the native protein are joined with a linker and different
M-terminus and C-terminus of the protein are created. In the
example shown the sequence rearrangement results in a new
gene encoding a protein with a new N-terminus created at
amino acid 97 of the original protein, the original C-
terminus (a.a. 174) joined to the amino acid 11 (a.a. 1- 10
are deleted) through a linker region and a new C-terminus
created at amino acid 96 of the original sequence.
Figure 3 shows a schematic of Method II, for creating
new proteins in which the original M-terminus and C-terminus
of the native protein are joined without a linker and
different N-terminus and C-terminus of the protein are
created. In the example shown the se~uence rearrangement
results in a new gene encoding a protein with a new N-
terminus created at amino acid 97 of the original protein,
the original C-terminus (a.a. 174) joined to the original N-
terminus and a new C-terminus created at amino acid 96 of
the original se~uence.

CA 02234061 1998-04-06
W O 97/12985 28 PCT~US96/15774
Figure 4 shows a schematic of Method III, for creating
new proteins in which the original N-terminus and C-terminus
of the native protein are joined with a linker and different
N-terminus and C-terminus of the protein are created. In the
example shown the se~uence rearrangement results in a new
gene encoding a protein with a new M-terminus created at
amino acid 97 of the original protein, the original C-
terminus (a.a. 174) joined to amino acid 1 through a linker
region and a new C-terminus created at amino acid 96 of the
original sequence.

CA 02234061 1998-04-06
W O 97/12985 PCTAJS96/15774
Detailed Descri~tion of the Invention
The present invention encompasses multi-functional
hematopoietic receptor agonists formed from covalently
linked polypeptides, each of which may act through a
different and specific cell receptor to initiate
complementary biological activities. Hematopoiesis re~uires
a complex series of cellular events in which stem cells
generate continuously into large populations of maturing
cells in all major lineages. There are currently at least 20
known regulators with hematopoietic proliferative activity.
Most of these proliferative regulators can ~nly stimulate
one or another type of colony formation in vitro, the
precise pattern of colony formation stimulated by each
regulator is quite distinctive. No two regulators stimulate
exactly the same pattern of colony formation, as evaluated
by colony numbers or, more importantly, by the lineage and
maturation pattern of the cells making up the developing
colonies. Proliferative responses can most readily be
analyzed in simplified in vitro culture systems. Three quite
different parameters can be distinguished: alteration in
colony size, alteration in colony numbers and cell lineage.
Two or more factors may act on the progenitor cell, inducing
the formation of larger number of progeny thereby increasing
the colony size. Two or more factors may allow increased
number of progenitor cells to proliferate either because
distinct subsets of progenitors cells exist that respond
exclusively to one factor or because some progenitors
require stimulation by two or more factors before being able
to respond. Activation of additional receptors on a cell by
the use of two or more factors is likely to enhance the
mitotic signal because of coalescence of initially differing
signal pathways into a common final pathway reaching the
nucleus ~Metcalf, Nature 339:27, 1989). Other mechanisms
.

CA 02234061 1998-04-06
W O 97/12985 PCT~US96/15774
could explain synergy. For example, if one signaling pathway
is limited by an intermediate activation of an additional
signaling pathway which is caused by a second factor, then
this may result in a super additi~e response. In some cases,
5 activation of one receptor type can induce an enhanced
expression of other receptors tMetcalf, Blood 82:3515-3523, ~
1993). Two or more factors may result in a di~ferent pattern
of cell lineages than from a single factor. The use of
multi-functional hematopoietic receptor agonists may have a
10 potential clinical advantage resulting from a proliferative
response that is not possible by any single factor.
The receptors of hematopoietic and other growth factors
can be grouped into two distinct families of related
proteins: (1) tyrosine kinase receptors, including those for
epidermal growth factor, M-CSF (Sherr, Bloo~ 75:1, 1990) and
SCF (Yarden et al., EMBO J, 6:3341, 1987): and (2)
hematopoietic receptors, not containing a tyrosine kinase
domain, but exhibiting obvious homology in their
extracellular domain (Bazan, PNAS U~A 87:6934-6938, 1990).
Included in this latter group are erythropoietin tEPo)
(D~Andrea et al., Cell ~7:277, 1989), GM-CSF (Gearing et
al., EMBO ~. 8:3667, 1989), IL-3 (Kitamura et al., Cell
66:1165, 1991), G-CSF (Fukunaga et al., J. Bio. Chem.
265:14008-15, 1990), I~-4 (~arada et al., PNAS USA 87:857,
1990), IL-5 (Takaki et al., EMBO ~. 9.4367, 1990), IL-6
(Yamasaki et al., Science 241:825, 1988), IL-7 (Goodwin et
al., Cell 60:941-51, l99G), LIF (Gearing et al., EMBO ~.
10:2839, 1991) and IL-2 (Cosman et al., Mol-Immunol. 23:
935-94, 1986). Most of the latter group of receptors exists
in a high-affinity form as heterodimers. After ligand
binding, the specific ~-~h~ing become associated with at
least one other receptor chain (~-chain, ~-chain). Many of
these factors share a common receptor subunit. The ~-ch~- n~
for GM-CS~, IL-3 and IL-5 share the same ~-chain (Kitamura
et al., Cell 66:1165, 1991), Takaki et al., EMBO ~.

CA 02234061 1998-04-06
W O 97/12985 31 PCTrUS96/15774
10:2833-8, 1991) and receptor complexes for IL-6, LIF and
L-11 share a common ~-chain ~gpl30) (Taga et al., Cell
~8:573-81, 1989; Gearing et al., Science 255:1434-7, 1992).
The receptor complexes o~ IL-2, IL-4, IL-7, IL-9 and IL-15
share a common ~-chain (Kondo et al., Science 262:1874,
1993; Russell et al., Science 266: 10~2-1045, 1993;
Noguchi et al., Science 262:1877, 1993; Giri et al., ~MBO
. 13:2822-2830, 1994).
The use of a multiply acting hematopoietic ~actor may
also have a potential advantage by reducing the demands
placed on factor-producing cells and their induction
systems. If there are limitations in the ability o~ a cell
to produce a ~actor, then by lowering the re~uired
concentrations of each of the factors, and using them in
combination may use~ully reduce demands on the ~actor-
producing cells. The use of a multiply acting hematopoietic
factor may lower the amount of the ~actors that would be
needed, probably reducing the likelihood o~ adverse side-
e~fects.
Movel compounds of this invention are represented by a
~ormula selected ~rom the group consisting o~:
R1-L1-R2, R2-L1-R1, Rl-R2/ and R2-R1
Where R1 and R2 are as defined above.
R2 is preferably a colony stimulating ~actor with a
di~ferent but complementary activity than R1. By
complementary activity is meant activity which enhances or
changes the response to another cell modulator. The R1
polypeptide is joined either directly or through a linker
segment to the R2 polypeptide. The term "directly~ defines
multi-functional hematopoietic receptor agonists in which
the polypeptides are joined without a peptide linker. Thus
L1 represents a chemical bond or polypeptide segment to
which both R1 and R2 are joined in ~rame, most commonly

CA 02234061 1998-04-06
W O 97/12985 32 PCT~US96/15774
is a linear peptide to which Rl and R2 are joined by amide
bonds linking the carboxy terminus of Rl to the amino
terminus o~- Ll and carboxy terminus of Ll to the amino
terminus of R2. By "joined in frame" is meant that there is
no translation termination or disruption between the reading
frames of the DNA encoding Rl and R2.
A non-exclusive list of other growth factors, i.e.
colony stimulating factors (CSFs), are cytokines,
lymphokines, interleukins, hematopoietic growth factors
which can be joined to (I), (II) or (III) include GM-CSF, G-
CSF, c-mpl ligand (also known as TPO or MGDF), M-CSF,
erythropoietin (EPO), IL-l, IL-4, IL-2, IL-3, IL-5, IL 6,
IL-7, IL-8, IL-9, IL-10, IL-ll, IL-12, IL-13, IL-15, LIF,
flt3/flk2 ligand, human growth hormone, s-cell growth
factor, B-cell di~ferentiation factor, eosinophil
differentiation factor and stem cell ~actor (SCF) also known
as steel factor or c-kit ligand. Additionally, this
invention encompasses the use of modified Rl or R2 molecules
or mutated or modified DNA se~uences encoding these Rl or R2
molecules. The present invention also includes multi-
functional hematopoietic receptor agonists in which Rl or R2
is an hIL-3 variant, c-mpl ligand variant, or G-CSF variant.
A /~hIL-3 variantN is de~ined as a hIL-3 molecule which has
amino acid substitutions and/or portions of hIL-3 deleted as
disclosed in WO 94/12638, WO 94/12639 and WO 95/00646, as
well as other variants known in the art. A "c-mpl ligand
variant" is defined an c-mpl ligand molecule which has amino
acid substitutions and/or portions of c-mpl ligand deleted,
disclosed in United States Application Serial Number
08/383,035 as well as other variants known in the art. A ~G-
CSF variant~ is de~ined an G-CSF molecule which has amino
acid substitutions and/or portions of G-CSF deleted, as
disclosed herein, as well as other variants known in the
art.

CA 02234061 1998-04-06
W O 97/12985 PCT~US96/15774
The linking group ~Ll) is generally a polypeptide of
between 1 and 500 amino acids in length. The linkers ~oining
the two molecules are preferably designed to (1) allow the
two molecules to fold and act independently of each other,
(2) not have a propensity for developing an ordered
secondary structure which could interfere with the
functional domains of the two proteins, (3) have m;nim~l
hydrophobic characteristics which could interact with the
functional protein domains and (4) provide steric separation
of Rl and R2 such that Rl and R2 could interact
simultaneously with their corresponding receptors on a
single cell. Typically surface amino acids in flexible
protein regions include Gly, Asn and Ser. Virtually any
permutation of amino acid sequences containing Gly, Asn and
Ser would be expected to satisfy the above criteria for a
linker sequence. Other neutral amino acids, such as Thr and
Ala, may also be used in the linker sequence. Additional
amino acids may also be included in the linkers due to the
addition of unique restriction sites in the linker se~uence
to facilitate construction of the multi-functional
hematopoietic receptor agonists.
Preferred Ll linkers of the present invention include
sequences selected from the group of ~ormulas:
(Gly3Ser)n (SEQ ID NO:4), (Gly4Ser)n (SEQ ID MO:5),
(Gly5Ser)n (SEQ ID NO:6), (GlynSer)n (SEQ ID NO:7) or
(AlaGlySer)n (SEQ ID NO:8).
One example of a highly-flexible linker is the glycine
and serine-rich spacer region present within the pIII
protein o~ the filamentous bacteriophages, e.g.
bacteriophages M13 or fd (Schaller et al., P~AS USA 72: 737-
741, 1975). This region provides a long, flexible spacer
region between two domains of the pIII surface protein. The
spacer region consists of the amino acid sequence:
GlyGlyGlySerGlyGlyGlySerGlyGlyGlySerGluGlyGlyGlySerGlu
.~

CA 02234061 1998-04-06
W O 97112985 PCTAUS96/15774
GlyGlyGlySerGluGlyGlyGlySerGluGlyGlyGlySerGlyGlyGlySer
(SEQ ID NO:9).
The present invention also includes linkers in which an
endopeptidase recognition sequence is included. Such a
cleavage site may be valuable to separate the individual
components of the multi-functional hematopoietic receptor
agonist to determine if they are properly folded and actlve
in vitro. Examples of various endopeptidases include, but
are not limited to, plasmin, enterokinase, kallikrein,
urokinase, tissue plasminogen activator, clostripain,
chymosin, collagenase, Russell's viper venom protease,
postproline cleavage enzyme, V8 protease, Thrombin and
factor Xa.
Peptide linker segments from the hinge region of heavy
chain immunoglobulins IgG, IgA, IgM, IgD or IgE provide an
angular relationship between the attached polypeptides.
Especially useful are those hinge regions where the
cysteines are replaced with serines. Preferred linkers of
the present invention include sequences derived from murine
IgG gamma 2b hinge region in which the cysteines have been
changed to serines These linkers may also include an
endopeptidase cleavage site. Examples of such linkers
include the following sequences:
IleSerGluProSerGlyProIleSerThrIleAsnProSerProProSerLys
GluSerHisLysSerPro (SEQ ID NO:10) and
IleGluGlyArgIleserGluproserGlyproIleserThrIleAsnproser
ProProSerLysGluSerHisLysSerPro (SEQ ID NO:ll).
The present invention is, however, not limited by the
form, size or number of linker sequences employed and the
only requirement of the linker is that functionally it does
not interfere with the folding and function of the
individual molecules of the multi-functional hematopoietic

CA 02234061 1998-04-06
W O 97112985 PCTrUS96/15774
receptor agonist.
Determinat~ on of the T.; ~ker L~.
The length of the amino acid sequence of the linker L2
to be used in R1 and/or R2 can be selected empirically or
with guidance ~rom structural information, or by using a
combination of the two approaches.
When no structural information is available, a small
10 series o~ linkers can be prepared for testing using a design
whose length is varied in order to span a range from 0 to 50
A and whose sequence is chosen in order to be consistent
with surface exposure (hydrophilicity, Hopp & Woods, Mol.
Immunol. 20: 483-489, 1983), Kyte & Doolittle, LJ. Mol. Biol.
157:105-132; solvent exposed surface area, Lee & Richards,
~J. Mol. Biol. 55:379-4~0, 1971) and the ability to adopt
the necessary conformation with out derangirlg the
conformation of R1 or R2 (conformationally ~lexible; Karplus
& Schulz, Naturwissenschaften 72:212-213, 1985). Assuming
an average of translation of 2.0 to 3.8 A per residue, this
would mean the length to test would be between 0 to 30
residues, with 0 to 15 residues being the preferred range.
Exemplary oE such an empirical series would be to construct
linkers using a cassette sequence such as Gly-Gly-Gly-Ser
(SEQ ID NO:12) repeated n times, where n is 1, 2, 3 or 4.
Those skilled in the art will recognize that there are many
such sequences that vary in length or composition that can
serve as linkers with the primary consideration being that
they be neither excessively long nor short (cf., Sandhu,
Critical Rev. Biotech. 12: 437-462, 1992); if they are too
long, entropy effects will likely destabilize the three-
dimensional ~old, and may also make folding kinetically
impractical, and if they are too short, they will likely
destabilize the molecule because of torsional or steric
strain.

CA 02234061 1998-04-06
W O 9711298~ 36 PCT~US96/15774
Those skilled in the analysis of protein structural
information will recognize that using the distance between
the chain ends, defined as the distance between the c-alpha ,~
carbons, can be used to define the length of the sequence to
be used, or at least to limit the number of possibilities
that must be tested in an empirical selection of linkers.
They will also recognize that it is sometimes the case that
the positions of the ends of the polypeptide chain are ill-
defined in structural models derived from x-ray di~raction
or nuclear magnetic resonance spectroscopy data, and that
when true, this situation will therefore need to be taken
into account in order to properly estimate the length of the
linker required From those residues whose positions are
well defined are selected two residues that are close in
sequence to the chain ends, and the distance between their
c-alpha carbons is used to calculate an approximate length
for a linker between them. Using the calculated length as a
guide, linkers with a range of number of residues
(calculated using 2 to 3.8A per residue) are then selected.
These linkers may be composed of the original sequence,
shortened or lengthened as necessary, and when lengthened
the additional residues may be chosen to be flexible and
hydrophilic as described above; or optionally the original
sequence may be substituted for using a series of linkers,
one example being the Gly-Gly-Gly-Ser (SEQ ID NO:12)
cassette approach mentioned above; or optionally a
combination of the original sequence and new sequence having
the appropriate total length may be used.
Determination of the Amino and Carbox~1 Termini of Rl and R~
Sequences of R1 and R2 capable of folding to
biologically active states can be prepared by appropriate

CA 02234061 1998-04-06
W O 97112985 PCT~US96/15774
37
selection ci the beginning (amino terminus) and ending
(carboxyl terminus) positions from within the original
A polypeptide chain while using the linker sequence L2 as
described above. Amino and carboxyl termini are selected
5 from within a common stretch of se~uence, referred to as a
breakpoint region, using the guidelines described below. A
novel amino acid sequence is thus generated by selecting
amino and carboxyl termini from within the same breakpoint
region. In many cases the selection o~ the new termini will
10 be such that the original position of the carboxyl terminus
immediately preceded that of the amino terminus. However,
those skilled in the art will recognize that selections of
termini anywhere within the region may func'ion, and that
these will effectively lead to either deletions or additions
15 to the amino or carboxyl portions of the new sequence.
It is a central tenet o~ molecular biology that the
primary amino acid sequence of a protein dictates folding to
the three-dimensional structure necessary for expression of
its biological function. Methods are known to those skilled
20 in the art to obtain and interpret three-~;mPnsional
structural information using x-ray diffraction of single
protein crystals or nuclear magnetic resonance spectroscopy
of protein solutions. Examples of structural information
that are relevant to the identification of breakpoint
25 regions include the location and type of protein secondary
structure (alpha and 3-10 helices, parallel and anti-
parallel beta sheets, chain reversals and turns, and loops;
Kabsch & Sander, Biopolymers 22: 2577-2637, 1983), the
degree of solvent exposure of amino acid residues, the
30 extent and type of interactions o~ residues with one another
(Chothia, Ann. Rev. Biochem. 53: 537-572, 1984) and the
static and dynamic distribution of conformations along the
polypeptide chain (Alber & Mathews, ~ethods Enzymol. 154:
511 533, 1987). In some cases additional information is
35 known about solvent exposure of residues; one example is a

CA 02234061 1998-04-06
W O 97/lZ985 3 PCT~US96/15774
site of post-translational attachment of carbohydrate which
is necessarily on the surface of the protein. When
experimental structural information is not a~ailable, or is
not feasible to obtain, methods are also available to
analyze the primary amino acid sequence in order to make
predictions of protein tertiary and secondary structure,
solvent accessibility and the occurrence o~ turns and loops.
Biochemical methods are also sometimes applicable for
empirically determining surface exposure when direct
structural methods are not feasible; for example, using the
identification of sites of chain scission following limited
proteolysis in order to infer surface exposure (Gentile
Salvatore, Eur. J. Biochem. 218:603-621, 1993)
Thus using either the experimentally derived struc~ural
information or predictive methods te.g., Srinivisan & Rose
Proteins: ~truct., Funct. & Genetics, 22: 81-99, 1995) the
parental amino acid sequence is inspected to classify
regions according to whether or not they are integral to the
maintenance of secondary and tertiary structure. The
occurrence of sequences within regions that are known to be
involved in periodic secondary structure (alpha and 3-10
helices, parallel and anti-parallel beta sheets) are regions
that should be avoided. Similarly, regions of amino acid
sequence that are observed or predicted to have a low degree
of solvent exposure are more likely to be part of the so-
called hydrophobic core of the protein and should also be
avoided for selection o~ amino and carboxyl termini. In
contrast, those regions that are known or predicted to be in
surface turns or loops, and especially those regions that
are known not to be required for biological activity, are
the preferred sites for location of the extremes of the
polypeptide chain. Continuous stretches of amino acid
sequence that are preferred based on the above criteria are
referred to as a breakpoint region.
,

CA 02234061 1998-04-06
W O 97112985 39 P~nJss6ns774
Non-covalent Multifunctional hemato~oietic qrowth f~ctors
L An alternative method for connecting two hematopoietic
growth factors is by means of a non-covalent interaction.
5 ~uch complexed proteins can be described by one of the
formulae:
R1-C1 + R2-c2; or Cl-Rl + C2-R2; Cl-R1 + R2-C2; or Cl-R1 +
R2-C2
R1 and R2 are as is defined above. Domains C1 and C2
are either identical or non-identical chemical structures,
typically ~roteinaceous, which can form a non-covalent,
specific association. Complexes between C1 and C2 result in
15 a one-to-one stoichiometric relationship between ~1 and R2
for each complex. Examples of domains which associate are
~leucine zipperN domains of transcription factors,
dimerization dom~i n~ of bacterial transcription repressors
and immunoglobulin constant domains. Covalent bonds link R
20 and C1, and R2 and C2, respectively. As indicated in the
formulae, the domains C1 and C2 can be present either at
the N-terminus or C-terminus of their corresponding
hematopoietic growth factor (R). These multimeri~ation
domains (C1 and C2) include those derived from the bZIP
25 family of proteins (Abel et al., Nature 3~1:24-25, 1989;
Landshulz et al., ~cience 240:1759-1764, 1988; Pu et al.,
Nuc. Acid Res. 21:4348-4355, 1993; Kozarides et al., Nature
336:646-651, 1988), as well as multimerization dom~;n~ of
the helix-loop-helix family of proteins (Abel et al., Nature
30 341:24-25, 1989; Murre et al., Cell 56:777-783, 1989;
Tapscott et al., Science 242: 405-411, 1988; Fisher et al.,
Genes & Dev. 5:2342-2352, 1991). Preferred multi-functional
hematopoietic receptor agonists of the present invention
include colony stimulating factors dimerized by virtue of
their incorporation as translational multi-functional

CA 02234061 1998-04-06
W O 97/12985 PCT~US96/15774
hematopoietic receptor agonists with the leucine zipper
dimerization do~i n~ of the bZIP family proteins Fos and
Jun. The leucine zipper domain of Jun is capable of
interactin~ with identical domains. On the other hand, the
leucine zipper ~m~ i n of Fos interacts with the Jun leucine
zipper domain, but does not interact with other Fos leucine
zipper domains. Mixtures of Fos and Jun predominantly
result in formation of Fos-Jun heterodimers. Consequently,
when joined to colony stimulating factors, the Jun domain
can be used to direct the formation of either homo- or
heterodimers. Preferential formation of heterodimers can be
achieved if one of the colony stimulating factor partners is
engineered to possess the Jun leucine zipper domain while
the other is engineered to possess the Fos zipper.
Additional peptide sequences may also be added to
facilitate purification or identification of multi-
functional hematopoietic receptor agonist proteins (e.g.,
poly-His). A hi~hly antigenic peptide may also be added that
would enabJ- rapid assay and facile purification of the
multi-functional hematopoietic receptor agonist protein by a
specific monoclonal antibody.
"Mutant amino acid sequence," ~mutant protein~,
"variant protein~, "mutein", or ~mutant polypeptide" refers
to a polypeptide having an amino acid sequence which varies
from a native se~uence due to amino acid deletions,
substitutions, or both, or is encoded by a nucleotide
sequence intentionally made variant from a native sequence..
"Native sequence" refers to an amino acid or nucleic acid
sequence which is identical to a wild-type or native form of
a gene or protein.
Hematcpoietic growth factors can be characterized by
their ability to stimulate colony formation by human

CA 02234061 1998-04-06
W O 97112985 41 PCT~US96~15774
hematopoietic progenitor cells. The colonies ~ormed include
erythroid, granulocyte, megakaryocyte, granulocytic
macrophages and mixtures thereof. Many of the hematopoietic
growth factors have demonstrated the ability to restore
bone marrow ~unction and peripheral blood cell populations
to therapeutically beneficial levels in studies performed
initially in primates and subsequently in humans. Many or
all of these biological activities of hematopoietic growth
factors involve signal transduction and high affinity
receptor b nding. Multi-functional hematopoietic receptor
agonists of the present invention may exhibit useful
properties such as having similar or greater biological
activity when compared to a single factor or by having
improved half-life or decreased adverse side effects, or a
combination of these properties.
Multi-functional hematopoietic receptor agonists which
have little or no agonist activity maybe useful as
antagonists, as antigens for the production of antibodies
for use in immunology or immunotherapy, as genetic probes or
as intermediates used to construct other use~ul hI~-3
muteins.
Biological activity of the multi-functional
hematopoietic receptor agonist proteins of the present
invention can be determined by DNA synthesis in factor-
dependent cell lines or by counting the colony ~orming units
in an in vitro bone marrow assay.
The multi-functional hematopoietic receptor agonists of
the present invention may have an improved therapeutic
profile as compared to single acting hematopoietic agonists.
For example, some multi-functional hematopoietic receptor
agonists of the present invention may have a si~ilar or more
potent growth factor activity relative to other
"

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W O 97/12985 42 PCTAUS96/15774
hematopoietic agonists without having a similar or
corresponding increase in side-effects.
The present invention also includes the DNA
sequences which code for the multi-functional hematopoietic
receptor agonist proteins, DNA sequences which are
substantially similar and perform substantially the same
function, and DNA sequences which differ from the DNAs
encoding the multi-functional hematopoietic receptor
agonists of the invention only due to the degeneracy of the
genetic code. Also included in the present invention are the
oligonucleotide intermediates used to construct the mutant
DNAs and the polypeptides coded for by these
oligonucleotides.
Genetic engineering techniques now standard in the art
(united States Patent 4,935,233 and Sambrook et al.,
UMolecular 'loning A Laboratory Manual", Cold Spring Harbor
Laboratory, 1989) may be used in the construction of the DNA
sequences of the present invention. One such method is
cassette mutagenesis (Wells et al., Gene 34:315-323, 1985)
in which a portion of the coding sequence in a plasmid is
replaced with synthetic oligonucleotides that encode the
desired amino acid substitutions in a portion of the gene
between two restriction sites.
Pairs of complementary synthetic oligonucleotides
encoding the desired gene can be made and annealed to each
other. The DNA sequence of the oligonucleotide would encode
sequence for amino acids of desired ~ene with the exception
of those substituted and/or deleted from the sequence.
Plasmid DNA can be treated with the chosen restriction
endonucleases then ligated to the annealed oligonucleotides.
The ligated mixtures can be used to trans~orm competent
JM101 cells to resistance to an appropriate antibiotic.
Single colonies can be picked and the plasmid DMA examined
by restriction analysis and/or DNA sequencing to identify

CA 0223406l l998-04-06
W O9~/12985 PCTnUS96/I57~4
plasmids with the desired genes.
Cloning of the DNA se~uences of the novel
multifunctional hematopoietic agonists wherein at least one
o~ the with the DNA sequence of the other colony
stimulating ~actor may be accomplished by the use of
intermediate vectors. Alternatively one gene can be cloned
directly into a vector cont~;ning the other gene. Linkers
and adapters can be used for }oining the DNA se~uences, as
well as replacing lost sequences, where a restriction site
was internal to the region of interest. Thus genetic
material (DNA) encoding one polypeptide, peptide linker, and
the other polypeptide is inserted into a suitable expression
vector which is used to transform bacteria, yeast, insect
cells or mammalian cells. The transformed organism is grown
and the protein isolated by standard techniques. The
resulting product is therefore a new protein which has a
colony stimulating factor joined by a linker region to a
second colony stimulating factor.
Another aspect of the present invention provides
plasmid DNA vectors ~or use in the expression o~ these novel
multi-~unctional hematopoietic receptor agonists. These
vectors contain the novel DNA sequences described above
which code for the novel polypeptides of the invention.
Appropriate vectors which can transform microorganisms
capable of expressing the multi-functional hematopoietic
receptor agonists include expression vectors comprising
nucleotide sequences coding for the multi-functional
hematopoietic receptor agonists joined to transcriptional
and translational regulatory sequences which are selected
according to the host cells used.
Vectors incorporating modified sequences as described
above are included in the present invention and are useful
in the production of the multi-functional hematopoietic
receptor agonist polypeptides. The vector employed in the
method also contains selected regulatory sequences in

CA 02234061 1998-04-06
W O 97/12985 P~T~US96/15774
operative association with the DNA coding sequences of the
invention and which are capable of directing the replication
and expression thereof in selected host cells.
As another aspect of the present invention, there is
provided a method for producing the novel multi-functional
hematopoietic receptor agonists. The method of the present
invention involves culturing suitable cells or cell line,
which has been transformed with a vector containing a DNA
sequence coding for expression of a novel multi-functional
hematopoietic receptor agonist. Suitable cells or cell
lines may be bacterial cells. For example, the various
strains of E. coli are well-known as host cells in the field
of biotechnolo~y. Examples of such strains include E. coli
strains JM-Q1 (Yanish-Perron et al. Gene 33: 103-119, 1985)
and MON105 (Obukowicz et al., Applied Envlronmental
Microbiology 58: 1511-1523, 1992). Also included in the
present invention is the expression of the multi-functional
hematopoietic receptor agonist protein utilizing a
chromosomal expression vector for E. coli based on the
bacteriophage Mu (Weinberg et al., Gene 126: 25-33, 1993).
Various strains of B. subtilis may also be employed in this
method. Many strains of yeast cells known to those skilled
in the art are also available as host cells for expression
of the polypeptides of the present invention. When
expressed in the E. coli cytoplasm, the gene encoding the
multi-functional hematopoietic receptor agonists of the
present invention may also be constructed such that at the
5~ end of the gene codons are added to encode Met -~la - or
Met at the N-terminus of the protein. The N termini o~
proteins made in the cytoplasm of E. coli are affected by
post-translational processing by methionine aminopeptidase
(Ben Bassat et al., ~. Bac. 169:751-757, 1987) and possibly
by other peptidases so that upon expression the methionine
is cleaved off the N-terminus. The multi-functional
hematopoietic receptor agonists of the present invention may

CA 02234061 1998-04-06
W O 97/12985 PCT~US96/15774
include multi-functionai hematopoietic receptor agonist
polypeptides having Met , Ala or Met -Ala at the N-
terminus. These mutant multi-~unctional hematopoietic
receptor agonists may also be expressed in E. coli by fusing
a secretion signal peptide to the N-terminus. This signal
peptide is cleaved from the polypeptide as part of the
secretion process.
Also suitable ~or use in the present invention are
mammalian cells, such as Chinese hams~er ovary cells (CHO).
General methods for expression of foreign genes in m~mm~lian
cells are reviewed in Kaufman, R. J., 1987) Genetic
Engineering, Principles and Methods, Vol. 9, J. K. Setlow,
editor, Plenum Press, New York. An expression vector is
constructed in which a strong promoter capable of
functioning in m~mm~l ian cells drives transcription of a
eukaryotic secretion signal peptide coding region, which is
translationally joined to the coding region for the multi-
~unctional hematopoietic receptor agonist. For example,
plasmids such as pcDNA I/Neo, pRc/RSV, and pRc/CMV (obtained
from Invitr~gen Corp., San Diego, California) can be used.
The eukaryotic secretion signal peptide coding region can be
from the gene itself or it can be from another secreted
mammalian protein (Bayne, M. L. et al., P~oc. Natl. Acad.
Sci. USA 84: 2638-2642, 1987). After construction o~ the
vector containing the gene, the vector DNA is transfected
into mammalian cells. Such cells can be, for example, the
COS7, HeLa, BHK, CHO, or mouse L lines. The cells can be
cultured, for example, in DMEM media (JRH Scientific). The
polypeptide secreted into the media can be recovered by
standard biochemical approaches following transient
expression for 24 - 72 hours after transfection of the cells
or after establishment of stable cell lines following
selection for antibiotic resistance. The selection of
suitable m~mm~l ian host cells and methods for
transformation, culture, amplification, screening and

CA 02234061 1998-04-06
W O 97/12985 46 PCTnUS96/15774
product production and puri~ication are known in the art.
See, e.g., Gething and Sambrook, Na~ure, 293:620-625,
1981), or alternatively, Kaufman et al, Mol. Cell. Biol.,
5(7):1750-1759, 1985) or Howley et al., U.S. Pat. No.
4,419,446. Another suitable m~mm~l ian cell line is the
monkey COS-1 cell line. A similarly useful mammalian cell
line is the CV-1 cell line.
Where desired, insect cells may be utilized as host
cells in the method of the present invention. See, e.g.,
Miller et al., Genetic Engineering, 8:277-298 (Plenum Press
1986) and ~eferences cited therein. In addition, general
methods for expression of foreign genes in insect cells
using Baculovirus vectors are described in: Summers, M. D.
and Smith, G. E., 1987) - A manual of methods for
Baculovirus vectors and insect cell culture procedures,
Texas Agricultural Experiment Station Bulletin No. 1555. An
expression vector is constructed comprising a Baculovirus
transfer vector, in which a strong saculovirus promoter
(such as the polyhedron promoter) drives transcription of a
eukaryotic secretion signal peptide coding region, which is
translationally joined to the coding region for the multi-
functional hematopoietic receptor agonist polypeptide. For
example, the plasmid pVL1392 (obtained from Invitrogen
Corp., San Diego, California) can be used. After
construction of the vector carrying the gene encoding the
multi-functional hematopoietic receptor a~onist polypeptide,
two micrograms of this DNA is co-transfected with one
microgram of Baculovirus DNA (see Summers & Smith, 1987)
into insect cells, strain SF9. Pure recombinant Baculovirus
carrying the multi-functional hematopoietic receptor agonist
is used to infect cells cultured, for example, in Excell 401
serum-free medium (JRH Biosciences, Lenexa, Kansas). The
multi-functional hematopoietic receptor agonist secreted
into the medium can be recovered by standard biochemical
approaches. Supernatants from mammalian or insect cells

CA 02234061 1998-04-06
W O 97/lZ985 PCT~US96/15774
expressing the multi-functional hematopoietic receptor
agonist protein can be first concentrated using any of a
number of commercial concentration units.
r
The multi-functional hematopoietic receptor agonists of
the present invention may be use~ul in the treatment of
diseases characterized by decreased levels of either
myeloid, erythroid, lymphoid, or megakaryocyte cells of the
hematopoietic system or combinations thereof. In addition,
they may be used to activate mature myeloid and/or lymphoid
cells. Among conditions susceptible to treatment with the
polypeptides of the present invention is leukopenia, a
reduction in the number of circulating leukocytes ~white
cells) in the peripheral blood. Leukopenia may be induced
by exposure to certain viruses or to radiation. It is often
a side effect of various forms of cancer therapy, e.g.,
exposure to chemotherapeutic drugs, radiation and of
infection or hemorrhage. Therapeutic treatment of
leukopenia with these multi-functional hematopoietic
receptor agonists of the present invention may avoid
undesirable side effects caused by treatment with presently
available drugs.
The multi-functional hematopoietic receptor agonists of
the present invention may be useful in the treatment of
neutropenia and, for example, in the treatment of such
- conditions as aplastic anemia, cyclic neutropenia,
idiopathic neutropenia, Chediak-Higashi syndrome, systemic
lupus erythematosus (SLE), leukemia, myelodysplastic
syndrome and myelofibrosis.
The multi-functional hematopoietic receptor agonist of
the present invention may be useful in the treatment or
prevention of thrombocytopenia. Currently the only therapy
for thrombocytopenia is platelet transfusion which are
costly and carry the significant risks of infection (HIV,
~ 35 HBV) and alloimunization. The multi-functional hematopoietic
,

CA 02234061 1998-04-06
W O 97112985 48 PCT~US96/lS774
receptor agonist may alleviate or diminish the need for
platelet transfusion. Severe thrombocytopenia may result
from genetic defects such as Fanconi's Anemia, Wiscott-
Aldrich, or May Hegglin syndromes. Acquired thrombocytopenia
may result from auto- or allo-antibodies as in Immune
Thrombocytopenia Purpura, Systemic Lupus Erythromatosis,
hemolytic anemia, or fetal maternal incompatibility. In
addition, splenomegaly, disseminated intravascular
coagulation, thrombotic thrombocytopenic purpura, infection
or prosthetic heart valves may result in thrombocytopenia.
Severe thrombocytopenia may also result from chemotherapy
and/or radiation therapy or cancer. Thrombocytopenia may
also result from marrow invasion by carcinoma, lymphoma,
leukemia or fibrosis.
The multi-functional hematopoietic receptor agonists of
the present invention may be useful in the mobilization of
hematopoietic progenitors and stem cells in peripheral
blood. Peripheral blood derived progenitors have been shown
to be effective in reconstituting patients in the setting of
autologous marrow transplantation. Hematopoietic growth
factors including ~-CSF and GM-CSF have been shown to
enhance tl~e number of circulating progenitors and stem cells
in the peripheral blood. This has simplified the procedure
for peripheral stem cell collection and dramatically
decreased the cost of the procedure by decreasing the number
of pheresis required. The multi-functional hematopoietic
receptor agonist may be useful in mobilization of stem cells
and further enhance the efficacy of peripheral s~em cell
transplantation.
The multi-functional hematopoietic receptor agonists of
the present invention may also be useful in the ex vivo
expansion of hematopoietic progenitors and stem cells.
Colony stimulating factors ~CSFs), such as hIL-3, have been

CA 02234061 1998-04-06
W O 97112985 P ~ nJS96/15774
administered alone, co-administered with other CSFs, or in
combination with bone marrow transplants subsequent to high
dose chemotherapy to treat the neutropenia and
thrombocytopenia which are often the result of such
treatment. However the period of severe neutropenia and
thrombocytopenia may not be totally eliminated. The myeloid
lineage, which is comprised of monocytes (macrophages),
granulocytes (including neutrophils) and megakaryocytes, is
critical in preventiny in~ections and bleeding which can be
life-threatening. Neutropenia and thrombocytopenia may also
be the result of disease, genetic disorders, drugs, toxins,
radiation and many therapeutic treatments such as
conventional oncology therapy.
Bone marrow transplants have been used to treat this
patient population. However, several problems are associated
with the use of bone marrow to reconstitute a compromised
hematopoietic system including: 1) the number o~ stem cells
in bone marrow, spleen, or peripheral blood is limited, 2)
Graft Versus Host Disease, 3) graft rejection and 4)
possible contamination with tumor cells. Stem cells make up
a very small percentage of the nucleated cells in the bone
marrow, spleen and peripheral blood. It is clear that a dose
response exists such that a greater number of stem cells
will enhance hematopoietic recovery. Therefore, the in vitro
expansion of stem cells should enhance hematopoietic
recovery and patient survival. Bone marrow from an
allogeneic donor has been used to provide bone marrow for
transplant. However, Graft Versus Host Disease and graft
rejection limit bone marrow transplantation even in
recipients with HLA-matched sibling donors. An alternative
to allogeneic bone marrow transplants is autologous bone
marrow transplants. In autologous bone marrow transplants,
some of the patient~s own marrow is harvested prior to
myeloablative therapy, e.g. high dose chemotherapy, and is
transplanted back into the patient afterwards. Autologous

CA 02234061 1998-04-06
W O 97/12985 5 PCT~US96/15774
transp}ants eliminate the risk of Graft Versus Host Disease
and graft rejection. However, autologous bone marrow
transplants still present problems in terms of the limited
number of stems cells in the marrow and possible
contamination with tumor cells. The limited number of stem
cells may be overcome by ex-vivo expansion of the stem
cells. In addition, stem cells can be specifically isolated,
based on the presence of speci~ic surface antigens such as
CD34+ in order to decrease tumor cell contamination of the
marrow graft.
The ~ollowing patents contain further details on
separating stem cells, CD34+ cells, culturing the cells with
hematopoietic factors, the use of ~he cells for the
treatment of patients with hematopoietic disorders and the
use of hematopoietic factors for cell expansion and gene
therapy.
5,061,620 relates to compositions comprising human
hematopoietic stem cells provided by separating the stem
cells from dedicated cells.
5,199,942 describes a method for autologous hematopoietic
cell transplantation comprising: (1) obt~i n ' ng hematopoietic
progenitor cells from a patient; (2) ex-vivo expansion of
cells with a growth factor selected from the group
consisting of IL-3, flt3 ligand, c-kit ligand, GM-CSF, IL-1,
GM-CSF~IL-3 fusion protein and combinations thereof; (3)
administering cellular preparation to a patient.
5,240,856 relates to a cell separator that includes an
apparatus for automatically controlling the cell separation
process.
WO 91/16116 describes devices and methods for selectively

CA 02234061 1998-04-06
W O 97/12985 51 PCTfUS96/15774
isolating and separating target cells ~rom a mixture of
cells.
.
WO 91/18972 describes methods for in vitro culturing o~ bone
marrow, by incubating suspension of bone marrow cells, using
a hollow ~iber bioreactor.
WO 92/18615 relates to a process for maintaining and
expanding bone marrow cells, in a culture medium containing
speci~ic mixtures o~ cytokines, for use in transplants.
WO 93/08268 describes a method for selectively expanding
stem cells, comprising the steps o~ ~a) separating CD34+
stem cells ~rom other cells and (b) incubating the separated
cells in a selective medium, such that the stem cells are
selectively expanded.
WO 93/18136 describes a process ~or in vitro support of
mammalian cells derived ~rom peripheral blood.
WO 93/18648 relates to a composi~ion comprising human
neutrophil precursor cells with a high content o~
myeloblasts and promyelocytes for treating genetic or
acquired neutropenia.
WO 94/08039 describes a method o~ enrichment ~or human
hematopoietic stem cells by selection ~or cells which
express c-kit protein.
w~ 94/11493 describes a stem cell population that are CD34+
and small in size, which are isolated using a counter~low
elutriation method.
Wo 94/27698 relates to a method combining immunoaf~inity
separation and continuous ~low centri~ugal separation ~or
.

CA 02234061 1998-04-06
W O 97/12985 S2 PCT~US96/15774
the selective separation of a nucleated heterogeneous cell
population from a heterogeneous cell mixture.
WO 94/25848 describes a cell separation apparatus for
collection and manipulation of target cells.
The long term culturing of highly enriched CD34+ precursors
of hematopoietic progenitor cells from human bone marrow in
cultures containing IL-la, IL-3, IL-6 or GM-CSF is discussed
in Brandt et al J. Clin, Invest. 86:932-941, 1990).
One aspect of the present invention provides a method for
selective ex-vivo expansion of stem cells. The term "stem
cell" refers to the totipotent hematopoietic stem cells as
well as early precursors and progenitor cells which can be
isolated from bone marrow, spleen or peripheral blood. The
term "expansion" re~ers to the differentiation and
proliferation of the cells The present invention provides a
method for selective ex-vivo expansion of stem cells,
comprising the steps of: (a) separating stem cells from
other cells, (b) culturing said separated stem cells with a
selective media which contains multi-functional
hematopoietic receptor agonist protein(s) and (c) harvesting
said stems cells. Stem cells, as well as committed
progenitor cells destined to become neutrophils,
erythrocytes, platelets, etc. may be distinguished from most
other cells by the presence or absence of particular
progenitor marker antigens, such as CD34, that are present
on the surface of these cells and/or by morphological
characteristics. The phenotype for a highly enriched human
stem cell fraction is reported as CD34+, Thy-1+ and lin-,
but it is to be understood that the present invention is not
limited to the expansion of this stem cell population. The
CD34+ enriched human stem cell fraction can be separated by
a number of reported methods, including affinity columns or

CA 02234061 1998-04-06
W O 97/12985 PCTnUS96/lS774
beads, magnetic beads or ~low cytometry using antibodies
directed to surface antigens such as the CD34+. Further,
physical separation methods such as counterflow elutriation
may be used to enrich hematopoietic progenitors. The CD34+
progenitors are heterogeneous, and may be divided into
several sub-populations characterized by the presence or
absence of co-expression o~ different lineage associated
cell sur~ace associated molecules. The most immature
progenitor cells do not express any known lineage associated
markers, s~c~h as HLA-DR or CD38, but they may express
CD90(thy-1). Other sur~ace antigens such as CD33, CD38,
CD41, CD71, HLA-DR or c-kit can also be used to selectively
isolate hematopoietic progenitors. The separated cells can
be incubated in selected medium in a culture flask, sterile
bag or in hollow fibers. Various colony stimulating ~actors
may be utilized in order to selectively expand cells.
Representative factors that have been utilized ~or ex-vivo
expansion o~ bone marrow include, c-kit ligand, IL-3, G-CSF,
GM-CSF, IL-1, IL-6, IL-ll, flt-3 ligand or combinations
thereo~. The proli~eration of the stem cells can be
monitored by enumerating the number of stem cells and other
cells, by standard techniques (e.g. hemacytometer, CFU,
LTCIC) or by flow cytometry prior and subsequent to
incubation.
Several methods ~or ex-vivo expansion of stem cells
have been reported utilizing a number o~ selection methods
and expansion using various colony stimulating ~actors
including c-kit ligand (Brandt et al., Blood 83:1507-1514
[1994], McKenna et al., Blood 86:3413-3420 [1995]), IL-3
(Brandt et al., Blood 83:1507-1514 [1994~, Sato et al.,
Blood 82:3600-3609 [1993]), G-CSF ~Sato et al., Blood
82:3600-3609 [1993]), GM-CSF (Sato et al., Blood 82:3600-
3609 [1993]), IL-l (Muench et al., Blood 81:3463-3473
[1993]), IL-6 (Sato et al., Blood 82:3600-3609 [1993]), IL-

CA 02234061 1998-04-06
W O 97/12985 PCT~US96/1~774
11 (Lemoli et al., Exp. Hem. 21:1668-1672 [1993~, Sato et
al., Blood 82:3600-3609 [lg93~), flt-3 ligand (McKenna et
al., Blood 86:3413 3420 [1995]) and/or combinations thereof
(Brandt et al., Blood 83:1507 1514 [1994], Haylock et al.,
Blood 80:1405-1412 [1992], Koller et al., Biotechnology
11:358-363 [1993], (Lemoli et al., Exp. Hem. 21:1668-1672
[1993]), McKenna et al., Blood 86:3413-3420 [1995], Muench
et al., Blood 81:3463-3473 rl993~, Patchen et al.,
Biotherapy 7:13-26 [1994], Sato et al., Blood 82:3600-3609
[1993], Smith et al., Exp. Hem. 21:870-877 [1993], Steen et
al., Stem Cells 12:214-224 [1994], Tsujino et al., Exp. Hem.
21:137g-1386 [1993]). Among the individual colony
stimulating factors, hIL-3 has been shown to be one of the
most potent in expanding peripheral blood CD34+ cells (Sato
et al., Blood 82:3600-3609 ~1993], Kobayashi et al., Blood
73:1836-1841 [1989]). However, no single factor has been
shown to be as effective as the combination of multiple
factors. The present invention p~ovides methods for ex vivo
expansion that utilize multi-functional hematopoietic
receptor agonists that are more effective than a single
factor alone.
Another aspect of the invention provides methods of
sustaining and/or expanding hematopoietic precursor cells
which includes inoculating the cells into a culture vessel
which contains a culture medium that has been conditioned by
exposure to a stromal cell line such as HS-5 (WO 96/02662,
Roecklein and Torok-Strob, Blood 85:997-1105, 1995) that has
been supplemented with a multi-functional hematopoietic
receptor agonist of the present invention.
Another projected clinical use of growth factors has
been in the in vitro activation of hematopoietic progenitors
and stem cells for gene therapy. Due to the long life-span
of hematopoietic progenitor cells and the distribution of

CA 02234061 1998-04-06
W O 97/1298~ PCTAUS96/15774
their dau~hter cells throughout the entire body,
hematopoietic progenitor cells are good candidates for ex
vivo gene transfection. In order to have the gene o~
interest incorporated into the genome of the hematopoietic
progenitor or stem cell one needs to stimulate cell divlsion
and DNA rer'ication. Hematopoietic stem cells cycle at a
very low fre~uency which means that growth factors may be
useful to promote gene transduction and thereby enhance the
clinical prospects for gene therapy. Potential applications
of gene therapy (review Crystal, Science 270: 404-410
[1995]) include; 1) the treatment o~ many congenital
metabolic disorders and immunode~iciencies (Kay and Woo,
Trends Genet. 1~ :253-257 [1994]), 2) neurological disorders
(Friedmann, Trends Genet. 10:210-214 [1994]), 3) cancer
(Culver and Blaese, Trends Genet. 10:174-178 [1994]) and 4)
infectious diseases (Gilboa and Smith, Trends Genet. 10:139-
144 [1994]).
There are a variety of methods, known to those with
skill in the art, ~or introducing genetic material into a
host cell. A number of vectors, both viral and non-viral
have been developed ~or transferring therapeutic genes into
primary cells. Viral based vectors include; 1) replication
de~icient recombinant retrovirus (Boris-Lawrie and Temin,
Curr. Opin. Genet. Dev. 3:102-109 [1993], Boris-Lawrie and
Temin, Annal. New York Acad. Sci. 716:59-71 [1994], Miller,
Current Top. Microbiol. Tmm17nol~ 158:1-24 [1992]) and
replication-de~icient recombinant adenovirus (Berkner,
BioTechniques 6:616-629 [1988], Berkner, Current Top.
Microbiol. Immunol. 158:39-66 [1992~, Brody and Crystal,
Annal. New York Acad. Sci. 716:90-103 [1994]). Non-viral
based vectors include protein/DNA complexes (Cristiano et
al., PNAS USA. 90:2122-2126 [1993], Curiel et al., PNAS USA
88:8850-8854 [1991], Curiel, Annal. New York Acad. Sci.
716:36-58 [1994]), electroporation and liposome mediated
delivery such as cationic liposomes (Farhood et al., Annal.

CA 02234061 1998-04-06
W O 97/12985 56 PCT~US96/15774
New York Acad. Sci. 71~:23-35 [1994~).
The present invention provides an improvement to the
existing methods of expanding hematopoietic cells, which new
genetic material has been introduced, in that it provides
methods utilizing multi-functional hematopoietic receptor
agonist proteins that have improved biological activity,
including an activity not seen by any single colony
stimulation factor.
Many drugs may cause bone marrow suppression or
hematopoietic deficiencies. Examples of such drugs are AZT,
DDI, alkylating agents and anti-metabolites used in
chemotherap~, antibiotics such as chloramphenicol,
penicillin, gancyclovir, daunomycin and sulfa drugs,
pheno~hiazones, tranquilizers such as meprobamate,
analgesics such as aminopyrine and dipyrone, anti-
convulsants such as phenytoin or carbamazepine, antithyroids
such as propylthiouracil and methimazole and diuretics. The
multi-functional hematopoietic receptor agonists of the
present invention may be useful in preventing or treating
the bone marrow suppression or hematopoietic deficiencies
which often occur in patients treated with these drugs.
Hematopoietic de~iciencies may also occur as a result
of viral, microbial or parasitic infections and as a result
of treatment for renal disease or renal failure, e.g.,
dialysis. The multi-functional hematopoietic receptor
agonists of the present invention may be useful in treating
such hematopoietic deficiencies.
The treatment of hematopoietic deficiency may include
administration of a pharmaceutical composition containing
the multi-functional hematopoietic receptor agonists to a
patient. The multi-functional hematopoietic receptor
agonists of the present invention may also be useful for the
activation and amplification of hematopoietic precursor
cells by treating these cells in vitro with the multi-
functional hematopoietic receptor agonist proteins of the

CA 0223406l l998-04-06
W O 97112985 PCT~US96/1~774
present invention prior to injecting the cells into a
patient.
Various immunodeficiencies, e.g., in T and/or B
lymphocytes, or immune disorders, e.g., rheumatoid
arthritis, may also be beneficially affec~ed by treatment
with the multi-functional hematopoietic receptor agonists of
the present invention. Immunodeficiencies may be the result
of viral infections, e.g., HTLVI, HTLVII, HTLVIII, severe
exposure to radiation, cancer therapy or the result of other
medical treatment. The multi-functional hematopoietic
receptor agonists of the present invention may also be
employed, alone or in combination with other colony
stimulating ~actors, in the treatment of other blood cell
deficiencies, including thrombocytopenia (platelet
deficiency), or anemia. Other uses for these novel
polypeptides are the in vivo and ex vivo treatment of
patients recovering from bone marrow transplants, and in the
developmen~ of monoclonal and polyclonal antibodies
generated by standard methods for diagnostic or therapeutic
use.
Other aspects of the present invention are methods and
therapeutic compositions for treating the conditions
referred to above. Such compositions comprise a
therapeutically effective amount of one or more of the
multi-functional hematopoietic receptor agonists of the
present invention in a mixture with a pharmaceutically
acceptable carrier. This composition can be administered
either parenterally, intravenously or subcutaneously. When
administered, the therapeutic composition for use in this
invention is preferably in the form of a pyrogen-free,
parenterally acceptable aqueous solution. The preparation
of such a parenterally acceptable protein solution, having
due regard to pH, isotonicity, stability and the like, is
within the skill of the art.
The dosage regimen involved in a method for treating

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W O 97/12985 58 PCT~US96/15774
the above-described conditions will be determined by the
attending physician considering various factors which modify
the action of drugs, e.g., the condition, body weight, sex
and diet of the patient, the severity of any infection, time
of administration and other clinical factors. Generally, a
daily regimen may be in the range of 0.2 - 150 ~g/kg of
multi-functional hematopoietic receptor agonist protein per
kilogram of body weight. Dosages would be adjusted relative
to the activity of a given multi-functional hematopoietic
receptor agonist protein and it would not be unreasonable to
note that dosage regimens may include doses as low as 0.1
microgram and as high as 1 milligram per kilogram of body
weight per day. In addition, there may exist specific
circumstances where dosages of multi-functional
hematopoietic receptor agonist would be adjusted higher or
lower than the range of 0 .2 - 15Q micrograms per kilogram o~
body weight. These include co-administration with other
colony stimulating factors or IL-3 variants or growth
factors; co-administration with chemotherapeutic drugs
and/or radiation; the use of glycosylated multi-functional
hematopoietic receptor agonist protein; and various patient-
related issues mentioned earlier in this section. As
indicated above, the therapeutic method and compositions may
also include co-administration with other human factors. A
non-exclusive list of other appropriate colony stimulating
factors (CSFs), cytokines, lymphokines, hematopoietic growth
factors and interleukins for simultaneous or serial co-
administration with the polypeptides of the present
invention includes GM-CSF, G-CSF, c-mpl ligand (also known
as TPO or MGDF), M-CSF, erythropoietin (EPO), IL-1, IL-4,
IL-2, IL-3, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-ll, IL-
12, IL-13, IL-15, IL-16, LIF, flt3/flk2 ligand, B-cell
growth factor, B-cell differentiation factor and eosinophil
differentiation factor, stem cell factor (SCF) also known as
steel factor or c-kit ligand, or combinations thereof. The

CA 02234061 1998-04-06
W O 97112985 5 PCTnUS96/15774
dosage recited above would be adjusted to compensate for
such additional components in the therapeutic composition.
Progress of the treated patient can be monitored by periodic
assessment of the hematological profile, e.g., differential
cell count and the like.
MATE~IA~S ~D METHODS
Unless noted otherwise, all specialty chemicals were
obtained ~rom Sigma, Co. (St. Louis, MO). Restriction
endonucleases and T4 DNA ligase were obtained from New
England Biolabs (Beverly, MA) or Boehringer Mannheim
(Indianapolis, IN).
~r~n~formation of E. coli strains
E. coli strains, such as DH5~ (Life Technologies,
Gaithersburg, MD) and TGl (Amersham Corp., Arlington
Heights, IL) are used for transformation of ligation
reactions and are the source of plasmid DNA for transfecting
mammalian cells. E. coli strains, such as JM101 (Yanisch-
Perron, et al., Gene, 33: 103-119, 1985) and MOM105
(Obukowicz, et al., Appl. and Envir. Micr., 58: 1511-1523,
1992) can be used for expressing the multi-functional
hematopoietic receptor agonist of the present invention in
the cytoplasm or periplasmic space.
MON105 ATCC~55204: F-, lambda-,IN(rrnD, rrE)l, rpoD+,
rpoH358
DH5~: F-, phi80dlacZdeltaM15, delta(lacZYA-argF)U169,
deoR, recAl, endAl, hsdR17(rk-,mk+), phoA, supE441amda-,
thi-1, gyrA96, relAl

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W O 97/12985 PCTfUS96/15774
TG1: delta(lac-pro), supE, thi-1, hsdD5/F' (traD36, proA+B+,
lacI~, lacZdeltaM15)
JM101 ATcc#33876: delta (pro lac), supE, thi, F~(traD36,
proA+B+, lacIq, lacZdeltaM15)
DH50~TM Subcloning efficiency cells are purchased as
competent cells and are ready for transformation using the
manufacturer's protocol, while both F~. col i strains T(~1 and
MOM105 are rendered competent to take up DNA using a CaCl2
method. Typically, 20 to 50 mL of cells are grown in LB
medium (1% bacto-tryptone, 0.5% bacto-yeast extract, 150 mM
NaCl) to a density o~ approximately 1.0 optical density unit
at 600 nanometers (OD600) as measured by a Baush & Lomb
Spectronic spectrophotometer (Rochester, NY). The cells are
collected by centrifugation and resuspended in one-fifth
culture volume of CaCl2 solution (50 rnM CaCl2, 10 mM Tris-
Cl, pH7.4) and are held at 4-C ~or 30 mirLutes. The cells
are again collected by centri~ugation and resuspended in
one-tenth culture volume of CaC12 solution. Ligated DNA is
added to 0.2 mL of these cells, and the samples are held at
4 C for 30-60 minutes. The samples are shifted to 42'C for
two minutes and 1.0 mL of LB is added prior to sha3~ing the
samples at 37 C for one hour. Cells from these samples are
spread on plates (LB medium plus 1.5% bacto-agar) containing
either ampicillin (100 micrograms/mL, ug/mL) when selecting
for ampicillin-resistant transformants, or spectinomycin (75
ug/mL) when selecting for spectinomycin-resistant
transformants. The plates are incubated overnight at 37 C.
Colonies are picked and inoculated into Ls plus
appropriate antibiotic (100 ug/mL ampicillin or 75 ug/mL
spectinomycin) and are grown at 37~C while shaking.
Methods ~or creation of ~enes with new N-terminus/C-terminus ~-

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W O 97/12985 61 PCTAUS96/1~774
Method I. Creation of genes with new N-terminus/C-terminus
which contain a linker region (L2).
Genes with new N-terminus/C-terminus which contain a
linker region (L2) separating the original C-terminus and N-
terminus can be made essentially following the method
described in L. S. Mullins, et al J. Am. Chem. Soc. 116,
5529-5533, 1994). Multiple steps of polymerase chain
reaction (PCR) amplifications are used to rearrange the DMA
sequence encoding the primary amino acid sequence of the
protein. The steps are illustrated in Figure 2.
In th~ first step, the first primer set ("new start"
and "linker start") is used to create and amplify, from the
original gene sequence, the DNA fragment ("Fragment Start )
that contains the sequence encoding the new N-terminal
portion of the new protein followed by the linker (L2) that
connects the C-terminal and N-terminal ends of the original
protein. In the second step, the second primer set (~new
stop" and 'llinker stop") is used to create and amplify, from
the original gene sequence, the DNA fragment (~Fragment
Stop") that encodes the same linker as used above, followed
by the new C-terminal portion of the new protein. The "new
start" and ~new stop~ primers are designed to include the
appropriate restriction sites which allow cloning of the new
gene into expression plasmids. Typical PCR conditions are
one cycle 95~C melting for two minutes; 25 cycles 94~C
denaturatio~ for one minute, 50~C annealing for one minute
and 72~C extension for one minute; plus one cycle 72~C
extension for seven minutes. A Perkin Elmer GeneAmp PCR
Core Reagents kit is used. A 100 ul reaction contains 100
pmole of each primer and one ug of template DNA; and lx PCR
buffer, 200 uM dGTP, 200 uM dATP, 200 uM dTTP, 200 uM dCTP,
2.5 units AmpliTaq DNA polymerase and 2 mM MgCl2. PCR
reactions are performed in a Model 480 ~NA thermal cycler
(Perkin Elmer Corporation, Norwalk, CT).

CA 02234061 1998-04-06
W O 97/12985 62 PCT~US96/15774
"Fragment Start" and "Fragment Stop", which have
complementary sequence in the linker region and the coding
sequence for the two amino acids on both sides of the
5 linker, are joined together in a third PCR step to make the
full-length gene encoding the new protein. The DNA
fragments "Fragment Start" and "Fragment Stop" are resolved
on a 19~ TAE gel, stained with ethidium bromide and isolated
using a Qiaex Gel Extraction kit (Qiagen). These fragments
10 are combined in equimolar quantities, heated at 70~C for ten
minutes and slow cooled to allow annealing through their
shared sequence in '~linker start" and "linker stop". In the
third PCR step, primers "new start" and "new stop" are added
to the annealed fragments to create and amplify the full-
15 length new N-terminus/C-terminus gene. Typical PCR
conditions are one cycle 95~C melting for two minutes; 25
cycles 94~C denaturation for one minute, 60~C annealing for
one minute and 72~C extension for one minute; plus one cycle
72~C extension for seven minutes. A Perkin Elmer GeneAmp
20 PCR Core Reagents kit is used. A 100 ul reaction contains
100 pmole o~ each primer and approximately 0.5 ug of DNA;
and lx PCR buffer, 200 UM dGTP, 200 uM dATP, 200 uM dTTP,
200 uM dCTP, 2.5 units AmpliTaq DNA polymerase and 2 mM
MgCl2. PCR reactions are purified using a Wizard PCR Preps
25 kit (Promega).
Method II. Creation of genes with new N-terminus/C-terminus
without a linker region.
New N-terminus/C-terminus genes without a linker
joining the original M-terminus and C-terminus can be made
using two steps of PCR amplification and a blunt end
ligation. rrhe steps are illustrated in Figure 3. In the
first step, the primer set ("new start" and "P-bl start") is
used to create and amplify, from the original gene sequence,

CA 02234061 1998-04-06
W O 97/12985 63 P ~ nUS96~S774
the DNA fragment ("Fragment Start") that contains the
sequence encodin~ the new M-terminal portion of the new
protein. In the second step, the primer set (~new stop~ and
~P-bl stop") is used to create and amplify, from gene
se~uence, the DNA fragment ("Fragment Stop") that contains
the sequence encoding the new C-terminal portion of the new
protein. The "new start" and "new stop" primers are designed
to include appropriate restriction sites which allow cloning
of the new gene into expression vectors. Typical PCR
conditions are one cycle 95~C melting for two minutes; 25
cycles 94~C denaturation for one minute, 50~C annealing for
45 seconds and 72~C extension ~or 45 seconds. Deep Vent
polymerase (New England Biolabs) is used to reduce the
occurrence of overhangs in conditions recommended by the
manu~acturer. The "P-bl start" and "P-bl stop" primers are
phosphorylated at the 5' end to aid in the subsequent blunt
end ligation of "Fragment Start~ and "Fragment Stop~ to each
other. A 100 ul reaction contained 150 pmole of each primer
and one ug of template DNA; and lx Vent buffer (New England
siolabs)~ 300 UM dGTP, 300 uM dATP, 300 uM dTTP, 300 uM
dCTP, and 1 unit Deep Vent polymerase. PCR reactions are
performed in a Model 480 DNA thermal cycler (Perkin Elmer
Corporation, Norwalk, CT). PCR reaction products are
puri~ied using a Wizard PCR Preps kit (Promega).
The primers are designed to include appropriate
restriction sites which allow for the cloning of the new
gene into expression vectors. Typically "Fragment Start~ is
designed to create NcoI restriction site , and "Fragment
Stop" is designed to create a HindIII restriction site.
Restriction digest reactions are puri~ied using a Magic DNA
Clean-up System kit (Promega). Fragments Start and Stop are
resolved on a 1% TAE gel, stained with ethidium bromide and
isolated using a Qiaex Gel Extraction kit (Qiagen). These
fragments are combined with and annealed to the ends of the

CA 02234061 1998-04-06
W O 97/12985 64 PCT~US96/15774
~ 3800 base pair NcoI/HindIII vector fragment of pMON3934 by
heating at 50~C for ten minutes and allowed to slow cool.
The three fragments are ligated together using Tg DNA ligase
(Boehringer Mannheim). The result is a plasmid containing
the full-length new N-terminus/C-terminus gene. A portion of
the ligation reaction is used to transform E. coli strain
DH5(X cells ~Life Technologies, Gaithersburg, MD). Plasmid
DNA is purified and sequence confirmed as below.
Method III. Creation of new N-terminus/C-terminus genes by
tandem-duplication method
New N-terminus/C-terminus genes can be made based on
the method described in R. A. Horlick, et al Protein Eng.
5:427-431, 1992). Polymerase chain reaction (PCR)
amplification of the new N-terminus/C-terminus genes is
performed using a tandemly duplicated template DNA. The
steps are illustrated in Figure 3.
The tandemly-duplicated template DNA is created by
cloning and contains two copies of the gene separated by DNA
se~uence encoding a linker connecting the original C- and N-
terminal ends of the two copies of the gene. Specific
primer sets are used to create and amplify a full-length new
N terminus/C-terminus gene from the tandemly-duplicated
template DNA. These primers are designed to include
appropriate restriction sites which allow for the cloning of
the new gene into expression vectors. Typical PCR conditions
are one cycle 95~C melting for two minutes; 25 cycles 94~C
denaturation for one minute, 50~C anneallng for one minute
and 72~C extension for one minute; plus one cycle 72~C
extension for seven minutes. A Perkin Elmer GeneAmp PCR
Core Reagents kit (Perkin Elmer Corporation, Norwalk, CT) is
used. A 100 ul reaction contains 100 pmole of each primer
and one ug of template DNA; and lx PCR buffer, 200 uM dGTP,

CA 02234061 1998-04-06
W O 97/12985 65 PCT~US96/15774
200 uM dATP, 200 uM dTTP, 200 uM dCTP, 2.5 units AmpliTaq
DNA polymerase and 2 mM MgCl2. PCR reactions are performed
in a Model 480 DNA thermal cycler (Perkin Elmer Corporation,
Norwalk, CT). PCR reactions are purified using a Wizard PCR
Preps kit (Promega).
Clo~; n~ of new N-terminus/C-terminus qenes into mulci-
functional receptor aaonist ex~ression vectors.
The new N-terminus/C-terminus gene is digested with
restriction endonucleases to create ends that are compatible
to insertion into an expression vector containing another
colony stimulating factor gene. This expression vector is
likewise digested with restriction endonucleases to form
compatible ends. A~ter purification, the gene and the
vector DMAs are combined and ligated using T4 DNA ligase. A
portion of the ligation reaction is used to trans~orm E.
coli. Plasmid DNA is purified and se~uenced to confirm the
correct insert. The correct clones are grown for protein
expression.
DNA ;~olation and characterization
Plasmid DNA can be isolated by a number of different
methods and using commercially available kits known to those
skilled in the art. A few such methods are shown herein.
Plasmid DNA is isolated using the Promega Wizard~ Miniprep
kit (Madison, WI), the Qiagen QIAwell Plasmid isolation kits
(Chatsworth, CA) or Qiagen Plasmid Midi kit. These kits
follow the same general procedure for plasmid DNA isolation.
Brie~ly, cells are pelleted by centrifugation (5000 x g),
plasmid DNA released with sequential NaOH/acid treatment,
and cellular debris is removed by centrifugation (10000 x
g). The supernatant (containing the plasmid DNA) is loaded

CA 02234061 1998-04-06
W O 97/12985 66 PCTAJS96/15774
onto a column containing a DMA-binding resin, the column is
washed, and plasmid DNA eluted with TE. After screening for
the colonies with the plasmid of interest, the E. coli cells
are inoculated into 50-100 mls of LB plus appropriate
antibiotic for overnight growth at 37~C in an air incubator
while shaking. The purified plasmid DNA is used for DNA
sequencing, further restriction enzyme digestion, additional
subcloning of DNA fragments and transfection into mammalian,
E. coli or other cells.
Se~uence confirmation.
Purified plasmid DNA is resuspended in dH2o and
quantitated by measuring the absorbance at 260/280 nm in a
Bausch and Lomb Spectronic 601 W spectrometer. DNA samples
are sequenced using ABI PRISM~ DyeDeoxy~ terminator
sequencing chemistry (Applied Biosystems Division of Perkin
Elmer Corporation, Lincoln City, CA) kits (Part Number
401388 or 402078) according to the manu~acturers suggested
protocol usually modifled by the addition of 5% DMSO to the
sequencing mixture. Sequencing reactions are performed in a
Model 480 DNA thermal cycler (Perkin Elmer Corporation,
Norwalk, CT) following the recommended amplification
conditions. Samples are purified to remove excess dye
terminators with Centri-Sep~ spin columns (Princeton
Separations, Adelphia, NJ) and lyophilized. Fluorescent dye
labeled sequencing reactions are resuspended in deionized
~ormamide, and sequenced on denaturing 4.75% polyacrylamide-
8M urea gels using an ABI Model 373A automated DNA
3C sequencer. Overlapping DNA sequence ~ragments are analyzed
and assembled into master DNA contigs using Sequencher v2.1
DNA analysis software (Gene Codes Corporation, Ann Arbor,
MI).
~ression of multi-~unctional rece~tor a~onists in
m~mm~ n cells

CA 02234061 1998-04-06
W O 97/1298~ 67 PCT~US96/15774
Mammalian Cell Transfection/Production of Conditioned Media
The B~K-21 cell line can be obtained from the ATCC
(~ockville, MD). The cells are cultured in Dulbecco~s
modified Eagle media (DMEM/high-glucose), supplemented to 2
mM (mM) L-glutamine and 10% fetal bovine serum ~FB~). This
formulation is designated BHK growth media. Selective media
is BHK growth media supplemented with 453 units/mL
hygromycin B (Calbiochem, San Diego, CA). The BHK-21 cell
line was previously stably trans~ected with the HSV
transactivating protein VP16, which transactivates the IE110
promoter ~ound on the plasmid pMoN3359 (See Hippenmeyer et
al., Bio/Technolo~y, pp.1037-1041, 1993). The VP16 protein
drives expression of genes inserted behind the IE110
promoter. BHK-21 cells expressing the transactivating
protein VP16 are designated sHK-VP16. The plasmid pMON1118
(See Highkin et al., Pou l t ry Sci ., 7 0: 970-981, 1991)
expresses ~he hygromycin resistance gene from the SV40
promoter. A similar plasmid is available from ATCC, pSV2-
hph.
BHK-VP16 cells are seeded into a 60 millimeter (mm)
tissue culture dish at 3 X 105 cells per dish 24 hours prior
to transfection. Cells are transfected for 16 hours in 3 mL
of NOPTIMEM"~ (Gibco-BRL, Gaithersburg, MD) containing 10
ug of plasmid DNA containing the gene of interest, 3 ug
hygromycin resistance plasmid, pMON1118, and 80 ug of Gibco-
BRL /~LIPOFECT~MINE"~ per dish. The media is subsequently
aspirated and replaced with 3 mL of growth media. At 48
hours post-transfection, media from each dish is collected
and assayed for activity (transient conditioned media). The
cells are removed from the dish by trypsin-EDTA, diluted
~ 1:10 and transferred to 100 mm tissue culture dishes
containing 10 mL of selective media. After approximately 7
days in selective media, resistant cells grow into colonies

CA 02234061 1998-04-06
W O 97112985 68 PCTrUS96/15774
several millimeters in diameter. The colonies are removed
from the dish with filter paper (cut to approximately the
same size as the colonies and soaked in trypsin/EDTA) and
transferred to individual wells of a 24 well plate
containing 1 mL of selective media. After the clones are
grown to confluence, the conditioned media is re-assayed,
and positive clones are expanded into growth media.
~x~ression of multi-functional rece~tor aqonists ;n E. coli
E. coll strain MON105 or JM101 harboring the plasmid of
interest are grown at 37~C in M9 plus casamino acids medium
with shaking in a air incubator Model G25 from New Brunswick
Scientific (Edison, New Jersey). Growth is monitored at
OD600 until it reaches a value of 1.0 at which time
Nalidixic acid (10 milligrams/mL) in 0.1 N NaOH is added to
a final concentration of 50 ~g/mL. The cultures are then
shaken at 37~C for three to four additional hours. A hi~h
degree of aeration is maintained throughout culture period
in order to achieve maximal production of the desired gene
product. The cells are examined under a light microscope
for the presence of inclusion bodies (IB). One mL ali~uots
of the culture are removed for analysis of protein content
by boiling the pelleted cells, treating them with reducing
buffer and electrophoresis via SDS-PAGE (see ~aniatis et al.
Molecular Cloning: A Laboratory Manual, 1982). The culture
is centrifuged (5000 x g) to pelle~ the cells.
~nclus;on Body pre~aration, Extraction, Refol~ina, Dialvsis,
D~ Chromatoaraphv, and Characterization of the mlllti-
funct;ona~ hemato~oietic ~ece~tor aaonists which accumulate
~s inclusion bodies in E. coli .
Isolation of Inclusion Bodies:
-

CA 02234061 1998-04-06
W O 97/1298~ PCTAUS96/15774
69
The cell pellet ~rom a 330 mL E. coli culture is
resuspended in 15 mL of sonication buffer (10 mM 2-amino-2-
(hydroxymethyl) 1,3-propanediol hydrochloride (Tris-HCl), pH
8.0 + 1 mM ethylenediaminetetraacetic acid (EDTA). These
- resuspended cells are sonicated using the microtip probe of
a Sonicator Cell Disruptor (Model W-375, Heat Systems-
Ultrasonics, Inc., Farmingdale, New York). Three rounds of
sonication in sonication buffer followed by centrifugation
are employed to disrupt the cells and wash the inclusion
bodies (IB). The ~irst round of sonication is a 3 minute
burst ~ollowed by a 1 minute burst, and the ~inal two rounds
of sonication are ~or 1 minute each.
Extraction and refolding of proteins from inclusion body
pellets:
Following the final centrifugation step, ~he IB pellet
is resuspended in 10 mL o~ 50 IrM Tris-HC1, p~ 9.5, 8 M urea
and 5 mM dithiothreitol (DTT) and stirred at room
temperature for approximately 45 minutes to allow for
denaturation o~ the expressed protein.
The extraction solution is transferred to a beaker
containing 70 mL of 5 mM Tris-HCl, pH 9.5 and 2.3 M urea and
25 gently stirred while exposed to air at 4~C ~or 18 to 48
hours to allow the proteins to refold. Refolding is
monitored by analysis on a Vydac (Hesperia, Ca.) C18
reversed phase high pressure liquid chromatography (RP-HPLC)
column (0.46x25 cm). A linear gradient of 40% to 65%
acetonitrile, containing 0.1% tri~luoroacetic acid (TFA), is
employed to monitor the refold. This gradient is developed
over 30 minutes at a flow rate of 1.5 mL per minute.
~ Denatured proteins generally elute later in the gradient
than the refolded proteins.

CA 02234061 1998-04-06
W O 97/12985 70 PCT~US96/15774
Purification:
Following the refold, contaminating ~. coli proteins
are removed by acid precipitation. The pH of the refold
solution is titrated to between pH 5.0 and pH 5.2 using 15%
(v/v) acetic acid (HOAc). This solution is stirred at 4~C
for 2 hours and then centrifuged for 20 minutes at 12,000 x
g to pelle~ any insoluble protein.
The supernatant from the acid precipitation step is
dialyzed using a Spectra/Por 3 membrane with a molecular
weight cut off (MWCO) of 3,50Q daltons. The dialysis is
against 2 changes of 4 liters (a 50-fold excess) of 10 mM
Tris-HCl, pH 8.0 for a total of 18 hours. Dialysis lowers
the sample conductivity and removes urea prior to DEAE
chromatography. The sample is then centrifuged (20 minutes
at 12,000 x g) to pellet any insoluble protein following
dialysis.
A Bio-Rad Bio-Scale DEAE2 column (7 x 52 mm) is used
for ion exchange chromatography. The column is equilibrated
in a buffer containing 10 mM Tris-HCl, pH 8.0, and a 0-to-
500 mM sodium chloride (NaCl) gradient, in equilibration
buf~er, over 45 column volumes is used to elute the protein.
A flow rate of 1.0 mL per minute is used throughout the run.
Column fractions (2.0 mL per fraction) are collected across
the gradient and analyzed by RP HPLC on a Vydac (~Iesperia,
Ca.) C18 column (0.46 x 25 cm). A linear gradient of 40% to
65% acetonitrile, containing 0.1% trifluoroacetic acid
(TFA), is employed. This gradient is developed over 30
minutes at a flow rate of 1.5 mL per minute. Pooled
fractions are then dialyzed against 2 changes of 4 liters
(50-to-500-fold excess) of 10 mM ammonium acetate (NH4Ac),
pH 4.0 for a total of 18 hours. Dialysis is performed using
a Spectra/Por 3 membrane with a MWCO of 3,500 daltons.
Finally, the sample is sterile filtered using a 0.22~m
syringe filter (~Star LB syringe filter, Costar, Cambridge,

CA 02234061 1998-04-06
W O 97112985 71 P~T~US96115774
Ma.), and stored at 4~C.
In some cases the folded proteins can be a~finity
purified using affinity reagents such as mAbs or receptor
subunits attached to a suitable matrix. Alternatively, (or
in addition) purification can be accomplished using any of a
- variety of chromatographic methods such as: ion exchange,
gel filtration or hydrophobic chromatography or reversed
phase HPLC.
These and other protein puri~ication methods are
described in detail in Methods in Enzymology, Volume 182
'Guide to Protein Purification' edited by Murray Deutscher,
Academic Press, San Diego, CA (1990).
15 Protein Characterization:
The purified protein is analyzed by RP-HPLC,
electrospray mass spectrometry, and SDS-PAGE. The protein
quantitation is done by amino acid composition, RP-~PLC, and
20 Bradford protein determination. In some cases tryptic
peptide mapping is performed in conjunction with
electrospray mass spectrometry to confirm the identity of
the protein.
25 ~L Proliferation Assav for Bioactive Human Interleukin-3
The factor-dependent cell line AML 193 was obtained
from the American Type Culture Collection (ATCC, Rockville,
MD). This cell line, established from a patient with acute
myelogenous leukemia, is a growth factor dependent cell line
30 which displayed enhanced growth in GM-CSF supplemented
medium (Lan~e, B., et al., Blood 70: 192, 1987; Valtieri,
M., et al., J. Immunol . 138:4042, 1987). The ability of
AML 193 cells to proliferate in the presence of human IL-3
r has also been documented. (Santoli, D., et al., J. Immunol.
35 139: 348, 1987). A cell line variant was used, AML 193

CA 02234061 1998-04-06
W O 97/12985 72 PCT~US96/15774
1.3, which was adapted for long term growth in IL-3 ~y
washing out the growth factors and starving the cytokine
dependent AML 193 cells for growth factors for 24 hours.
The cells are then replated at lx105 cells/well in a 24 well ,~
plate in media containing 100 U/mL IL-3. It took
approximately 2 months for the cells to grow rapidly in IL-
3. These cells are maintained as AML 193 1.3 thereafter by
supplementing tissue culture medium (see below) with human
IL-3
AML 193 1.3 cells are washed 6 times in cold ~anks
balanced salt solution (HBSS, Gibco, Grand Island, NY) by
centrifuging cell suspensions at 250 x g for 10 minutes
~ollowed by decantation of the supernatant. Pelleted cells
are resuspended in HBSS and the procedure is repeated until
six wash cycles are completed. Cells washed six times by
this procedure are resuspended in tissue culture medium at a
density ranging from 2 x 105 to 5 x 105 viable cells/mL.
This medium is prepared by supplementing Iscove's modified
Dulbecco's Medium (IMDM, Hazelton, Lenexa, KS) with albumin,
transferri~, lipids and 2-mercaptoethanol. Bovine albumin
(Boehringer-Mannheim, Indianapolis, IN) is added at 500
~g/mL; human transferrin (Boehringer-Mannheim, Indianapolis,
IN) is added at 100 ~g/mL; soy~ean lipid (Boehringer-
Mannheim, Indianapolis, IN) is added at 50 ~g/mL; and 2-
mercaptoethanol (Sigma, St. Louis, MO) is added at 5 x 10-5
M.
Serial dilutions of human interleukin-3 or multi-
functional hematopoietic receptor agonist proteins are made
in triplicate series in tissue culture medium supplemented
as stated above in 96 well Costar 3596 tissue culture
plates. Each well contained 50 ~l of medium containing
interleukin-3 or multi-functional hematopoietic receptor
agonist proteins once serial dilutions are completed.
Control wells contained tissue culture medium alone
~negative ccntrol). AML 193 1.3 cell suspensions prepared

CA 02234061 1998-04-06
WO 97/~2g85 PCTf'US96/lS774
as above are added to each well by pipetting 50 ~l (2.5 x
104 cells) into each well. Tissue culture plates are
incubated at 37~C with 5% CO2 in humidified air for 3 days.
On day 3, 0.5 ~Ci 3H-thymidine (2 Ci/mM, New England
Muclear, Boston, MA) is added in 50 ~l of tissue culture
medium. Cultures are incubated at 37~C with 5% CO2 in
humidified air for 18-24 hours. Cellular DNA is harvested
onto glass filter mats (Pharmacia LKB, Gaithersburg, MD)
using a TOMTEC cell harvester (TOMTEC, Orange, CT) which
utilized a water wash cycle followed by a 70% ethanol wash
cycle. Filter mats are allowed to air dry and then placed
into sample bags to which scintillation fluid (Scintiverse
II, Fisher Scientific, St. Louis, MO or BetaPlate
Scintillation Fluid, Pharmacia LKB, Gaithersburg, MD) is
added. Beta emissions of samples from individual tissue
culture wells are counted in a LKB BetaPlate model 1205
scintillation counter (Pharmacia LKB, Gaithersburg, MD) and
data is expressed as counts per minute of 3H-thymidine
incorporated into cells from each tissue culture well.
Activity of each human interleukin-3 preparation or multi-
functional hematopoietic receptor agonist protein
preparation is quantitated by measuring cell proliferation
(3H-thymidine incorporation~ induced by graded
concentrations of interleukin-3 or multi-functional
hematopoietic receptor agonist. Typically, concentration
ranges from 0.05 pM - 105 pM are quantitated in these
assays. Activity is determined by measuring the dose of
interleukin-3 or multi-functional hematopoietic receptor
agonist protein which provides 50% of maximal proliferation
(ECso = 0.5 x (maximum average counts per minute of 3H-
thymidine incorporated per well among triplicate cultures
of all concentrations of interleukin-3 tested - background
proliferation measured by 3H-thymidine incorporation
observed in triplicate cultures lacking interleukin-3).
- 35 This ECso value is also equivalent to 1 unit of bioactivity.

CA 02234061 1998-04-06
W O 97/12985 PCTAJS~6/1~774
Every assay is performed with native interleukin-3 as a
reference s~andard so that relative activity levels could be
assigned.
Typically, the multi-functional hematopoietic receptor
agonist proteins were tested in a concentration range of
2000 pM to 0.06 pM titrated in serial 2 fold dilutions.
Activity for each sample was determined by the
concentration which gave 50% of the maximal response by
fitting a four-parameter logistic model to the data. It was
observed that the upper plateau (maximal response) for the
sample and the standard with which it was compared did not
differ. Therefore relative potency calculation for each
sample was determined from EC50 estimations for the sample
and the standard as indicated above. AML 193.1.3 cells
proliferate in response to hIL-3, hGM-CSF and hG-CSF.
Therefore the following additional assays were performed for
some samples to demonstrate that the G-CSF receptor agonist
portion of the multi-functional hematopoietic receptor
agonist proteins was active. The proliferation assay was
performed with the multi-functional hematopoietic receptor
agonist plus and minus neutralizing monoclonal antibodies
to the hIL-3 receptor agonist portion. In addition, a fusion
molecule with the factor Xa cleavage site was cleaved then
purified and the halves of the molecule were assayed for
proliferative activity. These experiments showed that both
components of the multi-functional hematopoietic receptor
agonist proteins were active.
TF1 c-m~l liaand de~endent ;orQliferation assay
The c-mpl ligand proliferative activity can be assayed
usin~ a subclone of the pluripotential human cell line TF1
(Kitamura et al., J. Cell Physiol 140:323-334. [1989]). TFl
cells are maintained in h-IL3 (100 U/mL). To establish a
sub-clone responsive to c-mpl ligand, cells are maintained

CA 02234061 1998-04-06
W O 971~2g85 PCTAJS96/15774
in passage media containing 10% supernatant ~rom BHK cells
transfected with the gene expressing the 1-153 form of c-mpl
ligand (pMOM26448). Most o~ the cells die, but a subset of
cells survive. After dilution cloning, a c-mpl ligand
responsive clone is selected, and these cells are split into
passage media to a density of 0.3 x 106 cells/mL the day
prior to a~say set-up. Passage media for these cells is ~he
~ollowing: RPMI 1640 (Gibco), 10% FBS (Harlan, Lot #91206),
10% c-mpl ligand supernatant ~rom transfected sHK cells, 1
mM sodium pyruvate (Gibco), 2 mM glutamine (Gibco), and 100
ug/mL penicillin-streptomycin (Gibco). The next day, cells
are harvested and washed twice in RPMI or IMDM media with a
final wash in the ATL, or assay media. ATL medium consists
of the following:IMDM (Gibco), 500 ug/mL of bovine serum
albumin, 100 ug/mL of human transferrin, 50 ug/mL soybean
lipids, 4 x 10-8M beta-mercaptoethanol and 2 mL of A9909
(Sigma, antibiotic solution) per 1000 mL of ATL. Cells are
diluted in assay media to a final density of 0.25 x 106
cells/mL in a 96-well low evaporation plate (Costar) to a
final volume of 50 ul. Transient supernatants (conditioned
media) from transfected clones are added at a volume of 50
ul as duplicate samples at a final concentration of 50% and
diluted three-fold to a final dilution of 1.8%. Triplicate
samples of a dose curve of IL-3 variant pMON13288 starting
at 1 ng/mL and diluted using three-fold dilutions to
0.0014ng/mL is included as a positive control. Plates are
incubated at 5% CO2 and 37~ C. At day six of culture, the
plate is pulsed with 0.5 Ci of 3H/well (NEN) in a volume of
20 ul/well and allowed to incubate at 5% CO2 and 37~ C for
four hours. The plate is harvested and counted on a
Betaplate counter.
Other in vitro cell based ~roliferation assays
~ 35 Other in vitro cell based assays, known to those

CA 02234061 1998-04-06
W O 97/12985 76 PCT~US96/15774
skilled in the art, may also be useful to determine the
activity of the multi-functional hematopoietic receptor
agonists depending on the factors that comprise the molecule
in a similar manner as described in the AML 193.1.3 cell
proliferation assay. The following are examples of other
useful assays.
TF1 proliferation assay: TF1 is a pluripotential human cell
line (Kitamura et al., J. Cell Physiol 140:323-334. [1989])
that responds to hIL-3.
32D proliferation assay: 32D is a murine IL-3 dependent cell
line which does not respond to human IL-3 but does respond
to human G-CSF which is not species restricted.
Baf/3 proliferation assay: Baf/3 is a murine IL-3 dependent
cell line which does not respond to human IL-3 or human c-
mpl ligand but does respond to human G-CSF which is not
species restricted.
T1165 proliferation assay: T1165 cells are a IL-6 aependent
murine cell line (Nordan et al., 1986) which respond to IL-6
and IL-11.
Human Plasma Clot meg-CSF Assay: Used to assay megakaryocyte
colony formation activity (Mazur et al., 1981).
Tr~nqfected cçll lines:
Cell lines such as the murine Baf/3 cell line can be
transfected with a colony stimulating factor receptor, such
as the human G-CSF receptor or human c-mpl receptor, which
the cell line does not have. These transfected cell lines
can be used to determine the activity of the ligand for
which the receptor has been transfected into the cell line.
One such transfected Baf/3 cell line was made by

CA 02234061 1998-04-06
W O 97~2985 PCT~US96nS774
cloning the cDNA encoding c-mpl from a library made from a
c-mpl responsive cell line and cloned into the multiple
cloning site of the plasmid pcDNA3 (Invitrogen, San Diego
Ca.). Baf/3 cells were transfected with the plasmid via
electropora~ion. The cells were grown under G418 selection
in the presence of mouse IL-3 in Wehi conditioned media.
Clones were established through limited dilution.
In a similar manner the human G-CS~ receptor can be
transfected into the Baf/3 cell line and used to determine
the bioactivity of the multi-functional hematopoietic
receptor agoinsts.
Analysis cf c-mpl li~and proliferative activitv
Methods
1. Bone marrow proliferation assay
a. CD34~ Cell Purification:
Bone r.. arrow aspirates (15-20 mL) were obtained from
normal allogeneic marrow donors after informed consent.
Cells were diluted 1:3 in phosphate buffered saline (PBS,
Gibco-BRL), 30 mL were layered over 15 mL Histopaque-1077
(Sigma) and centrifuged for 30 minutes at 300 RCF. The
mononuclear interface layer was collected and washed in PBS.
CD34+ cells were enriched from the mononuclear cell
p~eparation using an affinity column per manufacturers
instructions (CellPro, Inc, Bothell WA). After enrichment,
the purity of CD34+ cells was 70% on average as determined
by using flow cytometric analysis using anti-CD34 monoclonal
antibody conjugated to fluorescein and anti-CD38 conjugated
to phycoery~hrin (Becton Dickinson, San ~ose CA).
Cells were resuspended at 40,000 cells/mL in X-Vivo 10
media (Bio-whittaker~ Walkersville, MD) and 1 mL was plated
~ 35 in 12-well tissue culture plates (Costar). The growth
_

CA 02234061 1998-04-06
W O 97/12985 78 PCTrUS9611~774
factor rhIL-3 was added at 100 ng/mL (pMON5873) was added to
some wells. hIL3 variants were used at 10 ng/mL to 100
ng/mL. Conditioned media from BHK cells transfected with
plasmid encoding c-mpl ligand or multi-~unctional
5 hematopoietic receptor agonists were tested by addition of
100 ~1 of supernatant added to 1 mL cultures (approximately
a 10% dilution). Cells were incubated at 37~C ~or 8-14 days
at 5% CO2 in a 37~C humidified incubator.
b. Cell Harvest and Analysis:
At the end of the culture period a total cell count was
obtained ~or each condition. For ~luorescence analysis and
ploidy determination cells were washed in megakaryocyte
buffer (MK buffer, 13.6 mM sodium citrate, 1 mM
theophylline, 2.2 ~lm PGEl, 11 mM glucose, 3% w/v BSA, in
PBS, pH 7.4,) (Tomer et al., Blood 70: 1735-1742, 19~7)
resuspended in 500 ,ul of MK buffer containing anti-CD41a
FITC antibody (1:200, AMAC, Westbrook, ME) and washed in MK
buffer. For DNA analysis cells were permeablized in MK
bu~er containing 0.5% Tween 20 ~Fisher, ~air Lawn MJ)for 20
min. on ice ~ollowed by fixation in 0.5% Tween-20 and 196
paraformaldehyde (Fisher Chemical) ~or 30 minutes followed
by incubation in propidium iodide ~Calbiochem, La Jolla Ca)
(50 ,Ug/mL) with RNA-ase (400 U/mL) in 55% v/v MK bu~fer
(200mOsm) for 1-2 hours on ice. Cells were analyzed on a
FACScan or Vantage flow cytometer ~Becton Dickinson, San
Jose, CA~. Green ~luorescence (CD41a-FITC) was collected
along with linear and log signals for red ~luorescence (PI)
to determine DNA ploidy. All cells were collected to
determine the percent of cells that were CD41+. Data
analysis was performed using software by LYSIS (Becton
Dickinson, San Jose, CA). Percent of cells expressing the
CD41 antigen was obtained from ~low cytometry
analysis(Percent). Absolute (Abs) number o~ CD41+ cells/mL
was calculated by: (Abs)=(Cell Count)*(Percent)/100.
_

CA 0223406l l998-04-06
W O 97/12985 PCT~US96/I5774
2. Megakaryocyte fibrin clot assay.
CD34+ enriched population were isolated as described above.
Cells were suspended at 25,000 cells/mL with or without
cytokine(s) in a media consisting of a base Iscoves IMDM
media supplemented with 0.3% B~A, 0.4mg/mL apo-transferrin,
6.67~M FeC12, 25~g/mL CaC12, 25~g/mL L-asparagine, 500~g/mL
~-amino-n-caproic acid and penicillin/streptomycin. Prior
to plating into 35mm plates, thrombin was added (0.25
Units/mL) to initiate clot formation. Cells were incubated
at 37~C for 13 days at 5% CO2 in a 37~C humidified
incubator.
At the end o~ the culture period plates were ~ixed with
methanol:acetone (1:3), air dried and stored at -200C until
staining. A peroxidase immunocytochemistry staining
procedure ~s used (Zymed, Histostain-SP. San Francisco, CA)
using a cocktail of primary monoclonal antibodies consisting
o~ anti-CD41a, CD42 and CD61. Colonies were counted after
staining and classified as negative, CFU-MK (small colonies,
1-2 foci and less that approx. 25 cells), BFU-MK (large,
multi-foci colonies with > 25 cells) or mixed colonies
(mixture of both posi~ive and negative cells.
Methvlcellulose Assa~
This assay reflects the ability o~ colony stimulating
factors to stimulate normal bone marrow cells to produce
different types of hematopoietic colonies in vitro (Bradley
et al., Aust. Exp Biol. Sci. 44:287-300, 1966), Pluznik et
al., J. Cell Comp. Physio 66:319-324, 1965).
Methods
Approximately 30 mL o~ fresh, normal, healthy bone marrow

CA 02234061 1998-04-06
W O 97112985 80 PCT~US96/15774
aspirate are obtained from individuals following informed
consent. Under sterile conditions samples are diluted 1:5
with a lX PBS (#14040.059 Li~e Technologies, ~aithersburg,
MD.) solution in a 50 mL conical tube (~25339-50 Corning, ,~
Corning MD). Ficoll (Histopaque 1077 Sigma H-8889) is
layered under the diluted sample and centrifuged, 300 x g
for 30 min. The mononuclear cell band is removed and washed
two times in lX PBS and once with 1~ BSA PBS (CellPro Co.,
Bothel, WA!. Mononuclear cells are counted and CD34+ cells
are selected using the Ceprate LC (CD34) Kit (CellPro Co.,
Bothel, WA) column. This fractionation is performed since
all stem and progenitor cells within the bone marrow display
CD34 surface antigen.
Cultures are set up in triplicate with a final volume of 1.0
mL in a 35 X 10 mm petri dish (Nunc#174926). Culture
medium is purchased from ~erry Fox Labs. (HCC-4230 medium
(Terry Fox Labs, Vancouver, s.C., Canada) and erythropoietin
(Amgen, Thousand oaks, CA.) is added to the culture media.
3,000-10,000 CD34+ cells are added per dish. Recombinant IL-
3, purified from mammalian cells or E. coli, and multi-
functional hematopoietic receptor agonist proteins, in
conditioned media from trans~ected mammalian cells or
purified from conditioned media from transfected m~mm~l ian
cells or ~. coli, are added to give final concentrations
ranging from .001 nM to 10 nM. Recombinant hIL-3, GM-CSF,
c-mpl ligand and multi-functional hematopoietic receptor
agonist are supplied in house. G-CSF (Neupogen) is from
Amgen (Thousand Oaks Calf.). Cultures are resuspended using
a 3cc syringe and 1.0 mL is dispensed per dish. Control
(baseline response) cultures received no colony stimulating
factors. Positive control cultures received conditioned
media (PHA stimulated human cells: Terry Fox ~ab. H2400).
Cultures are incubated at 37~C, 5% CO2 in humidified air.
Hematopoietic colonies which are defined as greater than 50

CA 0223406l l998-04-06
W O 97/12985 81 PCTnUS96~lS774
cells are counted on the day of peak response ~days 10-11)
using a Nikon inverted phase microscope with a 40x objective
combination. Groups of cells containing fewer than 50 cells
are referred to as clusters. Alternatively colonies can be
identified by spreading the colonies on a slide and stained
or they can be picked, resuspended and spun onto cytospin
slides for staining.
Hl~m~n Cord Blood Hemopoietic Growth Factor AssaYs
Bone marrow cells are traditionally used for in vitro assays
of hematopoietic colony stimulating factor (CSF) activity.
However, human bone marrow is not always available, and
there is considerable variability between donors. Umbilical
cord blood is comparable to bone marrow as a source of
hematopoietic stem cells and progenitors (Broxmeyer et al.,
PNAS USA 89:4109-113, 1992; Mayani et al., Blood 81:3252-
3258, 1993). In contrast to bone marrow, cord blood is more
readily available on a regular basis. There is also a
potential to reduce assay variability by pooling cells
obtained fresh from several donors, or to create a bank of
cryopreserved cells for this purpose. By modifying the
culture conditions, and/or analyzing for lineage specific
markers, it is be possible to assay specifically for
granulocyte / macrophage colonies (CFU-GM), for
megakaryocyte CSF activity, or for high proliferative
potential colony forming cell (HPP-CFC) activity.
Methods
Mononuclear cells (MNC) are isolated from cord blood within
24 hr. of collection, using a standard density gradient
(1.077 g/mL Histopaque). Cord blood MNC have been further
enriched for stem cells and progenitors by several
procedures, including immunomagnetic selection for CD14-,
CD34+ cells; panning for SBA-, CD34+ fraction using coated

CA 02234061 1998-04-06
W O 97/12985 82 PCTAUS96/15774
flasks from Applied Immune Science (Santa Clara, CA); and
CD34+ selection using a CellPro (Bothell, WA) avidin column.
Either freshly isolated or cryopreserved CD34+ cell enriched
fractions are used for the assay. Duplicate cultures for
each serial dilution of sample (concentration range from 1
pM to 1204 pM) are prepared with lx104 cells in lml of 0.9%
methycellulose containing medium without additional growth
factors (Methocult H4230 from Stem Cell Technologies,
Vancouver, BC.). In some experiments, Methocult H4330
containing erythropoietin (EPO) was used instead of
Methocult H4230, or Stem Cell Factor ~SCF), 50 ng/mL
(Biosource International, Camarillo, CA) was added. After
culturing for 7-9 days, colonies containing >30 cells are
counted. In order to rule out subjective bias in scoring,
assays are scored blind.
Additional details about recombinant DMA methods
which may be used to create the variants, express them in
bacteria, m~mm~l ian cells or insect cells, purification and
refold of the desired proteins and assays for determining
the bioactvity of the proteins may be found in co-filed
Applications WO 95/00646, WO 94/12639, WO 94/12638, WO
95/20976, WO 95/21197, WO 95/20977, WO 95/21254 and US
08/383,035 which are hereby incorporated by reference in
their entirety.
Further details known to those skilled in the art may
be found in T. Maniatis, et al., Molecular Clonin~, A
T~hor~torv Manual, Cold Spring Harbor Laboratory, 1982) and
references cited therein, incorporated herein by referencei
and in J. Sambrook, et al., Molecular CloPina, A Laboratorv
Ma~~ , 2nd edition, Cold Spring Harbor Laboratory, 1989)
and references cited therein, incorporated herein by
reference.

CA 02234061 1998-04-06
W O 97/12985 83 PCTnUS96~5774
TART.~ 1
OTlTGoNucLEoTID~s
c-mplNcoI
ACGTCCATGGCMTCNCCNGCNCCNCCTGCTTGTGCACTCCGAGTC
(SEQ ID NO:13)
N=A,C,G or T
Ecompl ATGCACGAATTCCCTGACGCAGAGGGTGGA
(SEQ ID NO:14)
c-mplHindIII TGACAAGCTTACCTGACGCAGAGGGTGGACCCT
(SEQ ID MO:15)
4L-5' AATTCGGCAA (SEQ ID NO:16)
4L-3' CATGTTGCCG (SEQ ID NO:17)
20 5L-5' AATTCGGCGGCAA ~SEQ ID NO:18)
5L-3' CATGTTGCCGCCG (SEQ ID NO:19)
8L-5' AATTCGGCGGCAACGGCGGCAA ~SEQ ID No:20)
8L-3' CATGTTGCCGCCGTTGCCGCCG (SEQ ID NO:21)
31-5' CGATCCATGGAGGTTCACCCTTTGCCT (SEQ ID No:22)
30 31-3' GATCAAGCTTATGGGCACTGGCTCAGTCT (SEQ ID No:23)
35-5' CGATACATGTTGCCTACACCTGTCCTG (SEQ ID NO:24)
35-3' GATCAAGCTTAAGGGTGAACCTCTGGGCA (SEQ ID NO:25)
39-5' CGATCCATGGTCCTGCTGCCTGCTGTG (SEQ ID NO:26)
39-3' GATCAAGCTTAAGGTGTAGGCAAAGGGTG (SEQ ID NO:27)
40 43-5' CGATCCATGGCTGTGGACTTTAGCTTGGGA
(SEQ ID NO:28)
43-3' GATCAAGCTTAAGGCAGCAGGACAGGTGT (SEQ ID No:29)
45 45-5' CGATCCATGGACTTTAGCTTGGGAGAA (SEQ ID NO:30)
45-3' GATCAAGCTTACACAGCAGGCAGCAGGAC (SEQ ID NO:31)
49-5' CGATCCATGGGAGAATGGAAAACCCAG (SEQ ID NO:32)
49-3' GATCAAGCTTACAAGCTAAAGTCCACAGC (SEQ ID NO:33)

CA 02234061 1998-04-06
W O 97/1298~ 84 PCTfUS96/15774
82-5' CGATCCATGGGACCCACTTGCCTCTCA ~SEQ ID NO:34)
82-3' GATCAAGCTTACAGTTGTCCCCGTGCTGC (SEQ ID NO:35)
109-5/ CAGTCCATGGGAACCCAGCTTCCTCCA (SEQ ID NO:36)
109-3' GATCAAGCTTAAAGGAGGCTCTGCAGGGC (SEQ ID NO:37)
10 116-5' CGATCCATGGGCAGGACCACAGCTCAC (SEQ ID NO:38)
116-3' GATCAAGCTTACTGTGGAGGAAGCTGGGTT
(SEQ ID NO:39)
15 120-5' CGATCCATGGCTCACAAGGATCCCAATGCC
(SEQ ID NO:40)
120-3~ GATCAAGCTTATGTGGTCCTGCCCTGTGG (SEQ ID NO:41)
20 123-5' CGATCCATGGATCCCAATGCCATCTTCCTG
(SEQ ID NO:42)
123-3' GATCAAGCTTACTTGTGAGCTGTGGTCCT (SEQ ID MO:43)
25 126-5' CGATCCATGGCCATCTTCCTGAGCTTCCAA
(SEQ ID No:44)
126-3' GATCAAGCTTAATTGGGATCCTTGTGAGCTGT
(SEQ ID NO:45)
SYNNOXAl.REQ AATTCCGTCG TAAACTGACC TTCTATCTGA AAACCTTGGA
GAACGCGCAG GCTCAACAGT ACGTAGAGGG CGGTGGAGGC
TCC (SEQ ID No:46)
~5 SYNNOXA2.REQ CCGGGGAGCC TCCACCGCCC TCTACGTACT GTTGAGCCTG
CGCGTTCTCC AAGGTTTTCA GATAGAAGGT CAGTTTACGA
CGG (SEQ ID No:47)
Llsyn.~or GTTACCCTTG AGCAAGCGCA 'GGAACAACAG GGTGGTGGCT
CTAACTGCTC TATAATGAT (SEQ ID NO:48)
Llsyn.rev CGATCATTAT AGAGCAGTTA GAGCCACCAC CCTGTTGTTC
CTGCGCTTGC TCAAGG (SEQ ID NO:49)
45 L3syn.for GTTACCCTTG AGCAAGCGCA GGAACAACAG GGTGGTGGCT
CTGGCGGTGG CAGCGGCGGC GGTTCTAACT GCTCTATAAT
GAT (SEQ ID NO:50)
L3syn.rev CGATCATTAT AGAGCAGTTA GAACCGCCGC CGCTGCCACC
GCCAGAGCCA CCACCCTGTT GTTCCTGCGC TTGCTCAAGG
(SEQ ID NO:51) r

CA 02234061 1998-04-06
W O 97/1298~ 85 PCT~US96/1~774
35start.seq GATCGACCAT GGCTCTGGAC CCGAACAACC TC
(SEQ ID MO:52)
34rev.seq CTCGATTACG TACAAAGGTG CAGGTGGT
(SEQ ID No:53)
70start.seq GATCGACCAT GGCTAATGCA TCAGGTATTG AG
(SEQ ID N3:54)
10 69rev.seq CTCGATTACG TATTCTAAGT TCTTGACA
(SEQ ID NO:55~
91start.seq GATCGACCAT GGCTGCACCC TCTCGACATC CA
(SEQ ID NO:56)
9Orev.seq CTCGATTACG TAGGCCGTGG CAGAGGGC
(SEQ ID No:57)
lOlstart.seq GATCGACCAT GGCTGCAGGT GACTGGCAAG AA
(SEQ ID No:58)
lOOrev.seq CTCGATTACG TACTTGATGA TGATTGGA
(SEQ ID No:59)
L-llstart.seq GCTCTGAGAG CCGCCAGAGC CGCCAGAGGG
CTGCGCAAGG TGGCGTAGAA CGCG (SEQ ID NO:60)
L-llstop.seq CAGCCCTCTG GCGGCTCTGG CGGCTCTCAG
AGCTTCCTGC TCAAGTCTTT AGAG (SEQ ID MO:61)
P-blstart.seq GGGCTGCGCA AGGTGGCG (SEQ ID NO:62)
P-blstop.seq ACACCATTGG GCCCTGCCAG C (SEQ ID NO:63)
35 39start.seq GATCGACCAT GGCTTACAAG CTGTGCCACC CC
(SEQ ID MO:64)
38stop.Se~ CGATCGAAGC TTATTAGGTG GCACACAGCT TCTCCT
(SEQ ID NO:65)
g7start.se~ GATCGACCAT GGCTCCCGAG TTGGGTCCCA CC
(SEQ ID Mo:66)
96stop.Seq CGATCGAAGC TTATTAGGAT ATCCCTTCCA GGGCCT
(SEQ ID NO:67)
126start.seq GATCGACCAT GGCTATGGCC CCTGCCCTGC AG
(SEQ ID No:68)
125stop.Seq CGATCGAAGC TTATTATCCC AGTTCTTCCA TCTGCT
(SEQ ID NO:69)

CA 02234061 1998-04-06
W O 97/12985 86 PCT~US96/15774
133start.seq GATCGACCAT GGCTACCCAG GGTGCCATGC CG
(SEQ ID NO:70~
132stop.seq CGATCGAAGC TTATTAGGGC TGCAGGGCAG GGGCCA
(SEQ ID MO:71)
142start.se~ GATCGACCAT GGCTTCTGCT TTCCAGCGCC GG
(SEQ ID No:72)
141stop.Seq CGATCGAAGC TTATTAGGCG AAGGCCGGCA TGGCAC
(SEQ ID MO:73)
GLYXAl GTAGAGGGCG GTGGAGGCTC C (SEQ ID NO:74)
15 GLYXA2 CCGGGGAGCC TCCACCGCCC TCTAC (SEQ ID NO:75)
lGGGSfor TTCTACGCCA CCTTGCGCAG CCCGGCGGCG GCTCTGACAT
GTCTACACCA TTG (SEQ ID NO:76)
20 lGGGSrev CAATGGTGTA GACATGTCAG AGCCGCCGCC GGGCTGCGCA
AGGTGGCGTA GAA (SEQ ID NO:77)
Synnoxal.req AATTCCGTCG TAAACTGACC TTCTATCTGA AAACCTTGGA
GAACGCGCAG GCTCAACAGT ACGTAGAGGG CGGTGGAGGC
TCC (SEQ ID NO:240)
Synnoxa2.req CCGGGGAGCC TCCACCGCCC TCTACGTACT GTTGAGCCTG
CGCGTTCTCC AAGGTTTTCA GATAGAAGGT CAGTTTACGA
CGG (SEQ ID NO:241)
~0

CA 02234061 1998-04-06
W O 97/12985 87 PCTfUS96/15774
TART.F. 2
GT~.NF. SEOUENCES
pMoN30304
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGT (SEQ ID NO:78)
pMoN26458
TCCCCAGCTCCACCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCAT
GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTG
CTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCA
CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAA
CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTC
CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCT
CACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGT
TTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTC (SEQ ID NO:79)
pMON28548
TCCCCAGCTCCACCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCAT
GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTG
CTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCA
CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAA
CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTC
CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCT
CACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGT
TTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAACATGGCG
TCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCAT
GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTG
CTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCA
CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAA
CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTC
CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGGGCAGGACCACAGCTCACAAGGATCCC
AATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTT
GTAGGAGGGTCCACCCTCTGCGTCAGG (SEQ ID NO:80)
pMON28500
TCCCCAGCTCCACCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCAT
GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTG
CTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCA

CA 02234061 1998-04-06
W O 97/12985 88 PCT~US96/15774
CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAA
CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTC
CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCT
CACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGT
TTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCAACATGGCGTCT
CCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTC
CTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTG
CCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAG
GACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTG
GGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTT
GGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCAC
AAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTC
CTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGG (SEQ ID NO:81)
pMON28501
TCCCCAGCTCCACCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCAT
GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTG
CTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCA
CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAA
CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTcTGGACAGGTCCGTCTCCTC
CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCT
CACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGT
TTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAACATGGCG
TCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCAT
GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTG
CTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCA
CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAA
CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTC
CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCT
CACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGT
TTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGG (SEQ ID MO:82)
pMON28502
TCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCAT
GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTG
CTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCA
CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAA
CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTC
CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCT
CACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGA~AGGTGCGT
TTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAACGGCGGC
AACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGT
GACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACA
CCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAG
ACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAG~GAGTGATGGCAGCA
CGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTC
CGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGG
ACCACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGA
AAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGG
(SEQ ID NO:83)

CA 02234061 1998-04-06
W O 97112985 8g PCTAUS96/15774
Syntanl
51 CATGGCTAAC TGCTCTATAA TGATCGATGA AATTATACAT CACTTAAAGA
51 GACCACCTGC ACCTTTGCTG GACCCGAACA ACCTCAATGA CGAAGACGTC
101 TCTATCCTGA TGGACCGAAA CCTTCGACTT CCAAACCTGG AGAGCTTCGT
151 AAGGGCTGTC AAGAACTTAG AAAATGCATC AGGTATTGAG GCAATTCTTC
201 GTAATCTCCA ACCATGTCTG CCCTCTGCCA CGGCCGCACC CTCTCGACAT
10251 CCAATCATCA TCAAGGCAGG TGACTGGCAA GAATTCCGGG AAAAACTGAC
301 GTTCTATCTG GTTACCCTTG AGCAAGCGCA GGAACAACAG GGTGGTGGCT
351 CTAACTGCTC TATAATGATC GATGAAATTA TACATCACTT AAAGAGACCA
401 CCTGCACCTT TGCTGGACCC GAACAACCTC AATGACGAAG ACGTCTCTAT
451 CCTGATGGAC CGAAACCTTC GACTTCCAAA CCTGGAGAGC TTCGTAAGGG
15501 CTGTCAAGAA CTTAGAAAAT GCATCAGGTA TTGAGGCAAT TCTTCGTAAT
551 CTCCAACCAT GTCTGCCCTC TGCCACGGCC GCACCCTCTC GACATCCAAT
601 CATCATCAAG GCAGGTGACT GGCAAGAATT CCGGGAAAAA CTGACGTTCT
651 ATCTGGTTAC CCTTGAGCAA GCGCAGGAAC AACAGTAC
(SEQ ID NO:84)
Syntan3
1 CATGGCTAAC TGCTCTATAA TGATCGATGA AATTATACAT CACTTAAAGA
2551 GACCACCTGC ACCTTTGCTG GACCCGAACA ACCTCAATGA CGAAGACGTC
101 TCTATCCTGA TGGACCGAAA CCTTCGACTT CCAAACCTGG AGAGCTTCGT
151 AAGGGCTGTC AAGAACTTAG AAAATGCATC AGGTATTGAG GCAATTCTTC
201 GTAATCTCCA ACCATGTCTG CCCTCTGCCA CGGCCGCACC CTCTCGACAT
251 CCAATCATCA TCAAGGCAGG TGACTGGCAA GAATTCCGGG AAAAACTGAC
30301 GTTCTATCTG GTTACCCTTG AGCAAGCGCA GGAACAACAG GGTGGTGGCT
351 CTGGCGGTGG CAGCGGCGGC GGTTCTAACT GCTCTATAAT GATCGATGAA
401 ATTATACATC ACTTAAAGAG ACCACCTGCA CCTTTGCTGG ACCCGAACAA
451 CCTCAATGAC GAAGACGTCT CTATCCTGAT GGACCGAAAC CTTCGACTTC
501 CAAACCTGGA GAGCTTCGTA AGGGCTGTCA AGAACTTAGA AAATGCATCA
35551 GGTATTGAGG CAATTCTTCG TAATCTCCAA CCATGTCTGC CCTCTGCCAC
601 GGCCGCACCC TCTCGACATC CAATCATCAT CAAGGCAGGT GACTGGCAAG
651 AATTCCGGGA AAAACTGACG TTCTATCTGG TTACCCTTGA GCAAGCGCAG
701 GAACAACAGT AC (SEQ ID NO:85)
pMON31104
1 ATGGCTCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCCTGAT
51 GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA
45101 AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG TAATCTCCAA
151 CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC CAATCATCAT
201 CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG TTCTATCTGG
251 TTACCCTTGA GCAAGCGCAG GAACAACAGG GTGGTGGCTC TAACTGCTCT
301 ATAATGATCG ATGAAATTAT ACATCACTTA AAGAGACCAC CTGCACCTTT
50351 GTACGTAGAG GGCGGTGGAG GCTCCCCGGG TGAACCGTCT GGTCCAATCT
r401 CTACTATCAA CCCGTCTCCT CCGTCTAAAG AATCTCATAA ATCTCCAAAC
451 ATGGCTACCC AGGGTGCCAT GCCGGCCTTC GCCTCTGCTT TCCAGCGCCG
.

CA 02234061 1998-04-06
W O 97/1298S o PCTrUS96/15774
5 01 GGCAGGAGGG GTCCTGGTTG CTAGCCATCT GCAGAGCTTC CTGGAGGTGT
551 CGTACCGCGT TCTACGCCAC CTTGCGCAGC CCTCTGGCGG CTCTGGCGGC
601 TCTCAGAGCT TCCTGCTCAA GTCTTTAGAG CAAGTGAGAA AGATCCAGGG
651 CGATGGCGCA GCGCTCCAGG AGAAGCTGTG TGCCACCTAC AAGCTGTGCC
701 ACCCCGAGGA GCTGGTGCTG CTCGGACACT CTCTGGGCAT CCCCTGGGCT
751 CCCCTGAGCT CCTGCCCCAG CCAGGCCCTG CAGCTGGCAG GCTGCTTGAG
801 CCAACTCCAT AGCGGCCTTT TCCTCTACCA GGGGCTCCTG CAGGCCCTGG
851 AAGGGATATC CCCCGAGTTG GGTCCCACCT TGGACACACT GCAGCTGGAC
901 GTCGCCGACT TTGCCACCAC CATCTGGCAG CAGATGGAAG AACTGGGAAT
951 GGCCCCTGCC CTGCAGCCCT AATAA (SEQ ID No:86)
pMON31105
1 ATGGCTAATG CATCAGGTAT TGAGGCAATT CTTCGTAATC TCCAACCATG
51 TCTGCCCTCT GCCACGGCCG CACCCTCTCG ACATCCAATC ATCATCAAGG
101 CAGGTGACTG GCAAGAATTC CGGGAAAAAC TGACGTTCTA TCTGGTTACC
151 CTTGAGCAAG CGCAGGAACA ACAGGGTGGT GGCTCTAACT GCTCTATAAT
201 GATCGATGAA ATTATACATC ACTTAAAGAG ACCACCTGCA CCTTTGCTGG
251 ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCCTGAT GGACCGAAAC
301 CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA AGAACTTAGA
351 ATACGTAGAG GGCGGTGGAG GCTCCCCGGG TGAACCGTCT GGTCCAATCT
401 CTACTATCAA CCCGTCTCCT CCGTCTAAAG AATCTCATAA ATCTCCAAAC
451 ATGGCTACCC AGGGTGCCAT GCCGGCCTTC GCCTCTGCTT TCCAGCGCCG
501 GGCAGGAGGG GTCCTGGTTG CTAGCCATCT GCAGAGCTTC CTGGAGGTGT
551 CGTACCGCGT TCTACGCCAC CTTGCGCAGC CCTCTGGCGG CTCTGGCGGC
601 TCTCAGAGCT TCCTGCTCAA GTCTTTAGAG CAAGTGAGAA AGATCCAGGG
651 CGATGGCGCA GCGCTCCAGG AGAAGCTGTG TGCCACCTAC AAGCTGTGCC
701 ACCCCGAGGA GCTGGTGCTG CTCGGACACT CTCTGGGCAT CCCCTGGGCT
751 CCCCTGAGCT CCTGCCCCAG CCAGGCCCTG CAGCTGGCAG GCTGCTTGAG
801 CCAACTCCAT AGCGGCCTTT TCCTCTACCA GGGGCTCCTG CAGGCCCTGG
851 AAGGGATATC CCCCGAGTTG GGTCCCACCT TGGACACACT GCAGCTGGAC
901 GTCGCCGACT TTGCCACCAC CATCTGGCAG CAGATGGAAG AACTGGGAAT
951 GGCCCCTGCC CTGCAGCCCT AATAA (SEQ ID NO:87)
pMON31106
1 ATGGCTGCAC CCTCTCGACA TCCAATCATC ATCAAGGCAG GTGACTGGCA
51 AGAATTCCGG GAAAAACTGA CGTTCTATCT GGTTACCCTT GAGCAAGCGC
101 AGGAACAACA GGGTGGTGGC TCTAACTGCT CTATAATGAT CGATGAAATT
151 ATACATCACT TAAAGAGACC ACCTGCACCT TTGCTGGACC CGAACAACCT
201 CAATGACGAA GACGTCTCTA TCCTGATGGA CCGAAACCTT CGACTTCCAA
251 ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGCATCAGGT
301 ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC
351 CTACGTAGAG GGCGGTGGAG GCTCCCCGGG TGAACCGTCT GGTCCAATCT
401 CTACTATCAA CCCGTCTCCT CCGTCTAAAG AATCTCATAA ATCTCCAAAC
451 ATGGCTACCC AGGGTGCCAT GCCGGCCTTC GCCTCTGCTT TCCAGCGCCG
501 GGCAGGAGGG GTCCTGGTTG CTAGCCATCT GCAGAGCTTC CTGGAGGTGT
551 CGTACCGCGT TCTACGCCAC CTTGCGCAGC CCTCTGGCGG CTCTGGCGGC
601 TCTCAGAGCT TCCTGCTCAA GTCTTTAGAG CAAGTGAGAA AGATCCAGGG .'
651 CGATGGCGCA GCGCTCCAGG AGAAGCTGTG TGCCACCTAC AAGCTGTGCC

CA 02234061 1998-04-06
W O 97/12985 91 PCTAUS9~15774
701 ACCCCGAGGA GCTGGTGCTG CTCGGACACT CTCTGGGCAT CCCCTGGGCT
751 CCCCTGAGCT CCTGCCCCAG CCAGGCCCTG CAGCTGGCAG GCTGCTTGAG
801 CCAACTCCAT AGCGGCCTTT TCCTCTACCA GGGGCTCCTG CAGGCCCTGG
851 AAGGGATATC CCCCGAGTTG GGTCCCACCT TGGACACACT &CAGCTGGAC
5901 GTCGCCGACT TTGCCACCAC CATCTGGCAG CAGATGGAAG AACTGGGAAT
951 GGCCCCTGCC CTGCAGCCCT AATAA (SEQ ID NO:88)
pMON31107
1 ATGGCTGCAG GTGACTGGCA AGAATTCCGG GAAAAACTGA CGTTCTATCT
51 GGTTACCCTT GAGCAAGCGC AGGAACAACA GGGTGGTGGC TCTAACTGCT
101 CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC ACCTGCACCT
151 TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA
15201 CCGAAACCTT CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA
251 ACTTAGAAAA TGCATCAGGT ATTGAGGCAA TTCTTCGTAA TCTCCAACCA
301 TGTCTGCCCT CTGCCACGGC CGCACCCTCT CGACATCCAA TCATCATCAA
3Sl GTACGTAGAG GGCGGTGGAG GCTCCCCGGG TGAACCGTCT GGTCCAATCT
401 CTACTATCAA CCCGTCTCCT CCGTCTAAAG AATCTCATAA ATCTCCAAAC
20451 ATGGCTACCC AGGGTGCCAT GCCGGCCTTC GCCTCTGCTT TCCAGCGCCG
501 GGCAGGAGGG GTCCTGGTTG CTAGCCATCT GCAGAGCTTC CTGGAGGTGT
551 CGTACCGCGT TCTACGCCAC CTTGCGCAGC CCTCTGGCGG CTCTGGCGGC
601 TCTCAGAGCT TCCTGCTCAA GTCTTTAGAG CAAGTGAGAA AGATCCAGGG
651 CGATGGCGCA GCGCTCCAGG AGAAGCTGTG TGCCACCTAC AAGCTGTGCC
25701 ACCCCGAGGA GCTGGTGCTG CTCGGACACT CTCTGGGCAT CCCCTGGGCT
751 CCCCTGAGCT CCTGCCCCAG CCAGGCCCTG CAGCTGGCAG GCTGCTTGAG
801 CCAACTCCAT AGCGGCCTTT TCCTCTACCA GGGGCTCCTG CAGGCCCTGG
851 AAGGGATATC CCCCGAGTTG GGTCCCACCT TGGACACACT GCAGCTGGAC
901 GTCGCCGACT TTGCCACCAC CATCTGGCAG CAGATGGAAG AACTGGGAAT
30951 GGCCCCTGCC CTGCAGCCCT AATAA (SEQ ID NO:89)
pMON31108
351 ATGGCTCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCCTGAT
51 GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA
101 AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG TAATCTCCAA
151 CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC CAATCATCAT
201 CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG TTCTATCTGG
40251 TTACCCTTGA GCAAGCGCAG GAACAACAGG GTGGTGGCTC TGGCGGTGGC
301 AGCGGCGGCG GTTCTAACTG CTCTATAATG ATCGATGAAA TTATACATCA
351 CTTAAAGAGA CCACCTGCAC CTTTGTACGT AGAGGGCGGT GGAGGCTCCC
401 CGGGTGAACC GTCTGGTCCA ATCTCTACTA TCAACCCGTC TCCTCCGTCT
451 AAAGAATCTC ATAAATCTCC AAACATGGCT ACCCAGGGTG CCATGCCGGC
45501 CTTCGCCTCT GCTTTCCAGC GCCGGGCAGG AGGGGTCCTG GTTGCTAGCC
551 ATCTGCAGAG CTTCCTGGAG GTGTCGTACC GCGTTCTACG CCACCTTGCG
601 CAGCCCTCTG GCGGCTCTGG CGGCTCTCAG AGCTTCCTGC TCAAGTCTTT
651 AGAGCAAGTG AGAAAGATCC AGGGCGATGG CGCAGCGCTC CAGGAGAAGC
701 TGTGTGCCAC CTACAAGCTG TGCCACCCCG AGGAGCTGGT GCTGCTCGGA
50751 CACTCTCTGG GCATCCCCTG GGCTCCCCTG AGCTCCTGCC CCAGCCAGGC
~,801 CCTGCAGCTG GCAGGCTGCT TGAGCCAACT CCATAGCGGC CTTTTCCTCT
851 ACCAGGGGCT CCTGCAGGCC CTGGAAGGGA TATCCCCCGA GTTGGGTCCC

CA 02234061 1998-04-06
W O 97/12985 92 PCT~US96/15774
901 ACCTTGGACA CACTGCAGCT GGACGTCGCC GACTTTGCCA CCACCATCTG
951 GCAGCAGATG GAAGAACTGG GAATGGCCCC TGCCCTGCAG CCCTAATAA
~SEQ ID NO:90) f
pMON31109
1 ATGGCTAATG CATCAGGTAT TGAGGCAATT CTTCGTAATC TCCAACCATG
51 TCTGCCCTCT GCCACGGCCG CACCCTCTCG ACATCCAATC ATCATCAAGG
101 CAGGTGACTG GCAAGAATTC CGGGAAAAAC TGACGTTCTA TCTGGTTACC
151 CTTGAGCAAG CGCAGGAACA ACAGGGTGGT GGCTCTGGCG GTGGCAGCGG
201 CGGCGGTTCT AACTGCTCTA TAATGATCGA TGAAATTATA CATCACTTAA
251 AGAGACCACC TGCACCTTTG CTGGACCCGA ACAACCTCAA TGACGAAGAC
301 GTCTCTATCC TGATGGACCG AAACCTTCGA CTTCCA~ACC TGGAGAGCTT
351 CGTAAGGGCT GTCAAGAACT TAGAATACGT AGAGGGCGGT GGAGGCTCCC
401 CGGGTGAACC GTCTGGTCCA ATCTCTACTA TCAACCCGTC TCCTCCGTCT
451 AAAG~ATCTC ATAAATCTCC AAACATGGCT ACCCAGGGTG CCATGCCGGC
501 CTTCGCCTCT GCTTTCCAGC GCCGGGCAGG AGGGGTCCTG GTTGCTAGCC
551 ATCTGCAGAG CTTCCTGGAG GTGTCGTACC GCGTTCTACG CCACCTTGCG
601 CAGCCCTCTG GCGGCTCTGG CGGCTCTCAG AGCTTCCTGC TCAAGTCTTT
651 AGAGCAAGTG AGAAAGATCC AGGGCGATGG CGCAGCGCTC CAGGAGAAGC
701 TGTGTGCCAC CTACAAGCTG TGCCACCCCG AGGAGCTGGT GCTGCTCGGA
751 CACTCTCTGG GCATCCCCTG GGCTCCCCTG AGCTCCTGCC CCAGCCAGGC
801 CCTGCAGCTG GCAGGCTGCT TGAGCCAACT CCATAGCGGC CTTTTCCTCT
851 ACCAGGGGCT CCTGCAGGCC CTGGAAGGGA TATCCCCCGA GTTGGGTCCC
901 ACCTTGGACA CACTGCAGCT GGACGTCGCC GACTT~GCCA CCACCATCTG
951 GCAGCAGATG GAAGAACTGG GAATGGCCCC TGCCCTGCAG CCCTAATAA
(SEQ ID NO:91)
pMOM31110
1 ATGGCTGCAC CCTCTCGACA TCCAATCATC ATCAAGGCAG GTGACTGGCA
51 AGAATTCCGG GAAAAACTGA CGTTCTATCT GGTTACCCTT GAGCAAGCGC
101 AGGAACAACA GGGTGGTGGC TCTGGCGGTG GCAGCGGCGG CGGTTCTAAC
151 TGCTCTATAA TGATCGATGA AATTATACAT CACTTAAAGA GACCACCTGC
201 ACCTTTGCTG GACCCGAACA ACCTCAATGA CGAAGACGTC TCTATCCTGA
251 TGGACCGAAA CCTTCGACTT CCAAACCTGG AGAGCTTCGT AAGGGCTGTC
301 AAGAACTTAG AAAATGCATC AGGTATTGAG GCAATTCTTC GTAATCTCCA
351 ACCATGTCTG CCCTCTGCCA CGGCCTACGT AGAGGGCGGT GGAGGCTCCC
401 CGGGTGAACC GTCTGGTCCA ATCTCTACTA TCAACCCGTC TCCTCCGTCT
451 AAAGAATCTC ATAAATCTCC AAACATGGCT ACCCAGGGTG CCATGCCGGC
501 CTTCGCCTCT GCTTTCCAGC GCCGGGCAGG AGGGGTCCTG GTTGCTAGCC
551 ATCTGCAGAG CTTCCTGGAG GTGTCGTACC GCGTTCTACG CCACCTTGCG
601 CAGCCCTCTG GCGGCTCTGG CGGCTCTCAG AGCTTCCTGC TCAAGTCTTT
651 AGAGCAAGTG AGAAAGATCC AGGGCGATGG CGCAGCGCTC CAGGAGAAGC
701 TGTGTGCCAC CTACAAGCTG TGCCACCCCG AGGAGCTGGT GCTGCTCGGA
751 CACTCTCTGG GCATCCCCTG GGCTCCCCTG AGCTCCTGCC CCAGCCAGGC
801 CCTGCAGCTG GCAGGCTGCT TGAGCCAACT CCATAGCGGC CTTTTCCTCT
851 ACCAGGGGCT CCTGCAGGCC CTGGAAGGGA TATCCCCCGA GTTGGGTCCC
901 ACCTTGGACA CACTGCAGCT GGACGTCGCC GACTTTGCCA CCACCATCTG
951 GCAGCAGATG GAAGAACTGG GAATGGCCCC TGCCCTGCAG CCCTAATAA
(SEQ ID NO:92) ~'

CA 02234061 1998-04-06
WO 97/12985 PCT/US96/15774
pMON3 1111
1 ATGGCTGCAG GTGACTGGCA AGAATTCCGG GAAAAACTGA CGTTCTATCT
51 GGTTACCCTT GAGCAAGCGC AGGAACAACA GGGTGGTGGC TCTGGCGGTG
101 GCAGCGGCGG CGGTTCTAAC TGCTCTATAA TGATCGATGA AATTATACAT
t 151 CACTTAAAGA GACCACCTGC ACCTTTGCTG GACCCGAACA ACCTCAATGA
201 CGAAGACGTC TCTATCCTGA TGGACCGAAA CCTTCGACTT CCAAACCTGG
251 AGAGCTTCGT AAGGGCTGTC AAGAACTTAG AAAATGCATC AGGTATTGAG
3 01 GCAATTCTTC GTAATCTCCA ACCATGTCTG CCCTCTGCCA CGGCCGCACC
351 CTCTCGACAT CCAATCATCA TCAAGTACGT AGAGGGCGGT GGAGGCTCCC
401 CGGGTGAACC GTCTGGTCCA ATCTCTACTA TCAACCCGTC TCCTCCGTCT
451 AAAGAATCTC ATAAATCTCC AAACATGGCT ACCCAGGGTG CCATGCCGGC
501 CTTCGCCTCT GCTTTCCAGC GCCGGGCAGG AGGGGTCCTG GTTGCTAGCC
551 ATCTGCAGAG CTTCCTGGAG GTGTCGTACC GCGTTCTACG CCACCTTGCG
601 CAGCCCTCTG GCGGCTCTGG CGGCTCTCAG AGCTTCCTGC TCAAGTCTTT
651 AGAGCAAGTG AGAAAGATCC AGGGCGATGG CGCAGCGCTC CAGGAGAAGC
701 TGTGTGCCAC CTACAAGCTG TGCCACCCCG AGGAGCTGGT GCTGCTCGGA
751 CACTCTCTGG GCATCCCCTG GGCTCCCCTG AGCTCCTGCC CCAGCCAGGC
801 CCTG~AGCTG GCAGGCTGCT TGAGCCAACT CCATAGCGGC CTTTTCCTCT
851 ACCAGGGGCT CCTGCAGGCC CTGGAAGGGA TATCCCCCGA GTTGGGTCCC
901 ACCTTGGACA CACTGCAGCT GGACGTCGCC GACTTTGCCA CCACCATCTG
951 GCAGCAGATG GAAGAACTGG GAATGGCCCC TGCCCTGCAG CCCTAATAA
(SEQ ID NO:93)
pMON13 1 8 2
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
3 0 151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
3 01 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
3 51 CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTT
3 5 401 ACAAGCTGTG CCACCCCGAG GAGCTGGTGC TGCTCGGACA CTCTCTGGGC
451 ATCCCCTGGG CTCCCCTGAG CTCCTGCCCC AGCCAGGCCC TGCAGCTGGC
501 AGGCTGCTTG AGCCAACTCC ATAGCGGCCT TTTCCTCTAC CAGGGGCTCC
551 TGCAGGCCCT GGAAGGGATA TCCCCCGAGT TGGGTCCCAC CTTGGACACA
601 CTGCAGCTGG ACGTCGCCGA CTTTGCCACC ACCATCTGGC AGCAGATGGA
651 AGAACTGGGA ATGGCCCCTG CCCTGCAGCC CACCCAGGGT GCCATGCCGG
701 CCTTCGCCTC TGCTTTCCAG CGCCGGGCAG GAGGGGTCCT GGTTGCTAGC
751 CATCTGCAGA GCTTCCTGGA GGTGTCGTAC CGCGTTCTAC GCCACCTTGC
801 GCAGCCCTCT GGCGGCTCTG GCGGCTCTCA GAGCTTCCTG CTCAAGTCTT
8 51 TAGAGCAAGT GAGAAAGATC CAGGGCGATG GCGCAGCGCT CCAGGAGAAG
901 CTGTGTGCCA CCTAATAA (SEQ ID NO:94)
pMON13 183
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA

CA 02234061 1998-04-06
W O 97/12985 94 PCT~US96/15774
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTTACAAG
451 CTGTGCCACC CCGAGGAGCT GGTGCTGCTC GGACACTCTC TGGGCATCCC
501 CTGGGCTCCC CTGAGCTCCT GCCCCAGCCA GGCCCTGCAG CTGGCAGGCT
551 GCTTGAGCCA ACTCCATAGC GGCCTTTTCC TCTACCAGGG GCTCCTGCAG
10601 GCCCTGGAAG GGATATCCCC CGAGTTGGGT CCCACCTTGG ACACACTGCA
651 GCTGGACGTC GCCGACTTTG CCACCACCAT CTGGCAGCAG ATGGAAGAAC
701 TGGGAATGGC CCCTGCCCTG CAGCCCACCC AGGGTGCCAT GCCGGCCTTC
751 GCCTCTGCTT TCCAGCGCCG GGCAGGAGGG GTCCTGGTTG CTAGCCATCT
801 GCAGAGCTTC CTGGAGGTGT CGTACCGCGT TCTACGCCAC CTTGCGCAGC
15851 CCTCTGGCGG CTCTGGCGGC TCTCAGAGCT TCCTGCTCAA GTCTTTAGAG
901 CAAGTGAGAA AGATCCAGGG CGATGGCGCA GCGCTCCAGG AGAAGCTGTG
951 TGCCACCTAA TAA (SEQ ID NO:95)
20pMON13184
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
25151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTC
30401 CCGAGTTGGG TCCCACCTTG GACACACTGC AGCTGGACGT CGCCGACTTT
451 GCCACCACCA TCTGGCAGCA GATGGAAGAA CTGGGAATGG CCCCTGCCCT
501 GCAGCCCACC CAGGGTGCCA TGCCGGCCTT CGCCTCTGCT TTCCAGCGCC
551 GGGCAGGAGG GGTCCTGGTT GCTAGCCATC TGCAGAGCTT CCTGGAGGTG
601 TCGTACCGCG TTCTACGCCA CCTTGCGCAG CCCTCTGGCG GCTCTGGCGG
35651 CTCTCAGAGC TTCCTGCTCA AGTCTTTAGA GCAAGTGAGA AAGATCCAGG
701 GCGATGGCGC AGCGCTCCAG GAGAAGCTGT GTGCCACCTA CAAGCTGTGC
751 CACCCCGAGG AGCTGGTGCT GCTCGGACAC TCTCTGGGCA TCCCCTGGGC
801 TCCCCTGAGC TCCTGCCCCA GCCAGGCCCT GCAGCTGGCA GGCTGCTTGA
851 GCCAACTCCA TAGCGGCCTT TTCCTCTACC AGGGGCTCCT GCAGGCCCTG
40901 GAAGGGATAT CCTAATAA (SEQ ID NO:96)
pMOM13185
451 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG ,~
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC

-
CA 02234061 1998-04-06
W O 97/12985 95 PCT~US96/15774
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTCCCGAG
451 TTGGGTCCCA CCTTGGACAC ACTGCAGCTG GACGTCGCCG ACTTTGCCAC
501 CACCATCTGG CAGCAGATGG AAGAACTGGG AATGGCCCCT GCCCTGCAGC
551 CCACCCAGGG TGCCATGCCG GCCTTCGCCT CTGCTTTCCA GCGCCGGGCA
5601 GGAGGGGTCC TGGTTGCTAG CCATCTGCAG AGCTTCCTGG AGGTGTCGTA
651 CCGCGTTCTA CGCCACCTTG CGCAGCCCTC TGGCGGCTCT GGCGGCTCTC
701 AGAGCTTCCT GCTCAAGTCT TTAGAGCAAG TGAGAAAGAT CCAGGGCGAT
751 GGCGCAGCGC TCCAGGAGAA GCTGTGTGCC ACCTACAAGC TGTGCCACCC
801 CGAGGAGCTG GTGCTGCTCG GACACTCTCT GGGCATCCCC TGGGCTCCCC
10851 TGAGCTCCTG CCCCAGCCAG GCCCTGCAGC TGGCAGGCTG CTTGAGCCAA
901 CTCCATAGCG GCCTTTTCCT CTACCAGGGG CTCCTGCAGG CCCTGGAAGG
951 GATATCCTAA TAA (SEQ ID NO:97)
15pMON13186
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
20151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTA
25401 TGGCCCCTGC CCTGCAGCCC ACCCAGGGTG CCATGCCGGC CTTCGCCTCT
451 GCTTTCCAGC GCCGGGCAGG AGGGGTCCTG GTTGCTAGCC ATCTGCAGAG
501 CTTCCTGGAG GTGTCGTACC GCGTTCTACG CCACCTTGCG CAGCCCTCTG
551 GCGGCTCTGG CGGCTCTCAG AGCTTCCTGC TCAAGTCTTT AGAGCAAGTG
601 AGAAAGATCC AGGGCGATGG CGCAGCGCTC CAGGAGAAGC TGTGTGCCAC
30651 CTACAAGCTG TGCCACCCCG AGGAGCTGGT GCTGCTCGGA CACTCTCTGG
701 GCATCCCCTG GGCTCCCCTG AGCTCCTGCC CCAGCCAGGC CCTGCAGCTG
751 GCAGGCTGCT TGAGCCAACT CCATAGCGGC CTTTTCCTCT ACCAGGGGCT
801 CCTGCAGGCC CTGGAAGGGA TATCCCCCGA GTTGGGTCCC ACCTTGGACA
851 CACTGCAGCT GGACGTCGCC GACTTTGCCA CCACCATCTG GCAGCAGATG
35901 GAAGAACTGG GATAATAA (SEQ ID NO:98)
pMON13187
401 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
45251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTATGGCC
451 CCTGCCCTGC AGCCCACCCA GGGTGCCATG CCGGCCTTCG CCTCTGCTTT
50501 CCAGCGCCGG GCAGGAGGGG TCCTGGTTGC TAGCCATCTG CAGAGCTTCC
~~551 TGGAGGTGTC GTACCGCGTT CTACGCCACC TTGCGCAGCC CTCTGGCGGC
601 TCTGGCGGCT CTCAGAGCTT CCTGCTCAAG TCTTTAGAGC AAGTGAGAAA
.

CA 02234061 1998-04-06
W O 97/12985 6 PCTAUS96/15774
651 GATCC'AGGGC GATGGCGCAG CGCTCCAGGA GAAGCTGTGT GCCACCTACA
701 AGCTGTGCCA CCCCGAGGAG CTGGTGCTGC TCGGACACTC TCTGGGCATC
751 CCCTGGGCTC CCCTGAGCTC CTGCCCCAGC CAGGCCCTGC AGCTGGCAGG
801 CTGCTTGAGC CAACTCCATA GCGGCCTTTT CCTCTACCAG GGGCTCCTGC
5851 AGGCCCTGGA AGGGATATCC CCCGAGTTGG GTCCCACCTT GGACACACTG
901 CAGCTGGACG TCGCCGACTT TGCCACCACC ATCTGGCAGC AGATGGAAGA
951 ACTGGGATAA TAA (SEQ ID NO:99)
10pMON13188
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
15151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTA
20401 CCCAGGGTGC CATGCCGGCC TTCGCCTCTG CTTTCCAGCG CCGGGCAGGA
451 GGGGTCCTGG TTGCTAGCCA TCTGCAGAGC TTCCTGGAGG TGTCGTACCG
501 CGTTCTACGC CACCTTGCGC AGCCCTCTGG CGGCTCTGGC GGCTCTCAGA
551 GCTTCC'TGCT CAAGTCTTTA GAGCAAGTGA GAAAGATCCA GGGCGATGGC
601 GCAGCGCTCC AGGAGAAGCT GTGTGCCACC TACAAGCTGT GCCACCCCGA
25651 GGAGCTGGTG CTGCTCGGAC ACTCTCTGGG CATCCCCTGG GCTCCCCTGA
701 GCTCCTGCCC CAGCCAGGCC CTGCAGCTGG CAGGCTGCTT GAGCCAACTC
751 CATAGCGGCC TTTTCCTCTA CCAGGGGCTC CTGCAGGCCC TGGAAGGGAT
801 ATCCCCCGAG TTGGGTCCCA CCTTGGACAC ACTGCAGCTG GACGTCGCCG
851 ACTTTGCCAC CACCATCTGG CAGCAGATGG AAGAACTGGG AATGGCCCCT
30901 GCCCTGCAGC CCTAATAA (SEQ ID N~:100)
pMON13189
351 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTACCCAG
451 GGTGCCATGC CGGCCTTCGC CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT
501 CCTGGTTGCT AGCCATCTGC AGAGCTTCCT GGAGGTGTCG TACCGCGTTC
551 TACGCCACCT TGCGCAGCCC TCTGGCGGCT CTGGCGGCTC TCAGAGCTTC
601 CTGCTCAAGT CTTTAGAGCA AGTGAGAAAG ATCCAGGGCG ATGGCGCAGC
651 GCTCCAGGAG AAGCTGTGTG CCACCTACAA GCTGTGCCAC CCCGAGGAGC
701 TGGTGCTGCT CGGACACTCT CTGGGCATCC CCTGGGCTCC CCTGAGCTCC
751 TGCCCCAGCC AGGCCCTGCA GCTGGCAGGC TGCTTGAGCC AACTCCATAG
801 CGGCCTTTTC CTCTACCAGG GGCTCCTGCA GGCCCTGGAA GGGATATCCC
851 CCGAGTTGGG TCCCACCTTG GACACACTGC AGCTGGACGT CGCCGACTTT

CA 02234061 1998-04-06
W O 97/1298S PCTAJS96~5774
97
901 GCCACCACCA TCTGGCAGCA GATGGAAGAA CTGGGAATGG CCCCTGCCCT
951 GCAGCCCTAA TAA (SEQ ID NO:101)
5pMON13190
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
10151 AGGGCmGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTT
15401 CTGCTTTCCA GCGCCGGGCA GGAGGGGTCC TGGTTGCTAG CCATCTGCAG
451 AGCTTCCTGG AGGTGTCGTA CCGCGTTCTA CGCCACCTTG CGCAGCCCTC
501 TGGCGGCTCT GGCGGCTCTC AGAGCTTCCT GCTCAAGTCT TTAGAGCAAG
551 TGAGAAAGAT CCAGGGCGAT GGCGCAGCGC TCCAGGAGAA GCTGTGTGCC
601 ACCTACAAGC TGTGCCACCC CGAGGAGCTG GTGCTGCTCG GACACTCTCT
20651 GGGCATCCCC TGGGCTCCCC TGAGCTCCTG CCCCAGCCAG GCCCTGCAGC
701 TGGCAGGCTG CTTGAGCCAA CTCCATAGCG GCCTTTTCCT CTACCAGGGG
751 CTCCTGCAGG CCCTGGAAGG GATATCCCCC GAGTTGGGTC CCACCTTGGA
801 CACACTGCAG CTGGACGTCG CCGACTTTGC CACCACCATC TGGCAGCAGA
851 TGGAAGAACT GGGAATGGCC CCTGCCCTGC AGCCCACCCA GGGTGCCATG
25901 CCGGCCTTCG CCTAATAA ~SEQ ID NO:102)
pMON13191
301 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
35251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTTCTGCT
451 TTCCAGCGCC GGGCAGGAGG GGTCCTGGTT GCTAGCCATC TGCAGAGCTT
40501 CCTGGAGGTG TCGTACCGCG TTCTACGCCA CCTTGCGCAG CCCTCTGGCG
551 GCTCTGGCGG CTCTCAGAGC TTCCTGCTCA AGTCTTTAGA GCAAGTGAGA
601 AAGATCCAGG GCGATGGCGC AGCGCTCCAG GAGAAGCTGT GTGCCACCTA
651 CAAGCTGTGC CACCCCGAGG AGCTGGTGCT GCTCGGACAC TCTCTGGGCA
701 TCCCCTGGGC TCCCCTGAGC TCCTGCCCCA GCCAGGCCCT GCAGCTGGCA
45751 GGCTGCTTGA GCCAACTCCA TAGCGGCCTT TTCCTCTACC AGGGGCTCCT
801 GCAGGCCCTG GAAGGGATAT CCCCCGAGTT GGGTCCCACC TTGGACACAC
851 TGCAGCTGGA CGTCGCCGAC TTTGCCACCA CCATCTGGCA GCAGATGGAA
901 GAACTGGGAA TGGCCCCTGC CCTGCAGCCC ACCCAGGGTG CCATGCCGGC
g51 CTTCGCCTAA TAA (SEQ ID NO:103
pMON13192

CA 02234061 1998-04-06
W O 97112985 PCTrUS96/15774
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
5151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTT
10401 ACAAGCTGTG CCACCCCGAG GAGCTGGTGC TGCTCGGACA CTCTCTGGGC
451 ATCCCCTGGG CTCCCCTGAG CTCCTGCCCC AGCCAGGCCC TGCAGCTGGC
501 AGGCTGCTTG AGCCAACTCC ATAGCGGCCT TTTCCTCTAC CAGGGGCTCC
551 TGCAGGCCCT GGAAGGGATA TCCCCCGAGT TGGGTCCCAC CTTGGACACA
601 CTGCAGCTGG ACGTCGCCGA CTTTGCCACC ACCATCTGGC AGCAGATGGA
15651 AGAACTGGGA ATGGCCCCTG CCCTGCAGCC CACCCAGGGT GCCATGCCGG
701 CCTTCGCCTC TGCTTTCCAG CGCCGGGCAG GAGGGGTCCT GGTTGCTAGC
751 CATCTGCAGA GCTTCCTGGA GGTGTCGTAC CGCGTTCTAC GCCACCTTGC
801 GCAGCCCACA CCATTGGGCC CTGCCAGCTC CCTGCCCCAG AGCTTCCTGC
851 TCAAGTCTTT AGAGCAAGTG AGAAAGATCC AGGGCGATGG CGCAGCGCTC
20901 CAGGAGAAGC TGTGTGCCAC CTAATAA (SEQ ID NO:104)
pMON13193
251 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTG&A GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTTACAAG
451 CTGTGCCACC CCGAGGAGCT GGTGCTGCTC GGACACTCTC TGGGCATCCC
501 CTGGGCTCCC CTGAGCTCCT GCCCCAGCCA GGCCCTGCAG CTGGCAGGCT
551 GCTTGAGCCA ACTCCATAGC GGCCTTTTCC TCTACCAGGG GCTCCTGCAG
601 GCCCTGGAAG GGATATCCCC CGAGTTGGGT CCCACCTTGG ACACACTGCA
651 GCTGGACGTC GCCGACTTTG CCACCACCAT CTGGCAGCAG ATGGAAGAAC
701 TGGGAATGGC CCCTGCCCTG CAGCCCACCC AGGGTGCCAT GCCGGCCTTC
751 GCCTCTGCTT TCCAGCGCCG GGCAGGAGGG GTCCTGGTTG CTAGCCATCT
801 GCAGAGCTTC CTGGAGGTGT CGTACCGCGT TCTACGCCAC CTTGCGCAGC
851 CCACACCATT GGGCCCTGCC AGCTCCCTGC CCCAGAGCTT CCTGCTCAAG
901 TCTTTAGAGC AAGTGAGAAA GATCCAGGGC GATGGCGCAG CGCTCCAGGA
951 GAAGCTGTGT GCCACCTAAT AA (SEQ ID NO:105)
pMON25190
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG.=CAATTCTTCG

CA 02234061 1998-04-06
W O 97/1298S PCT~US96/1S774
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTC
5401 CCGAGTTGGG TCCCACCTTG GACACACTGC AGCTGGACGT CGCCGACTTT
451 GCCACCACCA TCTGGCAGCA GATGGAAGAA CTGGGAATGG CCCCTGCCCT
501 GCAGCCCACC CAGGGTGCCA TGCCGGCCTT CGCCTCTGCT TTCCAGCGCC
551 GGGCAGGAGG GGTCCTGGTT GCTAGCCATC TGCAGAGCTT CCTGGAGGTG
601 TCGTACCGCG TTCTACGCCA CCTTGCGCAG CCCACACCAT TGGGCCCTGC
10651 CAGCTCCCTG CCCCAGAGCT TCCTGCTCAA GTCTTTAGAG CAAGTGAGAA
701 AGATCCAGGG CGATGGCGCA GCGCTCCAGG AGAAGCTGTG TGCCACCTAC
751 AAGCTGTGCC ACCCCGAGGA GCTGGTGCTG CTCGGACACT CTCTGGGCAT
801 CCCCTGGGCT CCCCTGAGCT CCTGCCCCAG CCAGGCCCTG CAGCTGGCAG
851 GCTGCTTGAG CCAACTCCAT AGCGGCCTTT TCCTCTACCA GGGGCTCCTG
15901 CAGGCCCTGG AAGGGATATC CTAATAA (SEQ ID NO:106)
pMON25191
201 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
25251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTCCCGAG
451 TTGGC~l'CCCA CCTTGGACAC ACTGCAGCTG GACGTCGCCG ACTTTGCCAC
30501 CACCATCTGG CAGCAGATGG AAGAACTGGG AATGGCCCCT GCCCTGCAGC
551 CCACCCAGGG TGCCATGCCG GCCTTCGCCT CTGCTTTCCA GCGCCGGGCA
601 GGAGGGGTCC TGGTTGCTAG CCATCTGCAG AGCTTCCTGG AGGTGTCGTA
651 CCGCGTTCTA CGCCACCTTG CGCAGCCCAC ACCATTGGGC CCTGCCAGCT
701 CCCTGCCCCA GAGCTTCCTG CTCAAGTCTT TAGAGCAAGT GAGAAAGATC
35751 CAGGGCGATG GCGCAGCGCT CCAGGAGAAG CTGTGTGCCA CCTACAAGCT
801 GTGCCACCCC GAGGAGCTGG TGCTGCTCGG ACACTCTCTG GGCATCCCCT
851 GGGCTCCCCT GAGCTCCTGC CCCAGCCAGG CCCTGCAGCT GGCAGGCTGC
901 TTGAGCCAAC TCCATAGCGG CCTTTTCCTC TACCAGGGGC TCCTGCAGGC
951 CCTGGAAGGG ATATCCTAAT AA (SEQ ID NO:107)
pMON13194
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
4551 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
50301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTA
401 TGGCCCCTGC CCTGCAGCCC ACCCAGGGTG CCATGCCGGC CTTCGCCTCT

CA 02234061 1998-04-06
W O 97/12985 10 PCTAUS96/15774
451 GCTTTCCAGC GCCGGGCAGG AGGGGTCCTG GTTGCTAGCC ATCTGCAGAG
501 CTTCCTGGAG GTGTCGTACC GCGTTCTACG CCACCTTGCG CAGCCCACAC
551 CATTGGGCCC TGCCAGCTCC CTGCCCCAGA GCTTCCTGCT CAAGTCTTTA
601 GAGCAAGTGA GAAAGATCCA GGGCGATGGC GCAGCGCTCC AGGAGAAGCT
5651 GTGTGCCACC TACAAGCTGT GCCACCCCGA GGAGCTGGTG CTGCTCGGAC
701 ACTCTCTGGG CATCCCCTGG GCTCCCCTGA GCTCCTGCCC CAGCCAGGCC
751 CTGCAGCTGG CAGGCTGCTT GAGCCAACTC CATAGCGGCC TTTTCCTCTA
801 CCAGGGGCTC CTGCAGGCCC TGGAAGGGAT ATCCCCCGAG TTGGGTCCCA r
851 CCTTGGACAC ACTGCAGCTG GACGTCGCCG ACTTTGCCAC CACCATCTGG
10901 CAGCAGATGG AAGAACTGGG ATAATAA (SEQ ID NO:108)
pMON13195
151 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCAGCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
20251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTATGGCC
451 CCTGCCCTGC AGCCCACCCA GGGTGCCATG CCGGCCTTCG CCTCTGCTTT
25501 CCAGCGCCGG GCAGGAGGGG TCCTGGTTGC TAGCCATCTG CAGAGCTTCC
551 TGGAGGTGTC GTACCGCGTT CTACGCCACC TTGCGCAGCC CACACCATTG
601 GGCCCTGCCA GCTCCCTGCC CCAGAGCTTC CTGCTCAAGT CTTTAGAGCA
651 AGTGAGAAAG ATCCAGGGCG ATGGCGCAGC GCTCCAGGAG AAGCTGTGTG
701 CCACCTACAA GCTGTGCCAC CCCGAGGAGC TGGTGCTGCT CGGACACTCT
30751 CTGGGCATCC CCTGGGCTCC CCTGAGCTCC TGCCCCAGCC AGGCCCTGCA
801 GCTGGCAGGC TGCTTGAGCC AACTCCATAG CGGCCTTTTC CTCTACCAGG
851 GGCTCCTGCA GGCCCTGGAA GGGATATCCC CCGAGTTGGG TCCCACCTTG
901 GACACACTGC AGCTGGACGT CGCCGACTTT GCCACCACCA TCTGGCAGCA
951 GATGGAAGAA CTGGGATAAT AA (SEQ ID NO:109)
pMON13196
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
4051 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
45301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTA
401 CCCAGGGTGC CATGCCGGCC TTCGCCTCTG CTTTCCAGCG CCGGGCAGGA
451 GGGGTCCTGG TTGCTAGCCA TCTGCAGAGC TTCCTGGAGG TGTCGTACCG
501 CGTTCTACGC CACCTTGCGC AGCCCACACC ATTGGGCCCT GCCAGCTCCC
50551 TGCCCCAGAG CTTCCTGCTC AAGTCTTTAG AGCAAGTGAG AAAGATCCAG
601 GGCGATGGCG CAGCGCTCCA GGAGAAGCTG TGTGCCACCT ACAAGCTGTG ,~
651 CCACCCCGAG GAGCTGGTGC TGCTCGGACA CTCTCTGGGC ATCCCCTGGG

CA 02234061 1998-04-06
W O 971~2985 101 PCT~US96/1~77~
701 CTCCCCTGAG CTCCTGCCCC AGCCAGGCCC TGCAGCTGGC AGGCTGCTTG
751 AGCCAACTCC ATAGCGGCCT TTTCCTCTAC CAGGGGCTCC TGCAGGCCCT
801 GGAAGGGATA TCCCCCGAGT TGGGTCCCAC CTTGGACACA CTGCAGCTGG
851 ACGTCGCCGA CTTTGCCACC ACCATCTGGC AGCAGATGGA AGAACTGGGA
5901 ATGGCCCCTG CCCTGCAGCC CTAATAA (SEQ ID NO:110)
pMON13197
101 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGC&CAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTACCCAG
451 GGTGCCATGC CGGCCTTCGC CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT
501 CCTGGTTGCT AGCCATCTGC AGAGCTTCCT GGAGGTGTCG TACCGCGTTC
551 TACGCCACCT TGCGCAGCCC ACACCATTGG GCCCTGCCAG CTCCCTGCCC
601 CAGAGCTTCC TGCTCAAGTC TTTAGAGCAA GTGAGAAAGA TCCAGGGCGA
651 TGGCGCAGCG CTCCAGGAGA AGCTGTGTGC CACCTACAAG CTGTGCCACC
701 CCGAGGAGCT GGTGCTGCTC GGACACTCTC TGGGCATCCC CTGGGCTCCC
751 CTGAGCTCCT GCCCCAGCCA GGCCCTGCAG CTGGCAGGCT GCTTGAGCCA
801 ACTCCATAGC GGCCTTTTCC TCTACCAGGG GCTCCTGCAG GCCCTGGA~G
851 GGATATCCCC CGAGTTGGGT CCCACCTTGG ACACACTGCA GCTGGACGTC
901 GCCGACTTTG CCACCACCAT CTGGCAGCAG ATGGAAGAAC TGGGAATGGC
951 CCCTGCCCTG CAGCCCTAAT AA (SEQ ID NO:lll)
pMON13198
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTT
401 CTGCTTTCCA GCGCCGGGCA GGAGGGGTCC TGGTTGCTAG CCATCTGCAG
451 AGCTTCCTGG AGGTGTCGTA CCGCGTTCTA CGCCACCTTG CGCAGCCCAC
501 ACCATTGGGC CCTGCCAGCT CCCTGCCCCA GAGCTTCCTG CTCAAGTCTT
551 TAGAGCAAGT GAGAAAGATC CAGGGCGATG GCGCAGCGCT CCAGGAGAAG
601 CTGTGTGCCA CCTACAAGCT GTGCCACCCC GAGGAGCTGG TGCTGCTCGG
651 ACACTCTCTG GGCATCCCCT GGGCTCCCCT GAGCTCCTGC CCCAGCCAGG
701 CCCTGCAGCT GGCAGGCTGC TTGAGCCAAC TCCATAGCGG CCTTTTCCTC
751 TACCAGGGGC TCCTGCAGGC CCTGGAAGGG ATATCCCCCG AGTTGGGTCC
801 CACCTTGGAC ACACTGCAGC TGGACGTCGC CGACTTTGCC ACCACCATCT
851 GGCAGCAGAT GGAAGAACTG GGAATGGCCC CTGCCCTGCA GCCCACCCAG
901 GGTGCCATGC CGGCCTTCGC CTAATAA (SEQ ID NO:112)

CA 0223406l l998-04-06
W O 97/12985 102 PCTrUS96/15774
pMON13199
51 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
10251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTCGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTTCTGCT
451 TTCCAGCGCC GGGCAGGAGG GGTCCTGGTT GCTAGCCATC TGCAGAGCTT
501 CCTGGAGGTG TCGTACCGCG TTCTACGCCA CCTTGCGCAG CCCACACCAT
551 TGGGCCCTGC CAGCTCCCTG CCCCAGAGCT TCCTGCTCAA GTCTTTAGAG
601 CAAGTGAGAA AGATCCAGGG CGATGGCGCA GCGCTCCAGG AGAAGCTGTG
651 TGCCACCTAC AAGCTGTGCC ACCCCGAGGA GCTGGTGCTG CTCGGACACT
701 CTCTGGGCAT CCCCTGGGCT CCCCTGAGCT CCTGCCCCAG CCAGGCCCTG
20751 CAGCTGGCAG GCTGCTTGAG CCAACTCCAT AGCGGCCTTT TCCTCTACCA
801 GGGGCTCCTG CAGGCCCTGG AAGGGATATC CCCCGAGTTG GGTCCCACCT
8 51 TGGACACACT GCAGCTGGAC GTCGCCGACT TTGCCACCAC CATCTGGCAG
901 CAGATGGAAG AACTGGGAAT GGCCCCTGCC CTGCAGCCCA CCCAGGGTGC
951 CATGCCGGCC TTCGCCTAAT AA (SEQ ID NO:113)
pMON3 1112
1 ATGGCTAACT GCTCTAACAT GATCGATGAA ATCATCACCC ACCTGAAGCA
51 GCCACCGCTG CCGCTGCTGG ACTTCAACAA CCTCAATGGT GAAGACCAAG
30101 ATATCCTAAT GGACAATAAC CTTCGTCGTC CAAACCTCGA GGCATTCAAC
151 CGTGCTGTCA AGTCTCTGCA GAATGCATCA GCAATTGAGA GCATTCTTAA
201 AAATCTCCTG CCATGTCTGC CGCTAGCCAC GGCCGCACCC ACGCGACATC
251 CAATCCATAT CAAGGACGGT GACTGGAATG AATTCCGTCG TAAACTGACC
301 TTCTATCTGA AAACCTTGGA GAACGCGCAG GCTCAACAGT ACGTAGAGGG
3 5 3 51 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTACCCAG
451 GGTGCCATGC CGGCCTTCGC CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT
501 CCTGGTTGCT AGCCATCTGC AGAGCTTCCT GGAGGTGTCG TACCGCGTTC
551 TACGCCACCT TGCGCAGCCC TCTGGCGGCT CTGGCGGCTC TCAGAGCTTC
601 CTGCTCAAGT CTTTAGAGCA AGTGAGAAAG ATCCAGGGCG ATGGCGCAGC
651 GCTCCAGGAG AAGCTGTGTG CCACCTACAA GCTGTGCCAC CCCGAGGAGC
701 TGGTGCTGCT CGGACACTCT CTGGGCATCC CCTGGGCTCC CCTGAGCTCC
7 51 TGCCCCAGCC AGGCCCTGCA GCTGGCAGGC TGCTTGAGCC AACTCCATAG
801 CGGCCTTTTC CTCTACCAGG GGCTCCTGCA GGCCCTGGAA GGGATATCCC
458 51 CCGAGTTGGG TCCCACCTTG GACACACTGC AGCTGGACGT CGCCGACTTT
901 GCCACCACCA TCTGGCAGCA GATGGAAGAA CTGGGAATGG CCCCTGCCCT
951 GCAGCCCTAA TAA ~SEQ ID NO:114)
pMON31113
1 ATGGCTAACT GCTCTAACAT GATCGATGAA ATCATCACCC ACCTGAAGCA
51 GCCACCGCTG CCGCTGCTGG ACTTCAACAA CCTCAATGGT GAAGACCAAG

CA 02234061 1998-04-06
W O 97/12985 103 PCTnUS96/I5774
101 ATATCCTGAT GGAAAATAAC CTTCGTCGTC CAAACCTCGA GGCATTCAAC
151 CGTGCTGTCA AGTCTCTGCA GAATGCATCA GCAATTGAGA GCATTCTTAA
201 AAATCTCCTG CCATGTCTGC CCCT&GCCAC GGCCGCACCC ACGCGACATC
' 251 CAATCATCAT CCGTGACGGT GACTGGAATG AATTCCGTCG TAAACTGACC
301 TTCTATCTGA AAACCTTGGA GAACGCGCAG GCTCAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTACCCAG
451 GGTGCCATGC CGGCCTTCGC CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT
501 CCTGGTTGCT AGCCATCTGC AGAGCTTCCT GGAGGTGTCG TACCGCGTTC
551 TACGCCACCT TGCGCAGCCC ACACCATTGG GCCCTGCCAG CTCCCTGCCC
601 CAGAGCTTCC TGCTCAAGTC TTTAGAGCAA GTGAGAAAGA TCCAGGGCGA
651 TGGCGCAGCG CTCCAGGAGA AGCTGTGTGC CACCTACAAG CTGTGCCACC
701 CCGAGGAGCT GGTGCTGCTC GGACACTCTC TGGGCATCCC CTGGGCTCCC
751 CTGAGCTCCT GCCCCAGCCA GGCCCTGCAG CTGGCAGGCT GCTTGAGCCA
801 ACTCCATAGC GGCCTTTTCC TCTACCAGGG GCTCCTGCAG GCCCTGGAAG
851 GGATATCCCC CGAGTTGGGT CCCACCTTGG ACACACTGCA GCTGGACGTC
901 GCCGACTTTG CCACCACCAT CTGGCAGCAG ATGGAAGAAC TGGGAATGGC
951 CCCTGCCCTG CAGCCCTAAT AA (SEQ ID MO:115)
pMON31114
1 ATGGCl'AACT GCTCTAACAT GATCGATGAA ATCATCACCC ACCTGAAGCA
51 GCCACCGCTG CCGCTGCTGG ACTTCAACAA CCTCAATGGT GAAGACCAAG
101 ATATCCTGAT GGAAAATAAC CTTCGTCGTC CAAACCTCGA GGCATTCAAC
151 CGTGCTGTCA AGTCTCTGCA GAATGCATCA GCAATTGAGA GCATTCTTAA
201 AAATCTCCTG CCATGTCTGC CCCTGGCCAC GGCCGCACCC ACGCGACATC
251 CAATCATCAT CCGTGACGGT GACTGGAATG AATTCCGTCG TAAACTGACC
301 TTCTATCTGA AAACCTTGGA GAACGCGCAG GCTCAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTACCCAG
451 GGTGCCATGC CGGCCTTCGC CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT
501 CCTGGTTGCT AGCCATCTGC AGAGCTTCCT GGAGGTGTCG TACCGCGTTC
551 TACGCCACCT TGCGCAGCCC TCTGGCGGCT CTGGCGGCTC TCAGAGCTTC
601 CTGCTCAAGT CTTTAGAGCA AGTGAGAAAG ATCCAGGGCG ATGGCGCAGC
651 GCTCCAGGAG AAGCTGTGTG CCACCTACAA GCTGTGCCAC CCCGAGGAGC
701 TGGTGCTGCT CGGACACTCT CTGGGCATCC CCTGGGCTCC CCTGAGCTCC
751 TGCCCCAGCC AGGCCCTGCA GCTGGCAGGC TGCTTGAGCC AACTCCATAG
801 CGGCCTTTTC CTCTACCAGG GGCTCCTGCA GGCCCTGGAA GGGATATCCC
851 CCGAGTTGGG TCCCACCTTG GACACACTGC AGCTGGACGT CGCCGACTTT
901 GCCACCACCA TCTGGCAGCA GATGGAAGAA CTGGGAATGG CCCCTGCCCT
951 GCAGCCCTAA TAA (SEQ ID NO:116)
pMON31115
1 ATGGCTAACT GCTCTAACAT GATCGATGAA ATCATCACCC ACCTGAAGCA
51 GCCACCGCTG CCGCTGCTGG ACTTCAACAA CCTCAATGGT GAAGACCAAG
101 ATATCCTAAT GGACAATAAC CTTCGTCGTC CAAACCTCGA GGCATTCAAC
151 CGTGCTGTCA AGTCTCTGCA GAATGCATCA GCAATTGAGA GCATTCTTAA
201 AAATCTCCTG CCATGTCTGC CGCTAGCCAC GGCCGCACCC ACGCGACATC
251 CAATCCATAT CAAGGACGGT GACTGGAATG AATTCCGTCG TAAACTGACC
301 TTCTATCTGA AAACCTTGGA GAACGCGCAG GCTCAACAGT ACGTAGAGGG

CA 02234061 1998-04-06
W O 97/12985 104 PCT~US96/15774
351 CGGT&GAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTACCCAG
451 GGTGCCATGC CGGCCTTCGC CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT
501 CCTGGTTGCT AGCCATCTGC AGAGCTTCCT GGAGGTGTCG TACCGCGTTC
5 551 TACGCCACCT TGCGCAGCCC ACACCATTGG GCCCTGCCAG CTCCCTGCCC
601 CAGAGCTTCC TGCTCAAGTC TTTAGAGCAA GTGAGAAAGA TCCAGGGCGA r
651 TGGCGCAGCG CTCCAGGAGA AGCTGTGTGC CACCTACAAG CTGTGCCACC
701 CCGAGGAGCT GGTGCTGCTC GGACACTCTC TGGGCATCCC CTGGGCTCCC
751 CTGAGCTCCT GCCCCAGCCA GGCCCTGCAG CTGGCAGGCT GCTTGAGCCA
801 ACTCCATAGC GGCCTTTTCC TCTACCAGGG GCTCCTGCAG GCCCTGGAAG
851 GGATATCCCC CGAGTTGGGT CCCACCTTGG ACACACTGCA GCTGGACGTC
901 GCCGACTTTG CCACCACCAT CTGGCAGCAG ATGGAAGAAC TGGGAATGGC
951 CCCTGCCCTG CAGCCCTAAT AA (SEQ ID NO:117)
pMoN28505
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGAcTTccAAAccTGGAGAGcTTcGTAAGGGcTGTcAAGAAcTTAGAAAATGcATcAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTG
GACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTG
GGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACT
TGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTG
CAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAGGATCCC
AATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTT
GTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAACATGGCGTCTCCCGCTCCG
CCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGC
AGACTGAGCCAGTGCCCA (SEQ ID NO:118)
pMoN28506
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTG
GGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACC
CTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCC
CTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTT
GGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTC
CTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCC
ACCCTCTGCGTCAGGGAATTCGGCGGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGAC
CTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAG
TGCCCAGAGGTTCACCCT (SEQ ID NO:~l9)

CA 02234061 1998-04-06
W O 97/12985 105 PCTfUS96n~774
pMON28507
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAA
ACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAG
GGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAG
CTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTT
CCTCCACAGGGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAA
CACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTC
AGGGAATTCGGCGGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTC
AGTAAACTGCTl'CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTT
CACCCTTTGCCTACACCT (SEQ ID NO:120)
pMOM28508
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAG
GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA
GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAG
GTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGC
AGGACCACAGCT~C~GGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGA
GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC
GGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTT
CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCT
ACACCTGTCCTGCTGCCT (SEQ ID NO:121)
pMON2850~
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACC
AAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGG
GGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGT
CTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACC

CA 0223406l l998-04-06
W O 97/~2985 106 PCTrUS96/}577~
ACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAG
GTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAAC
ATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGAC
TCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCT
5 GTCCTGCTGCCTGCTGTG (SEQ ID NO:122)
pMON28510
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
10 TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCCC
15 CGGGGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCTCA
TAAACTCCAAACATGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATT
CTGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCA
CTTGCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCT
GCAGGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAGGATCCC
20 AATGCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTG
TAGGGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCA~CATGGCGTCTCCCGCTCCGCC
TGCTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGA
CTGACCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACT
TTAGTTG (SEQ ID NO:123)
pMON28511
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
30 CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
35 CATAAATCTCCAAACATGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGA
CAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAG
GGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTC
CGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTC
GGCGGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTG
40 CTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTG
CCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATG
GAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATG
GCAGCACGGGGACAACTG (SEQ ID MO:124)
45 pMON28512
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
50 ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC

CA 02234061 1998-04-06
W O 97/12985 107 PCT~US96/15774
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAG
GATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTG
ATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAACATGGCGTCTCCC
GCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTT
CACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCT
GCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGAC
ATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGA
CCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGG
GCCCTGCAGAGCCTCCTT (SEQ ID NO:125)
pMON28513
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTG
AGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACC
CTCTGCGTCAGGGAATTCGGCGGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTC
CGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGC
CCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGA
GAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTT
CTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTC
CTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGA
ACCCAGCTTCCTCCACAG (SEQ ID NO:126)
pMON28514
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACAC
CTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGG
GAATTCGGCGGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGT
AAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCAC
CCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACC
CAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGA
GTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTT
TCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCT
CCACAGGGCAGGACCACA (SEQ ID NO:127)
pMON28515

CA 02234061 1998-04-06
W O 97/1~985 108 PCT~US96/15774
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTC~AAAGAATCT
CATAAATCTCCAAACATGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGA
GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC
GGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTT
CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCT
ACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAG
GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA
GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAG
GTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGC
AGGACCACAGCTCACAAG (SEQ ID NO:128)
pMON28516
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTAC;'CTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTG
CGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAACATG
GCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCC
CATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTC
CTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAG
GCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGA
CAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTC
CTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACA
GCTCACAAGGATCCCAAT (SEQ ID NO:129)
pMON28519
GcTAAcTGcTcTATAATGATcGATGAAATTATAcATcAcTTAAAGAGAccAccTGcAccT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATA~ATCTCCAAACATGGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTG
GACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTG
GGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACT
TGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTG
CAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAGGATCCC
AATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTT
GTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCAACATGGCGTCTCCCGCTCCGCCT

CA 02234061 1998-04-06
W O 97112985 109 PCT~US96/I~774
GCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGA
CTGAGCCAGTGCCCA (SEQ ID NO:130)
pMO~28520
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTG
GGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACC
CTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCC
CTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTT
GGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTC
CTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCC
ACCCTCTGCGTCAGGGAATTCGGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTC
CGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGC
CCAGAGGTTCACCCT (SEQ ID NO:131)
pMON28521
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAA
ACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAG
GGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAG
CTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTT
CCTCCACAGGGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAA
CACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTC
AGGGAATTCGGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGT
AAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCAC
CCTTTGCCTACACCT (SEQ ID NO:132)
pMON28522
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAG
GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA

CA 02234061 1998-04-06
W O 97/12985 110 PCTAUS96/15774
GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAG
GTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGC
AGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGA
GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC
AACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGT
GACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACA
CCTGTCCTGCTGCCT (SEQ ID NO:133)
pMON28523
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACC
AAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGG
GGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGT
CTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACC
ACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAG
GTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCAACATG
GCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAA~CTGCTTCGTGACTCC
CATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTC
CTGCTGCCTGCTGTG (SEQ ID NO:134)
pMON28524
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGA~ACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGAC
ATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGA
CCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGG
GCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAG
GATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTG
ATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCAACATGGCGTCTCCCGCT
CCGCCTGCTTGTGACCTCCGAGTCCTCAGTA~ACTGCTTCGTGACTCCCATGTCCTTCAC
AGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCT
GTGGACTTTAGCTTG (SEQ ID NO:135)
pMON28525
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
_

CA 02234061 1998-04-06
W O 97112985 111 PCT~US9~15774
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGA
CAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAG
GGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTC
CGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTC
GGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTT
CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCT
ACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAG
GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA
GCACGGGGACAACTG (SEQ ID NO:136)
pMON28526
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAG
GATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTG
ATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC~ACATGGCGTCTCCCGCT
CCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCAC
AGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCT
GTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATT
CTGGGAGCAG~GACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCC
ACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCC
CTGCAGAGCCTCCTT (SEQ ID NO:137)
pMON28527
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTG
AGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACC
CTCTGCGTCAGGGAATTCGGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGA
GTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCA
GAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAA
TGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTG
CTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTG
GGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACC
CAGCTTCCTCCACAG (SEQ ID NO:138)
pMON28528

CA 0223406l l998-04-06
W O 97/12985 112 PCTrUS96/15774
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACAC
CTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGG
GAATTCGGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAA
CTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCT
TTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAG
ATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTG
ATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCT
GGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCA
CAGGGCAGGACCACA ~SEQ ID NO:13g)
pMOM28529
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGA
GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC
AACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGT
GACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACA
CCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAG
ACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCA
CGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTC
CGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGG
ACCACAGCTCACAAG (SEQ ID MO:140)
pMON28530
GCTAACTGCTC'TATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTG
CGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCAACATGGCG
TCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCAT
GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTG
CTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCA
CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAA

CA 02234061 1998-04-06
W O 97112985 113 PCT~US96/I5774
CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTC
CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCT
CACAAGGATCCCAAT (~EQ ID NO:141)
pMON28533
GCTAACTGCTCTATAATGATCGATGA~ATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
GACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGTA
TGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCTCG
CATCCAATCATCATCAAGGCAGGTGACTG&CAAGAATTCCGGGAAAAACTGACGTTCTAT
TGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCCCCGG
TAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTA~AGAATCTCATAAA
TCTCCAAACATGGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTT
AGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCA
GTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTC
TCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGC
CTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAGGATCCCAATGCC
ATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGA
GGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAACGGCGGCAACATGGCGTCCCCAGCG
CCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCAC
AGCAGACTGAGCCAGTGCCCA (SEQ ID NO:142)
pMON28534
GCTAACTGCI~ J ATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGA~AATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTG
GGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACC
CTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCC
CTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTT
GGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTC
CTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCC
ACCCTCTGCGTCAGGGAATTCGGCGGCAACGGCGGCAACATGGCGTCCCCAGCGCCGCCT
GCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGA
CTGAGCCAGTGCCCAGAGGTTCACCCT (SEQ ID NO:143)
pMoN28535
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAA

CA 02234061 1998-04-06
W O 97/12985 114 PCT~US96/15774
ACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAG
GGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAG
CTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTT
CCTCCACAGGGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAA
CACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTC
AGGGAATTCGGCGGCAACGGCGGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTC
CGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGC
CCAGAGGTTCACCCTTTGCCTACACCT (SEQ ID NO:144)
pMON28536
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAG
GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA
GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAG
GTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGC
AGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGA
GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC
GGCAACGGCGGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGT
AAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCAC
CCTTTGCCTACACCTGTCCTGCTGCCT (SEQ ID NO:145)
pMON28537
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCA~GCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACC
AAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGG
GGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGT
CTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACC
ACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAG
GTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAAC
GGCGGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTG
CTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTG
CCTACACCTGTCCTGCTGCCTGCTGTG (SEQ ID NO:146)
pMON28538
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT ,~
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT

CA 0223406l l998-04-06
W O 97/12985 115 PCTAUS96/15774
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGAC
ATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGA
CCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGG
GCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAG
GATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTG
ATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAACGGCGGCAACATG
GCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCC
CATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTC
CTGCTGCCTGCTGTGGACTTTAGCTTG (SEQ ID NO:147)
pMoN28539
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGA
CAGGTccGTcTccTccTTGGGGcccTGcAGAGccTccTTGGAAcccAGcTTccTccAcAG
GGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTC
CGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTC
GGCGGCAACGGCGGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTC
AGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTT
CACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAA
ACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAG
GGAGTGATGGCAGCACGGGGACAACTG (SEQ ID NO:148)
pMOM28540
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAG
GATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTG
ATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAACGGCGGCAACATG
GCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCC
CATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTC
CTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAG
GCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGA
CAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTC
CTCCTTGGGGCCCTGCAGAGCCTCCTT (SEQ ID NO:149)

CA 02234061 1998-04-06
W O 97/12985 116 PCT~US96/15774
pMON28541
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACC'GTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTG
AGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACC
CTCTGCGTCAGGGAATTCGGCGGCAACGGCGGCAACATGGCGTCCCCAGCGCCGCCTGCT
TGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTG
AGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTT
AGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCA
GTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTC
TCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGC
CTCCTTGGAACCCAGCTTCCTCCACAG (SEQ ID NO:150)
20 pMON2~3 54 2
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
2 5 ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGA~AAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACAC
CTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGG
GAATTCGGCGGCAACGGCGGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGA
GTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCA
GAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAA
TGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTG
3 5 CTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTG
GGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACC
CAGCTTCCTCCACAGGGCAGGACCACA (SEQ ID NO:151)
pMON28543
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGA
GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC
GGCAACGGCGGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGT
AAACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCAC ~.
CCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACC

CA 0223406l l998-04-06
W O 97/1298~ 117 PCT~US96/15774
CAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGA
GTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTT
TCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCT
CCACA&GGCAGGACCACAGCTCACAAG (SEQ ID NO:152)
pMoN2 8544
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGAcATccAATcATcATcAAGGcAGGTGAcTGGcAAGAATTccGGGAAAAAcTGAcGTTc
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTG
CGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAACGGC
GGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTT
CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCT
AcAccTGTccTGcTGccTGcTGTGGAcTTTAGcTTGGGAGAATGGAAAAcccAGATGGAG
GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA
GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAG
GTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGC
AGGACCACAGCTCACAAGGATCCCAAT (SEQ ID NO:153)
pMON28545
GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT
TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT
CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT
ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT
CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC
TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC
CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT
CATAAATCTCCAAACATGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGA
GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC
GGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTT
CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCT
ACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAG
GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA
GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAG
GTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGGGCAGGACCACAGCT
CACAAG (SEQ ID NO:154)
pMON15981
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGATCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA A~AACTGACG

CA 0223406l l998-04-06
W O 97/12985 118 PCT~US96/15774
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GTCTTACAAG
451 CTGTGCCACC CCGAGGAGCT GGTGCTGCTC GGACACTCTC TGGGCATCCC
501 CTGGGCTCCC CTGAGCTCCT GCCCCAGCCA GGCCCTGCAG CTGGCAGGCT
551 GCTTGAGCCA ACTCCATAGC GGCCTTTTCC TCTACCAGGG GCTCCTGCAG
601 GCCCTGGAAG GGATATCCCC CGAGTTGGGT CCCACCTTGG ACACACTGCA
651 GCTGGACGTC GCCGACTTTG CCACCACCAT CTGGCAGCAG ATGGAAGAAC
701 TGGGAATGGC CCCTGCCCTG CAGCCCACCC AGGGTGCCAT GCCGGCCTTC
751 GCCTCTGCTT TCCAGCGCCG GGCAGGAGGG GTCCTGGTTG CTAGCCATCT
801 GCAGAGCTTC CTGGAGGTGT CGTACCGCGT TCTACGCCAC CTTGCGCAGC
851 CCGGCGGCGG CTCTGACATG GCTACACCAT TAGGCCCTGC CAGCTCCCTG
901 CCCCAGAGCT TCCTGCTCAA GTCTTTAGAG CAAGTGAGGA AGATCCAGGG
951 CGATGGCGCA GCGCTCCAGG AGAAGCTGTG TGCCACCTAA TAA;
(SEQ ID NO:155)
p~ON15982
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGATCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATA~AT CTCCAAACAT GTCTCCCGAG
451 TTGGGTCCCA CCTTGGACAC ACTGCAGCTG GACGTCGCCG ACTTTGCCAC
501 CACCATCTGG CAGCAGATGG AAGAACTGGG AATGGCCCCT GCCCTGCAGC
551 CCACCCAGGG TGCCATGCCG GCCTTCGCCT CTGCTTTCCA GCGCCGGGCA
601 GGAGGGGTCC TGGTTGCTAG CCATCTGCAG AGCTTCCTGG AGGTGTCGTA
651 CCGCGTTCTA CGCCACCTTG CGCAGCCCGG CGGCGGCTCT GACATGGCTA
701 CACCATTAGG CCCTGCCAGC TCCCTGCCCC AGAGCTTCCT GCTCAAGTCT
751 TTAGAGCAAG TGAGGAAGAT CCAGGGCGAT GGCGCAGCGC TCCAGGAGAA
801 GCTGTGTGCC ACCTACAAGC TGTGCCACCC CGAGGAGCTG GTGCTGCTCG
851 GACACTCTCT GGGCATCCCC TGGGCTCCCC TGAGCTCCTG CCCCAGCCAG
901 GCCCTGCAGC TGGCAGGCTG CTTGAGCCAA CTCCATAGCG GCCTTTTCCT
951 CTACCAGGGG CTCCTGCAGG CCCTGGAAGG GATATCCTAA TAA;
(~EQ ID NO:156)
pMON15965
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGATCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GTCTTCTGCT ,~
451 TTCCAGCGCC GGGCAGGAGG GGTCCTGGTT GCTAGCCATC TGCAGAGCTT
-

CA 02234061 1998-04-06
W O 97112985 ~CTAUS96/15774
119
501 CCTGGAGGTG TCGTACCGCG TTCTACGCCA CCTTGCGCAG CCCGGCGGCG
551 GCTCTGACAT GGCTACACCA TTAGGCCCTG CCAGCTCCCT GCCCCAGAGC
601 TTCCTGCTCA AGTCTTTAGA GCAAGTGAGG AAGATCCAGG GCGATGGCGC
651 AGCGCTCCAG GAGAAGCTGT GTGCCACCTA CAAGCTGTGC CACCCCGAGG
701 AGCTGGTGCT GCTCGGACAC TCTCTGGGCA TCCCCTGGGC TCCCCTGAGC
751 TCCTGCCCCA GCCAGGCCCT GCAGCTGGCA GGCTGCTTGA GCCAACTCCA
801 TAGCGGCCTT TTCCTCTACC AGGGGCTCCT GCAGGCCCTG GAAGGGATAT
851 CCCCCGAGTT GGGTCCCACC TTGGACACAC TGCAGCTGGA CGTCGCCGAC
901 TTTGCCACCA CCATCTGGCA GCAGATGGAA GAACTGGGAA TGGCCCCTGC
951 CCTGCAGCCC ACCCAGGGTG CCATGCCGGC CTTCGCCTAA TAA
(SEQ ID NO:157)
pMON15966
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGATCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GTCTATGGCC
451 CCTGCCCTGC AGCCCACCCA GGGTGCCATG CCGGCCTTCG CCTCTGCTTT
501 CCAGCGCCGG GCAGGAGGGG TCCTGGTTGC TAGCCATCTG CAGAGCTTCC
551 TGGAGGTGTC GTACCGCGTT CTACGCCACC TTGCGCAGCC CGGCGGCGGC
601 TCTGACATGG CTACACCATT AGGCCCTGCC AGCTCCCTGC CCCAGAGCTT
651 CCTGCTCAAG TCTTTAGAGC AAGTGAGGAA GATCCAGGGC GATGGCGCAG
701 CGCTCCAGGA GAAGCTGTGT GCCACCTACA AGCTGTGCCA CCCCGAGGAG
751 CTGGTGCTGC TCGGACACTC TCTGGGCATC CCCTGGGCTC CCCTGAGCTC
801 CTGCCCCAGC CAGGCCCTGC AGCTGGCAGG CTGCTTGAGC CAACTCCATA
851 GCGGCCTTTT CCTCTACCAG GGGCTCCTGC AGGCCCTGGA AGGGATATCC
901 CCCGAGTTGG GTCCCACCTT GGACACACTG CAGCTGGACG TCGCCGACTT
951 TGCCACCACC ATCTGGCAGC AGATGGAAGA ACTGGGATAA TAA
35(SEQ ID NO:158
pMON15967
1 ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG
4051 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT
101 CTATCCTGAT GGATCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA
151 AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG
201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC
251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG
301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG
351 CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC
401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GTCTACCCAG
451 GGTGCCATGC CGGCCTTCGC CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT
501 CCTGGTTGCT AGCCATCTGC AGAGCTTCCT GGAGGTGTCG TACCGCGTTC
551 TACGCCACCT TGCGCAGCCC GGCGGCGGCT CTGACATGGC TACACCATTA
601 GGCCCTGCCA GCTCCCTGCC CCAGAGCTTC CTGCTCAAGT CTTTAGAGCA
651 AGTGAGGAAG ATCCAGGGCG ATGGCGCAGC GCTCCAGGAG AAGCTGTGTG

CA 02234061 1998-04-06
W O 97/12985 120 PCT~US96/15774
701 CCACCTACAA GCTGTGCCAC CCCGAGGAGC TGGTGCTGCT CGGACACTCT
751 CTGGGCATCC CCTGGGCTCC CCTGAGCTCC TGCCCCAGCC AGGCCCTGCA
801 GCTGGCAGGC TGCTTGAGCC AACTCCATAG CGGCCTTTTC CTCTACCAGG
851 GGCTCCTGCA GGCCCTGGAA GGGATATCCC CCGAGTTGGG TCCCACCTTG
901 GACACACTGC AGCTGGACGT CGCCGACTTT GCCACCACCA TCTGGCAGCA
951 GATGGAAGAA CTGGGAATGG CCCCTGCCCT GCAGCCCTAA TAA
(SEQ ID NO:159)
pMON15960
1 ATGGCTACAC CATTGGGCCC TGCCAGCTCC CTGCCCCAGA GCTTCCTGCT
51 CAAGTCTTTA GAGCAAGTGA GGAAGATCCA GGGCGATGGC GCAGCGCTCC
101 AGGAGAAGCT GTGTGCCACC TACAAGCTGT GCCACCCCGA GGAGCTGGTG
151 CTGCTCGGAC ACTCTCTGGG CATCCCCTGG GCTCCCCTGA GCTCCTGCCC
201 CAGCCAGGCC CTGCAGCTGG CAGGCTGCTT GAGCCAACTC CATAGCGGCC
251 TTTTCCTCTA CCAGGGGCTC CTGCAGGCCC TGGAAGGGAT ATCCCCCGAG
301 TTGGGTCCCA CCTTGGACAC ACTGCAGCTG GACGTCGCCG ACTTTGCCAC
351 CACCATCTGG CAGCAGATGG AAGAACTGGG AATGGCCCCT GCCCTGCAGC
401 CCACCCAGGG TGCCATGCCG GCCTTCGCCT CTGCTTTCCA GCGCCGGGCA
451 GGAGGGGTCC TGGTTGCTAG CCATCTGCAG AGCTTCCTGG AGGTGTCGTA
501 CCGCGTTCTA CGCCACCTTG CGCAGCCCGG CGGCGGCTCT GACATGGCTA
551 CACCATTGGG CCCTGCCAGC TCCCTGCCCC AGAGCTTCCT GCTCAAGTCT
601 TTAGAGCAAG TGAGGAAGAT CCAGGGCGAT GGCGCAGCGC TCCAGGAGAA
651 GCTGTGTGCC ACCTACAAGC TGTGCCACCC CGAGGAGCTG GTGCTGCTCG
701 GACACTCTCT GGGCATCCCC TGGGCTCCCC TGAGCTCCTG CCCCAGCCAG
751 GCCCTGCAGC TGGCAGGCTG CTTGAGCCAA CTCCATAGCG GCCTTTTCCT
801 CTACCAGGGG CTCCTGCAGG CCCTGGAAGG GATATCCCCC GAGTTGGGTC
851 CCACCTTGGA CACACTGCAG CTGGACGTCG CCGACTTTGC CACCACCATC
901 TGGCAGCAGA TGGAAGAACT GGGAATGGCC CCTGCCCTGC AGCCCACCCA
1001 TCCTGGTTGC TAGCCATCTG CAGAGCTTCC TGGAGGTGTC GTACCGCGTT
1051 CTACGCCACC TTGCGCAGCC CTGATAA (SEQ ID NO:160
PMON32132
TCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCAT
GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTG
CTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCA
CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACA~
CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTC
CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCT
CACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGT
TTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGG (SEQ ID NO:249)
PMON3Zl33
TCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCAT
GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTG
CTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCA
CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAA
CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTC
CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGGGCAGGACCACAGCTCACAAGGATCCC ,-

CA 0223406l l998-04-06
W O 97/12985 121 PCTAUS96/15774
AATGCCATCTTCCTGAGCTTCCAACACCTGCTCC&AGGAAAGGTGCGTTTCCTGATGCTT
GTAGGAGGGTCCACCCTCTGCGTCAGG (SEQ ID NO:250)
pMON32134
TCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCAT
GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTG
CTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCA
CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAA
CTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTC
CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCT
CACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGT
TTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGG ~SEQ ID NO:251)
15 Pmonl3181
1 CCATGGCTAA CTGCTCTATA ATGATCGATG AAATTATACA TCACTTAAAG
51 AGACCACCTG CACCTTTGCT GGACCCGAAC AACCTCAATG ACGAAGACGT
101 CTCTATCCTG ATGGATCGAA ACCTTCGACT TCCAAACCTG GAGAGCTTCG
151 TAAGGGCTGT CAAGAACTTA GAAAATGCAT CAGGTATTGA GGCAATTCTT
201 CGTAATCTCC AACCATGTCT GCCCTCTGCC ACGGCCGCAC CCTCTCGACA
251 TCCAATCATC ATCAAGGCAG GTGACTGGCA AGAATTCCGG GAAAAACTGA
301 CGTTCTATCT GGTTACCCTT GAGCAAGCGC AGGAACAACA GTACGTAgag
351 ggcggtggag gctcCCCGGG TGAACCGTCT GGTCCAATCT CTACTATCAA
401 CCCGTCTCCT CCGTCTAAAG AATCTCATAA ATCTCCAAAC ATGTAAGGTA
451 CCGCATGCAA GCTT (SEQ ID No:257)
Pmonl3180.Seg
1 CCATGGCTAA CTGCTCTATA ATGATCGATG AAATTATACA TCACTTAAAG
51 AGACCACCTG CACCTTTGCT GGACCCGAAC AACCTCAATG ACGAAGACGT
101 CTCTATCCTG ATGGATCGAA ACCTTCGACT TCCAAACCTG GAGAGCTTCG
151 TAAGGGCTGT CAAGAACTTA GAAAATGCAT CAGGTATTGA GGCAATTCTT
201 CGTAATCTCC AACCATGTCT GCCCTCTGCC ACGGCCGCAC CCTCTCGACA
251 TCCAATCATC ATCAAGGCAG GTGACTGGCA AGAATTCCGG GAAAAACTGA
301 CGTTCTATCT GGTTACCCTT GAGCAAGCGC AGGAACAACA GTACGTAgag
351 ggcggtggag gctcCCCGGG TGGTGGTTCT GGCGGCGGCT CCAACATGTA
401 AGGTACCGCA TGCAAGCTT (SEQ ID NO:258)
_

CA 02234061 1998-04-06
W O 97/12985 122 PCT~US96/15774
T~RT.F. 3
PROTEIN SEOUENC~S
pMON26458pep
SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHis
ValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProValLeu
LeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAla
GlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGln
LeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeu
LeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThrAla
HisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeukeuArgGlyLysValArg
PheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPhe
(SEQ ID NO:161)
pMOM28548pep
SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHis
ValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProValLeu
LeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAla
GlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGln
LeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeu
LeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThrAla
HisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArg
PheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGlyGlyAsnMetAla
SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHis
ValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProValLeu
LeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAla
GlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGln
LeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeu
LeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnGlyArgThrThrAlaHisLysAspPro
AsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArgPheLeuMetLeu
ValGlyGlySerThrLeuCysValArg (SEQ ID NO-162)
pMON28500
SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHis
ValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProValLeu
LeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAla
GlnAspIleLeuGlyAlavalThrLeuLeuLeuGluGlyvalMetAlaAlaArgGlyGln
LeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeu
LeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThrAla
HisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArg
PheLeuMetLeuValGlyGlySerThrLeuGysValArgGluPheGlyAsnMetAlaSer
ProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHisVal
LeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProValLeuLeu
ProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAlaGln
AspIleLeuGlyAlavalThrLeuLeuLeuGluGlyvalMetAlaAlaArgGlyGlnLeu
GlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeuLeu ,-
GlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThrAlaHis

CA 0223406l l998-04-06
W O 97112985 123 PCT~US96/15774
LysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArgPhe
LeuMetLeuValGlyGlySerThrLeuCysValArg (SEQ ID NO:163)
pMON28501
; SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHis
ValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProValLeu
LeuProAlaValAspPheSerLeuGlyGluTrpLySThrGlnMetGluGluThrLysAla
GlnAspIleLeuGlyAlavalThrLeuLeuLeuGluGlyvalMetAlaAlaArgGlyGln
LeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeu
LeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThrAla
HisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArg
PheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGlyGlyAsnMetAla
SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHis
ValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProValLeu
LeuProAlaValAspPheSerLeuGlyGluTrpLySThrGlnMetGluGluThrLysAla
GlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGln
LeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeUSerGlyGlnValArgLeuLeu
LeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuPrOProGlnGlyArgThrThrAla
HisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArg
PheLeuMetLeuValGlyGlySerThrLeuCysValArg (SEQ ID NO:164)
pMOM28502
SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHis
ValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProValLeu
LeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAla
GlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGln
LeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeu
LeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThrAla
HisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArg
PheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGlyGlyAsnGlyGly
AsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArg
AspSerHisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThr
ProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGlu
ThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAla
ArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnVal
ArgLeuLeuLeuGlyAla~euGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArg
ThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGly
LysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArg
(SEQ ID NO:165)
13182.Pept
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ilt~ Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro

CA 02234061 1998-04-06
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Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Tyr Lys Leu Cys
His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro
Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala
Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly
5 Leu Leu Gln Ala Leu Glu Gly Il e Ser Pro Glu Leu Gly Pro Thr
Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile
Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro
Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu
10 Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly
Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val
Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys
Ala Thr (SF~Q ID NO: 166)
13183 . Pept
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
20 Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
25 Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Tyr Lys Leu Cys
His Pro Glu Glu Leu val Leu Leu Gly His Ser Leu Gly Ile Pro
Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala
3 0 Gly Cys Leu Ser &ln Leu ~Iis Ser Gly Leu Phe Leu Tyr Gln Gly
Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr
Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile
Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro
Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
3 5 Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu
Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly
Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val
Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys
Ala Thr (SEQ ID NO:167)
1318a . Pept
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
45 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
50 Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Pro Glu Leu Gly

CA 02234061 1998-04-06
W O 97/12985 125 PCT~US96/15774
Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr
Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu
Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln
Arg Arg Ala Gly Gly Val Leu Val Ala Ser His l eu Gln Ser Phe
5 Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser
- Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu
Gln val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys
Leu Cys Ala Thr Tyr Lys Leu Cy5 His Pro Glu Glu Leu Val Leu
Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys
10 Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His
Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly
Ile Ser ~SEQ ID NO:168)
15 13185 . Pept
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
2 0 Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg H1s Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
25 Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Pro Glu Leu Gly
Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr
Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu
Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln
3 0 Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe
Leu Glu Val Ser Tyr Arg Val Leu Arg E~is Leu Ala Gln Pro Ser
Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu
Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys
Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu
35 Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys
Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His
Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly
Ile Ser (SEQ ID NO: 169 )
13186 . Pept
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
45 Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile I,eu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
50 Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Met Ala Pro Ala
Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe

CA 02234061 1998-04-06
W O 97/12985 126 PCT~US96/15774
Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser
Phe Leu Glu Val Ser Tyr Ar~ Val Leu Arg His Leu Ala Gln Pro
Ser Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu
Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu
5 Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val
Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser
Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu
His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu
Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu
10 Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu
Leu Gly ( SEQ ID NO: 17 0 )
13187 . Pept
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
2 0 Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
2 5 Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Met Ala Pro Ala
Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe
Gln Arg Arg Ala Gly Gly Val Leu Val Ala Se~ HiS Leu Gln Ser
Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro
Ser Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu
3 0 Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu
Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val
Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser
Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu
His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu
3 5 Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu
Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu
Leu Gly ( SEQ ID NO: 171 )
40 13188 . Pept
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His HiS Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
45 Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
50 Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Thr Gln Gly Ala
Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val
Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg

CA 0223406l l998-04-06
W O 97~12985 127 PCT~US96tlS774
Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly Ser Gly Gly Ser
Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val Arg Lys Ile Gln
Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys Ala Thr Tyr ~ys
Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly
5 Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln
Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr
Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly
Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr
Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu
10 Gln Pro (SEQ ID NO: 172 )
13189 . Pept
15 Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Il~_ Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
20 Ala Ala Pro Ser Arg Xis Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu I,ys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Thr Gln Gly Ala
2 5 Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val
Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg
Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly Ser Gly Gly Ser
Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val Arg Lys Ile Gln
Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys
3 0 Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly
Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln
Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr
Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly
Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr
3 5 Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu
Gln Pro ( SEQ ID NO :173 )
13190 . Pept
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
45 Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Ser Ala Phe Gln
50 Arg Arg Ala Gly Gly Val Leu val Ala Ser His Leu Gln Ser Phe
Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser
Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu

CA 02234061 1998-04-06
W O 97/12985 128 PCT~US96/15774
Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys
Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu
Leu Gly HiS Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys
Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu HiS
5 Ser Gly Lell Phe :~eu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly
Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp
Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu
Gly Met Ala Pro Ala Leu Gln Pro Thr Gln Gly Ala Met Pro Ala
Phe Ala ( SEQ ID NO: 17 4 )
13191 . Pept
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
15 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
2 0 Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Ser Ala Phe Gln
Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe
2 5 Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser
Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu
Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys
Leu Cys Al,. Thr Tyr Lys Leu Cys HiS Pro Glu Glu Leu Val Leu
Leu Gly HiS Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys
3 0 Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His
Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly
Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp
Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu
Gly Met Ala Pro Ala Leu Gln Pro Thr Gln Gly Ala Met Pro Ala
3 5 Phe Ala ( SEQ ID NO: 17 5 )
13192 . Pept
40 Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
45 Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly GIy Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Tyr Lys Leu CyS
His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro
50 Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala
Gly Cys Leu Ser Gln Leu His Ser Gly I,eu Phe Leu Tyr Gln Gly ,~
Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr
-

CA 02234061 1998-04-06
W O 97/lZ985 129 PCT~US96/15774
Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile
Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro
Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
Ala Gly Gly Val Leu Val Ala Ser HiS Leu Gln Ser Phe Leu Glu
5 Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Thr Pro Leu
Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys Ser Leu
Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu
Lys Leu Cys Ala Thr ( SEQ ID NO: 17 6 )
13193 . Pept
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
15 val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
2Q Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Tyr Lys Leu Cys
His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro
Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala
25 Gly Cys Leu Ser Gln Leu HiS Ser Gly Leu Phe Leu Tyr Gln Gly
Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr
Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile
Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro
Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
3 0 Ala Gly Gly Val Leu Val Ala - Ser His Leu Gln Ser Phe Leu Glu
Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Thr Pro Leu
Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys Ser Leu
Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu
Lys Leu Cys Ala Thr (SEQ ID NO:177)
25190 . Pept
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile HiS His Leu Lys Arg
4 0 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
45 Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Pro Glu Leu Gly
Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr
~hr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu
50 Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln
Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe
Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Thr

CA 02234061 1998-04-06
W O 97tl2985 130 PCT~US96/1~774
Pro Leu Gl~ Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys
Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu
Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu
Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu
Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser
Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala
Leu Glu Gly Ile Ser ( SEQ ID NO: 17 8 )
pMON25191. Pep
Asn Cys Ser Ile Me~ Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn M~t Ala Pro Glu Leu Gly
Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr
Thr Ile TrE) Gln Gln Met Glu Glu Leu Gly Me~: Ala Pro Ala Leu
Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln
Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe
Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Thr
Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys
Ser ~eu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu
Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu
30 Leu Val Leu Leu Gly His Ser I eu Gly Ile Pro Trp Ala Pro Leu
Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser
Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala
Leu Glu Gly Ile Ser (SEQ ID NO:179)
131g4 . Pept
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Ilys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
40 Val Ser Ile Leu Met ASp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg HiS Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
45 Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Met Ala Pro Ala
Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe
Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser ~is Leu ~ln Ser
Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro
50 Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu
Lys Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala ,-
Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu
,

CA 0223406l l998-04-06
WO 97/12985 131 PCTAUS9fi~1~774
Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro
Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu
Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln
Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr
5 Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln
Met Glu Glu Leu Gly ( S13Q ID NO :180 )
13195 . Pept
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu ASp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
15 Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
20 Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Met Ala Pro Ala
Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe
Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser
Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro
Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu
2 5 Lys Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala
Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu
Glu Leu val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro
Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu
Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln
3 0 Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr
Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln
Met Glu Glu Leu Gly ( SEQ ID NO: 181 )
3 5 1319 6 . Pept
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
40 Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
45 Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Thr Gln Gly Ala
Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val
Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg
Val Leu Arg His Leu Ala Gln Pro Thr Pro Leu Gly Pro Ala Ser
Ser Leu Pro Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val Arg
50 Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys Ala
Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His
Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln
..

CA 02234061 1998-04-06
W O 97/1298~ 132 PCT~JS96/15774
Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu
Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro
Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp
Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala
5 Pro Ala Leu Gln Pro ( SEQ ID NO :182 )
13197 . Pept
10 Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu ~et Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
15 Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Glrl Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Thr GlrL Gly Ala
20 Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val
Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg
Val Leu Arg His Leu Ala Gln Pro Thr Pro Leu Gly Pro Ala Ser
Ser Leu Pro Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val Arg
Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys Ala
25 Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His
Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln
Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu
Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro
Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp
3 0 Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala
Pro Ala Leu Gln Pro ~SEQ ID NO: 183 )
1319 8 . Pept
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro I-eu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
40 Glu Ala Ile Leu Arg Asn Leu Gln Pro CyS Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Plle Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Ser Ala Phe Gln
45 Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe
Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Thr
Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys
Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu
Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu
50 Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu
Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser ,.
Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala

CA 02234061 1998-04-06
W O 97/12985 PCTnUS96/1577~
Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu
Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met
Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro Thr Gln Gly Ala
Met Pro Ala Phe Ala ( SEQ ID NO :184 )
13199 . Pept
10 Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
15 Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Ser Ala Phe Gln
2~ Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe
Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Thr
Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys
Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu
Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu
25 Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu
Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser
Gln Leu HiS Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala
Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu
Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met
3 0 Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro Thr Gln Gly Ala
Met Pro Ala Phe Ala (SEQ ID NO:185)
31104.Pep
Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met
Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala
Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg
Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg
40 His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gln Glu Phe Arg Glu
Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala Gln Glu Gln
Gln Gly Gly Gly Ser Asn Cys Ser Ile Met Ile Asp Glu Ile Ile
His His Leu Lys Arg Pro Pro Ala Pro Leu Tyr Val Glu Gly Gly
Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn
Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala
Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
Ala Gly Gly val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu
Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly
Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val
Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys
Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly
His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser

CA 02234061 1998-04-06
W O 97/12985 13~ PCTrUS96/15774
Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly
Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser
Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala
Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met
5 Ala Pro Ala Leu Gln Pro ~SEQ ID NO:186)
31105 . Pep
10 Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys
Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile
Lys Ala Gly Asp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr
Leu Val Thr Leu Glu Gln Ala Gln Glu Gln Gln Gly Gly Gly Ser
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His ~is Leu Lys Arg
15 Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Tyr Val Glu Gly Gly
Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn
Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala
20 Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
Ala Gly Gly Val Leu Val Ala Ser Xis Leu Gln Ser Phe Leu Glu
Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly
Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val
Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys
25 Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly
His Ser l,eu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser
Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly
Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser
Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala
3 0 Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met
Ala Pro Ala Leu Gln Pro ( SEQ ID NO: 187 )
31106 . Pep
Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gln
Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln
Ala Gln Glu Gln Gln Gly Gly Gly Ser Asn Cys Ser Ile Met Ile
Asp Glu Ile Ile His HiS Leu Lys Ar~ Pro Pro Ala Pro Leu Leu
40 Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met Asp
Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala val
Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn
Leu Gln Pro Cys Leu Pro Ser Ala Thr Ala Tyr Val Glu Gly Gly
Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn
45 Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala
Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu
Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly
Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val
50 Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys
Ala Thr Tyr Lys Leu Cys Xis Pro Glu Glu Leu Val Leu Leu Gly ,~
His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser

CA 02234061 1998-04-06
W O 97112985 135 PCTnUS96n5774
Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu HiS Ser Gly
Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser
Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala
Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met
5 Ala Pro Ala Leu Gln Pro ~SEQ ID N0:188)
31107 . Pep
10 Ala Gly Asp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu
Val Thr Leu Glu Gln Ala Gln Glu Gln Gln Gly Gly Gly Ser Asn
Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro
Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val
Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser
15 Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu
Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr Ala
Ala Pro Ser Arg His Pro Ile Ile Ile Lys Tyr Val Glu Gly Gly
Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn
Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala
20 Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu
Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly
Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val
Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys
25 Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly
His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser
Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly
Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser
Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp val Ala
3 0 Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met
Ala Pro Ala Leu Gln Pro (SEQ ID NO :189 )
31108 . Pep
Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met
Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala
Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg
Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg
HiS Pro Ile Ile Ile Lys Ala Gly Asp Trp Gln Glu Phe Arg Glu
Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln Ala Gln Glu Gln
Gln Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Asn Cys
Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro
Ala Pro Leu Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro
45 Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu
Ser His Lys Ser Pro Asn Met Ala Thr Gln Gly Ala Met Pro Ala
Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val Leu Val Ala
Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg
His Leu Ala Gln Pro Ser Gly Gly Ser Gly Gly Ser Gln Ser Phe
50 Leu Leu Lys Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly
Ala Ala Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His
Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp

CA 02234061 1998-04-06
W O 97/1298~ 13~ PCTAUS96/15774
Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly
Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu
Leu G1n Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu
Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp
5 Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro
(SEQ ID NO:l90)
31109 . Pep
10 Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys
Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Ile
Lys Ala Gly Asp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr
Leu Val Thr Leu Glu Gln Ala Gln Glu Gln Gln Gly Gly Gly Ser
Gly Gly Gly Ser Gly Gly Gly Ser Asn Cys Ser Ile Met Ile Asp
15 Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp
Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met Asp Arg
Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val :I.ys
Asn Leu Glu Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro
Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu
20 Ser His Lys Ser Pro Asn Met Ala Thr Gln Gly Ala Met Pro Ala
Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val Leu Val Ala
Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg
His Leu Ala Gln Pro Ser Gly Gly Ser Gly Gly Ser Gln Ser Phe
Leu Leu Lys Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly
2 5 Ala Ala Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His
Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp
Ala Pro Leu Ser Ser Cys Pro Ser Gln ~la Leu Gln Leu Ala Gly
Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu
Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu
3 0 Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp
Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro
(SEQ ID NO:l91)
31110 . Pep
Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp Gln
Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gln
Ala Gln Glu Gln &ln Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly
Gly Ser Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu
40 Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp
Glu Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn
Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser
Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser
Ala Thr Ala Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro
45 Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu
Ser His Lys Ser Pro Asn Met Ala Thr Gln Gly Ala Met Pro Ala
Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val Leu Val Ala
Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg
His Leu Ala Gln Pro Ser Gly Gly Ser Gly Gly Ser Gln Ser Phe
50 Leu Leu Lys Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly
Ala Ala Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His
Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp

CA 02234061 1998-04-06
W O 97/12985 137 PCT~US96/15774
Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly
Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu
Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu
Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp
Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro
(SEQ ID NO:192)
31111.Pep
Ala Gly Asp Trp Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu
Val Thr Leu Glu Gln Ala Gln Glu Gln Gln Gly Gly Gly Ser Gly
Gly Gly Ser Gly Gly Gly Ser Asn Cys Ser Ile Met Ile Asp Glu
Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro
Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met Asp Arg Asn
Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn
Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gln
Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile
Ile Ile Lys Tyr Val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro
Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro Ser Lys Glu
Ser His Lys Ser Pro Asn Met Ala Thr Gln Gly.Ala Met Pro Ala
Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val Leu Val Ala
Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg
His Leu Ala Gln Pro Ser Gly Gly Ser Gly Gly Ser Gln Ser Phe
Leu Leu Ly~ Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly
Ala Ala Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His
Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp
Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly
Cys Leu Ser Gln Leu HiS Ser Gly Leu Phe Leu Tyr Gln Gly Leu
Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu
Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp
Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro
(SEQ ID MO:193)
pMON15981
MetAlaAsnCysSerIleMetIleAspGluIleIleHiSHisLeuLysArgProProAla
ProLeuLeuAspProAsnAsnLeuAsnAspGluASpValSerIleLeuMetAspArgAsn
LeuArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSer
GlyIleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro
SerArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThr
pheTyrLeuvalThrLeuGluGlnAlaGlnGluGlnGlnTyrvalGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaTyrLysLeuCySHisproGluGluLeuvalLeuLeu
GlyHisSerLeuGlyIleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGln
LeuAlaGlyCysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGln
AlaLeuGluGlyIleSerProGluLeuGlyProThrLeUASpThrLeuGlnLeuAspVal
AlaAspPheAlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAlaProAlaLeu
GlnProThrGlnGlyAlaMetProAlaPheAlaSerAlaPheGlnArgArgAlaGlyGly
ValLeuValAlaSerHisLeuGlnSerPheLeuGluValSerTyrArgValLeUArgHis
LeuAlaGlnProGlyGlyGlySerAspMetAlaThrProLeuGlyProAlaSerSerLeu
ProGlnSerPheLeuLeuLysSerLeuGluGlnValArgLysIleGlnGlyAspGlyAla
AlaLeuGlnGluLysLeuCysAlaThr (SEQ ID MO:194)

CA 02234061 1998-04-06
W O 97/12985 138 PCTnJS96/1~774
pMON15982
MetAlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAla
ProLeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsn
LeuArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSer
GlyIleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro
SerArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThr
PheTyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGl.uProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaProGluLeuGlyProThrLeuAspThrLeuGlnLeu
AspValAlaAspPheAlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAlaPro
AlaLeuGlnProThrGlnGlyAlaMetProAlaPheAlaSerAlaPheGlnArgArgAla
GlyGlyValLeuValAlaSerHisLeuGlnSerPheLeuGluValSerTyrArgValLeu
ArgHisLeuAlaGlnproGlyGlyGlyserAspMetAlaThrproLeuGlyproAlaser
SerLeuProGlnSerPheLeuLeuLysSerLeuGluGlnValArgLysIleGlnGlyAsp
GlyAlaAlaLeuGlnGluLysLeuCysAlaThrTyrLysLeuCysHisProGluGluLeu
ValLeuLeuGlyHisSerLeuGlyIleProTrpAlaProLeuSerSerCysProSerGln
AlaLeuGlnLeuAlaGlyCysLeuSerGln~euHisSerGlyLeuPhe~euTyrGlnGly
LeuLeuGlnAlaLeuGluGlyIleSer (SEQ ID NO:195)
pMON15965
MetAlaAsnCysSerIleMetIleAspGluIleIleHiSHisLeuLysArgProProAla
ProLeuLeuAspproAsnAsnLeuAsnAspGluAspvalserIleLeuMetAspArgAsn
LeuArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSer
GlyIleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro
SerArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThr
PheTyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaSerAlaPheGlnArgArgAlaGlyGlyValLeuVal
AlaSerHisLeuGlnSerPheLeuGluValSerTyrArgValLeuArgHisLeuAlaGln
ProGlyGlyGlySerAspMetAlaThrProLeuGlyProAlaSerSerLeuProGlnSer
PheLeuLeuLysSerLeuGluGlnValArgLysIleGlnGlyAspGly~laAlaLeuGln
GluLysLeuCysAlaThrTyrLysLeuCysHisProGluGluLeuValLeuLeuGlyHis
SerLeuGlyIleProTrpAlaProLeuSerSerCySProSerGlnAlaLeuGlnLeuAla
GlyCysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGlnAlaLeu
GluGlyIleSerProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspValAlaAsp
PheAlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAlaProAlaLeuGlnPro
ThrGlnGlyAlaMetProAlaPheAla (SEQ ID NO:196)
pMON15966
MetAlaAsnCysSerIleMetIleAspGluIleIleHiSHiSLeuLysArgProProAla
ProLeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsn
LeuArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSer
GlyIleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro
SerArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThr
PheTyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaMetAlaProAlaLeuGlnProThrGlnGlyAlaMet ,~
ProAlaPheAlaSerAlaPheGlnArgArgAlaGlyGlyValLeuValAlaSerHisLeu

CA 0223406l l998-04-06
W O 97/~298S 139 PCT~US96/I5774
GlnSerPheLeuGluValSerTyrArgValLeuArgHisLeuAlaGlnProGlyGlyGly
SerAspMetAlaThrProLeuGlyProAlaSerSerLeUproGlnserpheLeuLeuLys
SerLeuGluGlnvalArgLysIleGlnGlyAspGlyAlaAlaLeuGlnGluLysLeucys
AlaThrTyrLysLeuCysHisProGluGluLeuValLeuLeuGlyHisSerLeuGlyIle
ProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGlnLeuAlaGlyCysLeuSer
GlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGlnAlaLeuGluGlyIleSer
ProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspValAlaAspPheAlaThrThr
IleTrpGlnGlnMetGluGluLeuGly (SEQ ID NO:197)
pMON15967
MetAlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAla
ProLeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsn
LeuArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSer
GlyIleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro
SerArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThr
PheTyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGly
SerproGlyGluproserGlyproIleserThrIleAsnproserproproserLysGlu
SerHisLysSerProAsnMetAlaThrGlnGlyAlaMetProAlaPheAlaSerAlaPhe
GlnArgArgAlaGlyGlyValLeuValAlaSerHisLeuGlnSerPheLeuGluValSer
TyrArgValLeuArgHisLeuAlaGlnProGlyGlyGlySerAspMetAlaThrProLeu
GlyProAlaSerSerLeuProGlnSerPheLeuLeuLySSerLeuGluGlnValArgLys
IleGlnGlyAspGlyAlaAlaLeuGlnGluLysLeucysAlaThrTyrLysLeucysHis
ProGluGluLeuValLeuLeuGlyHisSerLeuGlyIleProTrpAlaProLeuSerSer
CysProSerGlnAlaLeuGlnLeuAlaGlyCysLeuSerGlnLeuHisSerGlyLeuPhe
LeuTyrGlnGlyLeuLeuGlnAlaLeuGluGlyIleSerProGluLeuGlyProThrLeu
AspThrLeuGlnLeuAspValAlaAspPheAlaThrThrIleTrpGlnGlnMetGluGlu
LeuGlyMetAlaProAlaLeuGlnPro (SEQ ID NO:198)
pMON31112.pep
MetAlaAsnCysSerAsnMetIleAspGluIleIleThrHisLeuLysGlnProProLeu
ProLeuLeuAspPheAsnAsnLeuAsnGlyGluAspGlnAspIleLeuMetAspAsnAsn
LeuArgArgProAsnLeuGluAlaPheAsnArgAlaValLysSerLeuGlnAsnAlaSer
AlaIleGluSerIleLeuLysAsnLeuLeuProCysLeuProLeuAlaThrAlaAlaPro
ThrArgHisproIleHisIleLysAspGlyAspTrpAsnGlupheArgArgLysLeuThr
PheTyrLeuLysThrLeu&luAsnAlaGlnAlaGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaThrGlnGlyAlaMetProAlaPheAlaSerAlaPhe
GlnArgArgAlaGlyGlyValLeuValAlaSerHisLeuGlnSerPheLeuGluValSer
TyrArgValLeuArgHisLeuAlaGlnProSerGlyGlySerGlyGlySerGlnSerPhe
LeuLeuLysSerLeuGluGlnValArgLysIleGlnGlyAspGlyAlaAlaLeuGlnGlu
LysLeuCysAlaThrTyrLysLeuCysHisProGluGluLeuValLeuLeuGlyHisSer
LeuGlyIleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGlnLeuAlaGly
CysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGlnAlaLeuGlu
GlyIleSerProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspValAlaAspPhe
~ AlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAlaProAlaLeuGlnPro
(SEQ I~ NO:l99)

CA 0223406l 1998-04-06
W O 97/1~985 140 PCT~US96/15774
pMON31113.pep
MetAlaAsnCysSerAsnMetIleAspGluIleIleThrHisLeuLysGlnProProLeu
ProLeuLeuAspPheAsnAsnLeuAsnGlyGluAspGlnAspIleLeuMetGluAsnAsn
LeuArgArgProAsnLeuGluAlaPheAsnArgAlaValLysSerLeuGlnAsnAlaSer
AlaIleGluSerIleLeuLysAsnLeuLeuProCysLeuProLeuAlaThrAlaAlaPro
ThrArgHisProIleIleIleArgAspGlyAspTrpAsnGluPheArgArgLysLeuThr
PheTyrLeuLysThrLeuGluAsnAlaGlnAlaGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyPro~leSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaThrGlnGlyAlaMetProAlaPheAlaSerAlaPhe
GlnArgArgAlaGlyGlyValLeuValAlaSerHisLeuGlnSerPheLeuGluValSer
TyrArgValLeuArgHisLeuAlaGlnProThrProLeuGlyProAlaSerSerLeuPro
GlnSerPheLeuLeuLysSerLeuGluGlnValArgLysIleGlnGlyAspGlyAlaAla
LeuGlnGluLysLeuCysAlaThrTyrLySLeuCySHisProGluGluLeuValLeuLeu
GlyHisSerLeuGlyIleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGln
LeuAlaGlyCysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGln
AlaLeuGluGlyIleSerProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspVal
AlaAspPheAlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAlaProAlaLeu
GlnPro (SEQ ID NO:200)
pMON31114.pep
MetAlaAsnCysSerAsnMetIleAspGluIleIleThrHisLeuLysGlnProProLeu
ProLeuLeuAspPheAsnAsnLeuAsnGlyGluAspGlnAspIleLeuMetGluAsnAsn
LeuArgArgProAsnLeuGluAlaPheAsnArgAlaValLysSerLeuGlnAsnAlaSer
AlaIleGluSerIleLeuLysAsnLeuLeuProCysLeuProLeuAlaThrAlaAlaPro
ThrArgHisPr IleIleIleArgAspGlyAspTrpAsnGluPheArgArgLysLeuThr
PheTyrLeuLysThrLeuGluAsnAlaGlnAlaGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaThrGlnGlyAlaMetProAlaPheAlaSerAlaPhe
GlnArgArgAlaGlyGlyValLeuValAlaSerHisLeuGlnSerPheLeuGluValSer
TyrArgVal~euArgHisLeuAlaGlnProSerGlyGlySerGlyGlySerGlnSerPhe
LeuLeuLysSerLeuGluGlnValArgLysIleGlnGlyAspGlyAlaAlaLeuGlnGlu
LysLeuCysAlaThrTyrLysLeuCysHisProGluGluLeuValLeuLeuGlyHisSer
LeuGlyIleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGlnLeuAlaGly
CysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGlnAlaLeuGlu
GlyIleSerProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspValAlaAspPhe
AlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAlaProAlaLeuGlnPro
(SEQ ID NO:201)
pMON31115.pep
MetAlaAsnCysSerAsnMetIleAspGluIleIleThrHisLeuLysGlnProProLeu
ProLeuLeuAspPheAsnAsnLeuAsnGlyGluAspGlnAsplleLeuMetAspAsnAsn
LeuArgArgProAsnLeuGluAlaPheAsnArgAlaValLysSerLeuGlnAsnAlaSer
AlaIleGluSerIleLeuLysAsnLeuLeuProCysLeuProLeuAlaThrAlaAlaPro
ThrArgHisProIle~isIleLysAspGlyASpTrpAsnGluPheArgArgLysLeuThr
PheTyrLeuLysThrLeuGluAsnAlaGlnAlaGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaThrGlnGlyAlaMetProAlaPheAlaSerAlaPhe

CA 0223406l l998-04-06
W O 97/1298~ 141 PCT~US96~5774
GlnArgArgAlaGlyGlyValLeuValAlaSerHisLeuGlnSerPheLeuGluValSer
TyrArgValLeuArgHisLeuAlaGlnProThrProLeuGlyProAlaSerSerLeuPro
GlnSerPheLeuLeuLysSerLeuGluGlnValArgLysIleGlnGlyAspGlyAlaAla
LeuGlnGluLysLeuCysAlaThrTyrLysLeuCysHisProGluGluLeuValLeuLeu
GlyHisSerLeuGlyIleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGln
LeuAlaGlyCysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGln
AlaLeuGluGlyIleSerProGluLeuGlyProThrLeuAspThr~euGlnLeuAspVal
AlaAspPheAlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAlaProAlaLeu
GlnPro (SEQ ID No:202)
pMON28505
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThrphe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
2~ ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGluValHisProLeuProThrProValLeuLeuProAlaVal
AsppheserLeuGlyGluTrpLysThrGlnMetGluGluThrLysAlaGlnAspIleLeu
GlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGlnLeuGlyProThr
CysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeu
GlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThrAlaHisLysAspPro
AsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArgPheLeuMetLeu
ValGlyGlySerThrLeuCysValArgGluPheGlyGlyAsnMetAlaSerProAlaPro
ProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHisValLeuHisSer
ArgLeuSerGlnCysPro (SEQ ID No:203)
pMON28506
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetLeuProThrProValLeuLeuProAlaValAspPheSerLeu
GlyGluTrpLysThrGlnMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThr
LeuLeuLeuGluGlyValMetAlaAlaArgGlyGlnLeuGlyProThrCysLeuSerSer
LeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeu
GlyThrGlnLeuproproGlnGlyArgThrThrAlaHisLysAspproAsnAlaIlephe
LeuSerPheGlnHisLeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySer
ThrLeuCysValArgGluPheGlyGlyAsnMetAlaSerProAlaProProAlaCysAsp
LeuArgValLeuSerLysLeuLeuArgAspSerHisValLeuHisSerArgLeuSerGln
CysProGluValHisPro (SEQ ID MO:204)
pMoN28507
AlaAsncysserIleMetIleAspGluIleIleHisHisLeuLysArgproproAlapro
.

CA 0223406l l998-04-06
W O 97tl298~ 1~2 PCT~US96/lS774
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLys
ThrGlnMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGlu
GlyValMetAlaAlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGln
LeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeu
ProProGlnGlyArgThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGln
HisLeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysVal
ArgGluPheGlyGlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeu
SerLysLeuLeuArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluVal
HisProLeuProThrPro (SEQ ID No:205)
pMON28508
AlaAsnCysSerIleMetIleAspGluIleIleHiSHiSLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLySAsn~euGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluP~oSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGlu
GluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla
AlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeULeuGlyGlnLeuSerGlyGln
ValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGly
ArgThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArg
GlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGly
GlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeu
ArgAspSerHisValLeuHisSerArgLeuSerGlnCySProGluValHisProLeuPro
ThrProValLeuLeuPro (SEQ ID NC:206)
pMON28509
AlaAsnCysSerIleMetIleAspGluIleIleHiSHiSLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLySAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisproIleI~eIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThrphe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThr
LysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArg
GlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArg
LeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThr
ThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLyS
ValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGlyGlyAsn
MetAlaSerProAlaProProAlaCysAspLeuAr~ValLeuSerLysLeuLeuArgAsp
SerHisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrPro

CA 02234061 1998-04-06
W O 97/12985 143 PcTnJsg6ns774
ValLeuLeuProAlaVa~ (S~Q ID No:207)
pMOM28510
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGlyGluTrpLysThrGlnMetGluGluThrLysAlaGlnAsp
IleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGlnLeuGly
ProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeuLeuGly
AlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThrAlaHisLys
AspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArgPheLeu
MetLeuValGlyGlySerThrLeuCysValArgGluPheGlyGlyAsnMetAlaSerPro
AlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHisValLeu
HisSerArgLeuSerGlnCysProGluValHisProLeuProThrProValLeuLeuPro
AlaValAspPheSerLeu (SEQ ID NO:208)
pMON28511
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluASpValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGly
GlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGln
GlyArgThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeu
ArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPhe
GlyGlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeu
LeuArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeu
ProThrProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMet
GluGluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMet
AlaAlaArgGlyGlnLeu (SEQ ID No:209)
pMON28512
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGlyThrGlnLeuProProGlnGlyArgThrThrAlaHisLys
AspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArgPheLeu
MetLeuValGlyGlySerThrLeuCysValArgGluPheGlyGlyAsnMetAlaSerPro
.

CA 02234061 1998-04-06
W O 97/12985 144 PCTrUS96/1~77~
AlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHisValLeu
~isSerArgLeuSerGlnCysProGluValHisProLeuProThrProValLeuLeuPro
AlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAlaGlnAsp
IleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGlnLeuGly
ProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeuLeuGly
AlaLeuGlnSerLeuLeu (SEQ ID NO:210)
pMON28513
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspAr~AsnLeu
ArgLeuProAsnLeuGluSerPheValAryAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnprocysLeuproserAlaThrAlaAlaproser
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuvalThrLeuGluGlnAlaGlnGluGlnGlnTyrvalGluGlyGlyGlyGlyser
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysserproAsnMetGlyAr~ThrThrAlaHisLysAspproAsnAlaIlepheLeu
SerPheGlnIIisLeuLeuArgGlyLysValArgPheLeu~etLeuValGlyGlySerThr
LeuCysValArgGluPheGlyGlyAsnMetAlaSerProAlaProProAlaCysAspLeu
ArgValLeuSerLysLeuLeuArgAspSerHisValLeuHisSerArgLeuSerGlnCys
ProGluValHisProLeuProThrProValLeuLeuProAlaValAspPheSerLeuGly
GluTrpLysThrGlnMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThrLeu
LeuLeuGluGlyValMetAlaAlaArgGlyGlnLeuGlyProThrCySLeuSerSerLeu
LeuGlyGlnLeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGly
ThrGlnLeuProProGln (SEQ ID NO:211)
pMON28514
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThrphe
TyrLeuValThrLeuGluGlnAlaG~nGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHis
LeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArg
GluPheGlyGlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgvalLeuSer
LysLeuLeuArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluValHis
ProLeuProThrProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThr
GlnMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGly
ValMetAlaAlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeu
SerGlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuPro
ProGlnGlyArgThrThr (SEQ ID NO:212)
pMON28515
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThrphe

CA 02234061 1998-04-06
WO 9'71129'85 145 PCT~US96/15774
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArg
GlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGly
GlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeu
ArgAspSerHlsValLeuHisSerArgLeuSerGlnCySPrOGluValHisProLeuPro
ThrProValLeuLeuProAlaValAspPheSerLeUGlyGlUTrpLySThrGlnMetGlu
GluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla
AlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGln
ValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGly
ArgThrThrAlaHisLys (SEQ ID MO:213)
pMON28516
AlaAsnCysSerIleMetIleAspGluIleIleHisHiSLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThrphe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetAlaIlePheLeuSerPheG~ n~i sT~euLeuArgGlyLysval
ArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGlyGlyAsnMet
AlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSer
HisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProVal
LeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLys
AlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGly
GlnLeuGly~_~ThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeu
LeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThr
AlaHisLysAspProAsn (SEQ ID NO:214)
pMON28519
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThrphe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGluValHisProLeuProThrProValLeuLeuProAlaVal
AspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAlaGlnAspIleLeu
GlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGlnLeuGlyProThr
CysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeu
GlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThrAlaHisLysAspPro
AsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLySValArgPheLeuMetLeu
ValGlyGlySerThrLeuCysValArgGluPheGlyAsnMetAlaSerProAlaProPro
AlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHisValLeuHisSerArg
LeuSerGlnCysPro (SEQ ID NO:215)
pMON28520

CA 02234061 1998-04-06
W O 97/12985 146 PCTAJS96/15774
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuproAsnLeuGluserphevalArgAlavalLysAsnLeuGluAsnAlaserGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetLeuProThrProValLeuLeuProAlaValAspPheSerLeu
GlyGluTrpLysThrGlnMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThr
10 LeuLeuLeuGluGlyvalMe~tAlaAlaArgGlyGlnLeuGlyproThrcysLeuserser
LeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeu
GlyThrGlnLeuProProGlnGlyArgThrThrAlaHisLysAspProAsnAlaIlePhe
LeuSerPheGlnHisLeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySer
ThrLeuCysValArgGluPheGlyAsnMetAlaSerProAlaProProAlaCysAspLeu
ArgValLeuSerLysLeuLeuArgAspSerHisVal~euHisSerArgLeuSerGlnCys
ProGluValHisPro (SEQ ID NO:216)
pMON28521
AlaAsncysserIleMetIleAspGluIleIleHisHisLeuLysArgproproAlapro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThrphe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluproserGlyproIleserThrIleAsnproserproproserLysGluser
HisLysSerProAsnMetValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLys
ThrGlnMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGlu
GlyValMetAlaAlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGln
LeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyT~rGlnLeu
ProproGlnGlyArgThrThrAlaHisLysAspproAsnAlaIlepheLeuserpheGln
HisLeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysVal
ArgGluPheGlyAsnMetAlaSerProAlaProProAlaCysASpLeuArgValLeuSer
LysLeuLeuArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluValHis
ProLeuProThrPro (SEQ ID NO:217)
pMON28522
AlaAsnCysSerIleMetIleAspGluIleIleHis~isLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluproserGlyproIleserThrIleAsnproserproproserLysGluser
HisLysSerProAsnMetAlaValAspPheSerLeuGlyGluTr~LysThrGlnMetGlu
GluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla
AlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGln
ValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGly
ArgThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArg
GlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGly
AsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArg

~CA 02234061 1998-04-06
W O 97112985 147 PCT~US96/15774
AspSerHisV~lLeuHisSerArgLeuSerGlnCySProGluValHisProLeuProThr
ProValLeuLeuPro (SEQ ID NO:218)
pMON28523
AlaAsncysserIleMetIleAspGluIleIleHisHisLeuLysArgproproAlapro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
10 ArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThrphe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleASnProSerProProSerLysGluSer
HisLysSerProAsnMetAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThr
LysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArg
GlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArg
LeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThr
ThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLys
ValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGlyAsnMet
AlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSer
HisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProVal
LeuLeuProAlaVal (SEQ ID MO:219)
pMOM28524
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGlyGluTrpLysThrGlnMetGluGluThrLysAlaGlnAsp
IleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGlnLeuÇly
ProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeuLeuGly
AlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThrAlaHisLys
AspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArgPheLeu
MetLeuValGlyGlySerThrLeuCysValArgGluPheGlyAsnMetAlaSerProAla
ProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHisValLeuHis
SerArgLeuSerGlnCysProGluValHisProLeuProThrProValLeuLeuProAla
ValAspPheSerLeu (SEQ ID No:220)
pMON28525
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluASpValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThrphe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGly
GlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGln

CA 02234061 1998-04-06
W O 97/12985 lg8 PCT~US96/15774
GlyArgThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnKisLeuLeu
ArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPhe
GlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeu
ArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuPro
ThrProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGlu
GluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla
AlaArgGlyGlnLeu (SEQ ID NO:221)
pMON28526
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGlyThrGlnLeuProProGlnGlyArgThrThrAlaHisLys
AspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuA-rgGlyLysValArgPheLeu
MetLeuValGlyGlySerThrLeuCysValArgGluPheGlyASnMetAlaSerProAla
ProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHiSValLeuHis
SerArgLeuSerGlnCysProGluValHisProLeuProThrProValLeuLeuProAla
ValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAlaGlnAspIle
LeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGlnLeuGlyPro
ThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeuLeuGlyAla
LeuGlnSerLeuLeu (SEQ ID NO:222)
pMON28527
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLySAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThrphe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGlyArgThrThrAlaHisLysAspProAsnAlaIlePheLeu
SerPheGlnHisLeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThr
LeuCysValArgGluPheGlyAsnMetAlaSerProAlaProProAlaCysAspLeuArg
ValLeuSerLysLeuLeuArgAspSerHisValLeuHisSerArgLeuSerGlnCysPro
GluValHisProLeuProThrProValLeuLeuProAlaValAspPheSerLeuGlyGlu
TrpLysThrGlnMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeu
LeuGluGlyValMetAlaAlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeu
GlyGlnLeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThr
GlnLeuProProGln (SEQ I~ NO:223)
pMON28528
AlaAsncysserIleMetIleAspGluIleIleHisHisLeuLysArgproproAlapro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly ,~
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer

CA 02234061 1998-04-06
W O 97/12985 149 PCTnUS96/15774
ArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThrphe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHis
LeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArg
GluPheGlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSerLys
LeuLeuArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluValHisPro
LeuProThrProValLeuLeuProAlaValASpPheSerLeuGlyGluTrpLysThrGln
MetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyVal
MetAlaAlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSer
GlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProPro
GlnGlyArgThrThr (SEQ ID NO:224)
pMOM28529
AlaAsnCysSerIleMetIleAspGluIleIleXisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProI~eIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArg
GlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGly
AsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArg
AspSerHisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThr
ProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGlu
ThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAla
ArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnVal
ArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArg
ThrThrAlaHisLys (SEQ ID NO:225)
pMON28530
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThrphe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysVal
ArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGlyAsnMetAla
SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHis
ValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProValLeu
LeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAla
GlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGln
LeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeu
LeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThrAla
HisLysAspProAsn (SEQ ID NO:226)
pMON28533

CA 02234061 1998-04-06
W O 97/12985 150 PCTAJS96/1~774
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnprocysLeuproserAlaThrAlaAlaproser
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGluValHisProLeuProThrProValLeuLeuProAlaVal
AspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAlaGlnAspIleLeu
GlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGlnLeuGlyProThr
CysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeu
GlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThrAlaHisLysAspPro
AsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArgPheLeuMetLeu
ValGlyGlySerThrLeuCysValArgGluPheGlyGlyAsnGlyGlyAsnMetAlaSer
ProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHisVal
LeuHisSerArgLeuSerGlnCysPro (SEQ ID NO:227)
pMON28534
AlaAsncysserIleMetIleAspGluIleIleHisHisLeuLysArgproproAlapro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetLeuProThrProValLeuLeuProAlaValAspPheSerLeu
GlyGluTrpLysThrGlnMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThr
LeuLeuLeuGluGlyValMetAlaAlaArgGlyGlnLeuGlyProThrCysLeuSerSer
LeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeu
GlyThrGlnLeuproproGlnGlyArgThrThrAlaHisLysAspproAsnAlaIlephe
LeuSerPheGlnHisLeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySer
ThrLeuCysValArgGluPheGlyGlyAsnGlyGlyAsnMetAlaSerProAlaProPro
AlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHisValLeuHisSerArg
LeuSerGlnCysProGluValHisPro (SEQ ID NO:228)
pMoN28535
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThrphe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLys
ThrGlnMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGlu
GlyValMetAlaAlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGln
LeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeu
ProProGlnGlyArgThrThrAlaHisLySASpProAsnAlaIlePheLeuSerPheGln t~
HisLeuLeuArgGlyLysValArgPheLeUMetLeUValGlyGlySerThrLeuCysVal

CA 0223406l l998-04-06
W O 97/12985 151 PCr~US96/15774
ArgGluPheGlyGlyAsnGlyGlyAsnMetAlaSerProAlaProProAlaCysASpLeu
ArgValLeuSerLysLeuLeuArgAspSerHisValLeuHisSerArgLeuSerGlnCyS
ProGluValHisProLeuProThrPro (SEQ ID NO:229)
pMON28536
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
10 IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGlu
GluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla
AlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGln
ValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGly
ArgThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArg
GlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGly
GlyAsnGlyGlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSer
LysLeuLeuArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluValHis
ProLeuProThrProValLeuLeuPro (SEQ ID NO:230)
pMON28537
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThr
LysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArg
GlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArg
LeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThr
ThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLys
ValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGlyGlyAsn
GlyGlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeu
LeuArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeu
ProThrProValLeuLeuProAlaVal (SEQ ID NO:231)
pMON28538
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGlyGluTrpLysThrGlnMetGluGluThrLysAlaGlnAsp

CA 02234061 1998-04-06
W O 97/12985 152 PCTrUS96/15774
IleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGlnLeuGly
ProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeuLeuGly
AlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThrAlaHisLys
AspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArgPheLeu
MetLeuValGlyGlySerThrLeuCysValArgGluPheGlyGlyAsn&lyGlyAsnMet
AlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSer
HisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProVal
LeuLeuProA'aValAspPheSerLeu (SEQ ID NO:232)
pMON28539
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThrphe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGly
GlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGln
GlyArgThrThrAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeu
ArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPhe
GlyGlyAsnGlyGlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeu
SerLysLeuLeuArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluVal
HisProLeuProThrProValLeuLeuProAlaValASpPheSerLeuGlyGluTrpLys
ThrGlnMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGlu
GlyValMetAlaAlaArgGlyGlnLeu (SEQ ID MO:233)
pMON28540
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnprocysLeuproserAlaThrAlaAlaproser
ArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThrphe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGlyThrGlnLeu,ProProGlnGlyArgThrThrAlaHisLys
AspProAsnAlaIlePheLeuSerPheGlnHiSLeuLeuArgGlyLysValArgPheLeu
MetLeuValGlyGlySerThrLeuCysValArgGluPheGlyGlyAsnGlyGlyAsnMet
AlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSer
HisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProVal
LeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLys
AlaGlnAspIleLeuGlyAlavalThrLeuLeuLeuGluGlyvalMetAlaAlaArgGly
GlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeu
LeuLeuGlyAlaLeuGlnSerLeuLeu (SEQ ID No:234)
pMON28541
AlaAsnCysSerIleMetIleAspGluIleIleHiSHiSLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLySASnLeuGluAsnAlaSerGly

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IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetGlyArgThrThrAlaHisLysAspProAsnAlaIlePheLeu
SerPheGlnHisLeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThr
LeuCysValArgGluPheGlyGlyAsnGlyGlyAsnMetAlaSerProAlaProProAla
CysAspLeuArgValLeuSerLysLeuLeuArgAspSer~IiSValLeuHisSerArgLeu
SerGlnCysProGluValHisProLeuProThrProValLeuLeuProAlaValAspPhe
SerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAlaGlnAspIleLeuGlyAla
ValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGlnLeuGlyProThrCysLeu
SerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSer
LeuLeuGlyThrGlnLeuProProGln (SEQ ID NO:235)
pMON285~2
AlaAsnCysSerIleMetIleAspGluIleIleHlsHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnprocysLeuproserAlaThrAlaAlaproser
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetAlaHisLysAspProAsnAlaIlePheLeuSerPheGlnHis
LeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArg
GluPheGlyGlyAsnGlyGlyAsnMetAlaSerProAlaProProAlaCysAspLeuArg
ValLeuSerLysLeuLeuArgAspSerHisValLeuHisSerArgLeuSerGlnCysPro
GluValHisProLeuProThrProValLeuLeuProAlaValAspPheSerLeuGlyGlu
TrpLysThrGlnMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeu
LeuGluGlyValMetAlaAlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeu
GlyGlnLeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThr
GlnLeuProProGlnGlyArgThrThr (SEQ ID NO:236)
pMON28543
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArg
GlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGly
GlyAsnGlyGlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSer
LysLeuLeuArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluValHis
ProLeuProThrProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThr
GlnMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGly
ValMetAlaAlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeu
SerGlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuPro
ProGlnGlyArgThrThrAlaHisLys (SEQ ID No:237)

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pMoN28544
AlaAsncysserIleMetIleAspGluIleIleHisHisLeuLysArgproproAlapro
LeuLeuAspP-oAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnprocysLeuproserAlaThrAlaAlaproser
ArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThrphe
TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer
ProGlyGluproserGlyproIleserThrIleAsnproserproproserLysGluser
10 HisLysserproAsnMetAlaIlepheLeuserpheGlnHisLeuLeuArgGlyLysval
ArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGlyGlyAsnGly
GlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeu
ArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuPro
ThrProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGlu
GluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla
AlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGln
ValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGly
ArgThrThrAlaHisLysAspProAsn (SEQ ID NO:238)
pMoN28545
AlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAlaPro
LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsnLeu
ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly
IleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer
ArgHisproILeIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThrphe
TyrLeuValT~.rLeuGluGlnAlaGlnGluGlnGlnTyrValGlUGlyGlyGlyGlySer
ProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGluSer
HisLysSerProAsnMetAspProAsnAlaIlePheLeuSerPheGlnHiSLeuLeuArg
GlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGly
GlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeu
ArgAspSerHisValLeuHisSerArgLeuSerGlnCySProGluValHisProLeuPro
ThrProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGlu
GluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla
AlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGln
ValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnGlyArgThrThrAla
HisLys ~SEQ ID NO:239)
pMON32132
SerProAlaProProAlaCysAspLeuArgValLeuSerLySLeuLeuArgAspSerHis
ValLeuHisSerArgLeuSerGlnCysProGluValHiSProLeuProThrProValLeu
LeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAla
GlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGln
LeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeUSerGlyGlnValArgLeuLeu
LeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuPrOPrOGlnGlyArgThrThrAla
HisLysAspProAsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArg
PheLeuMetLeuValGlyGlySerThrLeuCySValArg ~SEQ ID NO:2 52)
PMON32133

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SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHis
ValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProValLeu
LeuProAlaValAspPheSerLeuGlyGluTrpLySThrGlnMetGluGluThrLysAla
GlnAspIleLeuGlyAlavalThrLeuLeuLeuGluGlyvalMetAlaAlaArgGlyGln
LeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeu
LeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnGlyArgThrThrAlaHisLysAspPro
AsnAlaIlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArgPheLeuMetLeu
ValGlyGlySerThrLeuCysValArg (SEQ ID NO:253)
PMON32134
SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHis
ValLeuHisSerArgLeuSerGlnCySProGluValHisProLeuProThrProValLeu
LeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAla
GlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGln
LeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeu
LeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThrAla
HisLysAspProAsnAlaIlePheLeuSerPheGlnHiSLeuLeuArgGlyLysValArg
PheLeuMetLeuValGlyGlySerThrLeuCysValArg (SEQ ID NO:254)

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lS6
The following examples will illustrate the invention in
greater detail although it will be understood that the
invention is not limited to these specific examples.
F~X~MPT.F~ 1
Construction of ~ar~ntal BH~ exoression vector
A. Removal of AflIII site from m~mm~l ian expression plasmid.
A new ~mm~l ian expression vector was constructed to
accept NcoI-HindIII or AflIII-HindIII gene fra~ments in-
frame and 3' to the hIL-3 receptor agonist pMON13146 (WO
94/12638) gene and a mouse IgG2b linker fragment. First,
the single AflIII site was removed from pMON3934, which is a
derivative of pMON3359. pMON3359 is a pUC18-based vector
containing a mammalian expression cassette. The cassette
includes a herpes simplex viral promoter IEllO ~-800 to
+120) followed by a modified human IL-3 signal peptide
sequence and an SV40 late poly-adenylation (poly-A) signal
which has been subcloned into the pUC18 polylinker (See
Hippenmeyer et al., Bio/Technology, 1993, pp.1037-1041).
The modified human IL-3 signal sequence, which facilitates
secretion of gene products outside of the cell, is flan~ed
by a BamHI site on the 5' end and a unique NcoI site on the
3' end. A unique HindIII site is 3' to the NcoI site and 5
to the poly-A sequence. The DNA sequence encoding the
signal peptide is shown below (res~riction enzyme sites are
indicated above). ~he ATG (methionine) codon within ~he
NcoI site is in-frame with the ini~iator ATG of the signal
peptide (underlined);

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BamHI NcoI
5'GGATCCACC~T~AGCCGCC~GCCCGTCCTGCTCCTGCTCCAACTCCTGGTCCGCCCCGCCATGG
(SEQ ID NO:255)
The single A~lIII site was removed ~rom pMoN3934 by
digestion with AflIII followed by filling in the overhangs
- by addition of a DNA polymerase and nucleotides. The
digested DNA fragment was purified via Magic PCR Clean up
kit (Promega) and ligated with T4 DNA ligase. The ligation
reaction was transformed into DH5~ ~ and the cells were
plated onto LB-agar plus ampicillin. Individual colonies
were screened for the loss of the AflIII site by restriction
analysis with A~lIII and HindIII which results in a single
fragment i~ the AflIII site was removed. The resulting
plasmid was designated pMoN30275.
B. Transfer o~ hIL-3 receptor agonist pMON13416/IgG2b
cassette into pMON30275.
The McoI-HindIII ~ragment (ca. 425 bp) from pMoN30245
was ligated to the McoI-HindIII fragment (ca. 3800 bp) of
the pMON30275. pMON30245 (WO 94/12638) contains the gene
coding ~or hIL-3 receptor agonist pMON13416 joined to a
mouse IgG2b hinge fragment. Immediately 3' to the IgG2b
hinge and 5~ to the HindIII site is an A~lIII site. Genes
can be cloned into the AflIII-HindIII sites as NcoI-HindIII
or AflIII-HindIII fragments in frame with the hIL-3 variant
pMON13416/IgG2b hinge to create novel chimeras. The NcoI
site and the AflIII site have compatible overhangs and will
ligate but both recognition sites are lost. The plasmid,
pMON30304 containing the DNA se~uence of (SEQ ID NO:78),
coding for hIL-3 variant pMON13416 joined with a mouse IgG2b
hinge region, was a result of this cloning.
.
~ 35 F~MPT~F 2

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Constructio~ of an intermediate plasmid cont~intna one co~v
of the c-m~l liqand (1-153) aene of the dimer template
In order to generate a plasmid DNA with the coding
sequence of c-mpl (1-153) ligand ~ollowed by a unique EcoRI
restriction site, the gene is isolated via reverse
transcriptase/polymerase chain reaction (RT/PCR). Human
fetal (lot #38130) and adult liver (lot #46018) A~ RNA are
obtained from Clontech (Palo Alto, CA) for source of c-mpl
ligand messenger RNA (mRNA). The first strand cDNA
reactions are carried out using a cDNA Cycle~ Kit obtained
from Invitrogen (San Diego, CA). In the RT reaction, random
primers and oligo dT primer are used to generate cDNA from a
combination of human and fetal liver mRNA. For
amplification of c-mpl ligand gene fragment encoding amino
acids 1-153, the RT product serves as the template for PCR
with a combination of the primers, Forward primer: c-mplNcoI
(SEQ ID NO:13) and Reverse primer: Ecompl. The c-mplNcoI
primer ann~als to the c-mpl ligand gene (bases #279-311
based on c-mpl ligand sequence from Gene bank accession
#L33410 or de Sauvage et al., Nature 369: 533-538 (1994))
and encodes a NcoI restriction enzyme site immediately 5~ to
the first codon (Ser~l) of c-mpl ligand. The NcoI
restriction enzyme site codes for methionine and alanine
codons prior to Ser+l and includes codon degeneracy for the
Ala codon and the first four codons (Ser, Pro, Ala, & Pro)
of c-mpl ligand. The Ecompl primer anneals to bases #720-
737 of c-mpl ligand and encodes an EcoRI site (GAATTC) in-
frame with the c-mpl ligand gene immediately following Arg-
153. The EcoRI site creates Glu and Phe codons following
Arg-153. The ca. 480 bp PCR product was purified, digested
with NcoI and EcoRI and ligated to the NcoI-EcoRI vector
fragment of pMON3993 (ca. 4550 bp.). pMON3993 was a
derivative of pMoM3359 (described in Example 1). The human

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159
IL-3 signal peptide sequence, which had been subcloned as a
BamHI fragment into the unique BamHI site between the IE110
promoter and poly-A signal, contains an NcoI site at its 3'
end and is followed by a unique EcoRI site. The plasmid,
pMON26458 containing the DNA sequence of ~SEQ ID NO:79),
coding for c-mpl ligand amino acids 1-153 (SEQ ID NO:161),
was the result of this cloning.
~MPLE 3
Construction of the parental plasmids containing the second
genes of the dimer templates
For amplification of c-mpl ligand gene fragments starting at
amino acid 1 (Ser) with a termination codon following amino
acid 153 (Arg), the RT reaction from Example 2 serves as the
template for PCR with a combination of the following
primers; c-mplNcoI (SEQ ID NO:13) (forward primer) and c-
mplHindIII ~SEQ ID NO:15) (reverse primer). The c-mplMcoI
(SEQ ID NO: 13) primer is described in Example 2. The c-
mplHindIII (SEQ ID NO:15) primer, which anneals to bases
#716-737 of c-mpl ligand, adds both a termination codon and
a HindIII restriction enzyme site immediately following the
final codon, Arg1 53.
Two types of PCR products are generated from the RT
cDNA samples, one with a deletion of the codons for amino
acids 112-115 and one without the deletion of these codons.
The c-mpl ligand PCR products (ca. 480 bp) are digested with
NcoI and HindIII restriction enzymes for transfer to a
mammalian expression vector, pMoN3934~ pMON3934 is digested
with McoI and HindIII (ca. 3800 bp) and will accept the PCR
products.
Plasmid, pMON32132 ~SEQ ID NO:249), coding for c-mpl
ligand amino acids 1-153 (~EQ ID NO:252) was a result of

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this cloning. Plasmid, pMON32134 (SEQ ID NO:250), coding for
c-mpl ligand amino acids 1-153 (SEQ ID NO:253) was a result
of this cloning. Plasmid, pMON32133 (SEQ ID NO:251), coding
for c-mpl ligand amino acids 1-153 with a deletion of codons
112-115 (~112-115) (SEQ ID NO:254) was also a result of this
cloning.
~.XAMpT . ~. 4
Generat;on of PCR dimer t~mnlate 5T- with a ~112-115 deletion
in the second c-m~l liaand ~ene
A PCR template for generating novel forms of c-mpl
ligand is constructed by ligating the 3.7 Kbp BstXI/EcoRI
fragment of pMoN26458 to the 1 Kbp NcoI/BstXI fragment from
pMON32133 (containing a deletion of amino acids 112-115)
along with the EcoRI/AflIII 5L synthetic oligonucleotide
linker 5L-5' (SEQ ID NO:18) and 5L-3' (SEQ ID NO:19).
The EcoRI end of the linker will ligate to the EcoRI
end of pMON26458. The AflIII end of the linker will ligate
to the NcoI site of pMON32133, and neither restriction site
will be retained upon ligation. The BstXI sites of
pMoN26458 and pMON32133 will ligate as well. Plasmid,
pMON28548, is a result of the cloning and contains the DNA
se~uence of (SEQ ID No:80) which encodes amino acids 1-153
c-mpl ligand fused via a GluPheGlyGlyAsnMetAla (SEQ ID
NO:222) linker to amino acids 1-153 c-mpl ligand that
contains a deletion of amino acids 112-115 (SEQ ID NO:162).
~.XAMPT.~. 5
Generation of PCR ~imer tem~late 4L
A PCR template for generating novel forms of c-mpl
ligand is constructed by ligating the 3.7 Kbp BstXI/EcoRI

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161
fragment of pMOM26458 to the 1 Kbp NcoI/BstXI fragment from
pMON32132 along with the EcoRI/AflIII 4L synthetic
oligonucleotide linker 4L-5' (SEQ ID NO:16) and 4L-3' (SEQ
ID NO:17).
The EcoRI end of the linker will ligate to the EcoRI
- end of pMON26458. The AflIII end of the linker will ligate
to the NcoI site of pMON32132, and neither restriction site
will be retained upon ligation. The BstXI sites of
pMON26458 ar~d pMON32132 will ligate as well. The plasmid,
pMoN28500, is a result of the cloning and contains the DNA
sequence of (SEQ ID NO:82) which encodes amino acids 1-153
c-mpl ligand fused via a GluPheGlyAsnMetAla (SEQ ID NO:223)
linker (4L) to amino acids 1-153 c-mpl ligand (SEQ ID
NO:163).
F~Mp~E 6
Generation of PCR dimer t~mr~late 5T.
A PCR template for generating novel forms of c-mpl
ligand is constructed by ligating the 3.7 Kbp BstXI/EcoRI
fragment of pMoN26458 to the 1 Kbp NcoI/BstXI fragment from
pMON32132 along with the EcoRI/AflIII 5L synthetic
oligonucleotide linker SL-5' (SEQ ID NO:18) and 5~-3' (SEQ
ID NO:l9).
The EcoRI end of the linker will ligate to the EcoRI
end of pMON26458. The AflIII end of the linker will ligate
to the NcoI site of pMOM32132, and neither restriction site
will be retained upon ligation. The BstXI sites of
pMON26458 and pMON32132 will ligate as well. Plasmid,
pMON28501 is a result of the cloning and contains the DNA
sequence of (SEQ ID NO: 82) which encodes amino acids 1-153
c-mpl ligand fused via a GluPheGlyGlyAsnMetAla (SEQ ID
NO:222~ linker t5~) to amino acids 1-153 c-mpl ligand (SEQ
ID NO:164).

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EX~MP~.F. 7
~neration of PCR ~imer t~m~lates 8L
A PCR template for generating novel forms of c-mpl
ligand is constructed by ligating the 3.7 Kbp BstXI/EcoRI
fragment of pMON26458 to the 1 Kbp NcoI/BstXI fragment from
pMON32134 along with the EcoRI/AflIII 8L synthetic
oligonucleotide linker 8L-5' (SEQ ID NO:20~ and 8L-3' ~SEQ
ID NO:21).
The EcoRI end of the linker will ligate to the EcoRI
end of pMON26458. The AflIII end of the linker will ligate
to the NcoI site of pMON32134, and neither restriction site
will be retained upon ligation. The BstXI sites o~
pMoN26458 and pMON32134 will ligate as well. Plasmid,
pMON28502 is a result of the cloning which contains the DNA
sequence of (SEQ ID NO:83) and encodes amino acids 1-153 c-
mpl ligand ~used via a GluPheGlyGlyAsnGlyGlyAsnMetAla (SEQ
ID No:224) linker ~8L) to amino acids 1-153 c-mpl ligand
(SEQ ID NO:165).
F~MPLES 8-44
Generation of novel c-m~l liqand aenes with new N-terminus
~nd C-terminus
A. PCR generation of genes encoding novel c-mpl ligand
receptor agonists.
Genes encoding novel c-mpl ligand receptor agonists
were generated using Method III (Horlick et al., Prot. Eng.
5:427-433, 1992 ). The PCR reactions were carried out using
dimer templates, pMONs 28500, 28501, 28502 or 28548 and one
of the sets of synthetic primer sets below (The first number
-

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163
refers to the position of the ~irst amino acid in the
original sequence. For example, the 31-5' and 31-3' refers
to the 5~ and 3' oligo primers, receptively, for the
sequence beginning at the codon corresponding to residue 31
of the original sequence.).
31-5' (SEQ ID NO:22) and 31-3~ (SEQ ID N~:23), 35-5' (SEQ ID
No:24) and 35-3' (SEQ ID NO:25), 39-5' (SEQ ID No:26) and
39-3' (SEQ lD NO:27), 43-5' (SEQ ID NO:28) and 43-3' (SEQ ID
No:29), 45-5' (SEQ ID NO:30) and 45-3' (SEQ ID NO:31), 49-5'
(SEQ ID NO:32) and 49-3' (SEQ ID N5:33), 82-5' (SEQ ID
NO:34) and 82-3' (SEQ ID NO:35), 109-5' (SEQ ID NO:36) and
109-3' (SEQ ID No:37), 115-5' (SEQ ID NO:38) and 115-3' (SEQ
ID NO:39), 120-5~ (SEQ ID No:4o) and 120-3~ (SEQ ID NO:41),
123-5~ (SEQ ID NO:42) and 123-3~ (SEQ ID NO:43), 126-5' (SEQ
ID NO:44) and 126-3' (SEQ ID MO:45).
The templates and oligonucleotide sets used in the PCR
reactions are shown in Table 4. The products that were
generated were about 480 bp and were purified via Magic PCR
Clean up kits (Promega).
B. Subcloning of novel c-mpl receptor agonist gene products
into mammalian expression vector for generation of chimeras.
The c-mpl receptor agonist gene PCR products were
digested with NcoI and HindIII or AflIII and HindIII
restriction enzymes (ca. 470 bp) for transfer to a m~mm~l ian
expression vector. The expression vector, pMON30304, was
digested with NcoI and HindIII (ca. 4200 bp) and accepts the
PCR products as McoI-HindIII or AflIII-HindIII fragments.
The restriction digest of the PCR product and the resulting
plasmids are shown in Table 4

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TABLE 4
PCR Product PCR Product Resulting Breakpoint
Example # PCR template Primer set Restriction Linker Plasmid in c-mpl
Digest pMONligand
Example 8 pMON28501 31 NcoI/HindIII 5L 28505 30-31
Example 9 pMON28501 35 AflIII/HindIII 5L 28506 34-35
Example 10 pMON28501 39 NcoI/HindIII 5L 28507 38-39
Example 11 pMON28501 43 NcoI/HindIII 5L 28508 42-43
Example 12 pMON28501 45 NcoI/HindIII 5L 28509 g4-45
Example 13 pMON28501 49 NcoI/HindIII 5L 28510 48-49
Example 14 pMON28501 82 NcoI/HindIII 5L 28511 81-82
Example 15 pMON28501 109 NcoI/HindIII 5L 28512 108-109
Example 16 p~ i28501 116 NcoI/HindIII 5L 28513 115-116
Example 171~MON28501 120 NcoI/HindIII 5L 28514 119-120
Example 18 pMON28501 123 NcoI/HindIII 5L 28515 122-123
Example 19 pMON28501 126 NcoI/HindIII 5L 28516 125-126
Example 20 pMCN28500 31 NcoI/HindIII 4L 28519 30-31
Example 21 pMON28500 35 AflIII/HindIII 4L 28520 34-35
Example 22 pMoN28500 39 NcoI/HindIII 4L 28521 38-39
Example 23 pMON28500 43 NcoI/HindIII 4L 28522 42-43
Example 24 pMON28500 45 NcoI/HindIII 4L 28523 44-45
Example 25 pMoN28500 49 NcoI/HindIII 4L 28524 48-49
Example 26 pMoN28500 82 NcoI/HindIII 4L 28525 81-82
Example 27 pMON28500 109 NcoI/HindIII 4L 28526 108-109
Example 28 pMON28500 116 NcoI/HindIII 4L 28527 115-116
Example 29 pMON28500 120 NcoI/HindIII 4L 28528 119-120
Example 30 pMON28500 123 NcoI/HindIII 4L 28529 122-123
Example 31 pMI~N28500 126 NcoI/HindIII 4L 28530~ 125-126
Example 32 pMoN28502 31 NcoI/HindIII 8L 28533 30-31
Example 33 pMON28502 35 AflIII/HindIII 8L 28534 34-35
Example 34 pMoN28502 39 NcoI/HindIII 8L 28535 38-39
Example 35 pMoN28502 43 NcoI/HindIII 8L 28536 42-43

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TABLE 4 cont.
PCR Pro~uct PCR Product Resulting Breakpoint
Example H PCR templaLe Primer set Restrictio~ Linker Plasmid in c-mpl
Digest pMONligand
Example 36p~ 28502 45 NcoI/HindIII 8L 28537 44-45
Example 37pMON28502 49 NcoI/HindIII BL 28538 48-49
Example 38pMON28502 82 NcoI/HindIII 8L 28539 81-82
~xa~ple 39pMON28502 109 NcoI/~indIII 8L 28540 108-109
Example 40pMON28502 116 NcoI/HlndIII 8L 285~1 115-116
EXAMPLE 41pMON28502 120 NcoI/HindIII 8L 28542 119-120
Example 42pMON28502 12~ NcoI/~indIII 8L 28543 122-123
Example 43pMON28502 126 NcoI/HindIII 8L 28544 125-126
Example 44pMoN28548 123 NcoI/HindIII 5L 28545 122-123
F'.~Z~MPT.F. 45
~onstruction of pMONl5960
Construction of pMON15960, an intermediate plasmid used for
constructing plasmids containing DNA sequences encoding G-
CSF Serl7 with a new N-terminus and C-terminus. Plasmid
pACYC177 (Chang, A.C.Y. and Cohen, S.N. ~. Bacteriol.
134:1141-1156, 1978) DNA was digested with restriction
enzymes HindIII and BamHI, resulting in a 3092 base pair
HindIII, BamHI fragment. Plasmid, pMON13037 (WO 95/21254),
DNA was digested with BglII and FspI, resulting in a 616
base pair BglII, FspI fragment. A second sample of plasmid,
pMON13037, DNA was digested with NcoI and HindIII,
resulting in a 556 base pair McoI, HindIII fragment. The
synthetic DNA oligonucleotides lGGGSfor (SEQ ID NO:76) and
lGGGSrev (SEQ ID NO:77) were annealed to each other, and
then digested with AflIII and FspI, resulting in a 21 base
pair AflIII, FspI fragment. The restriction fragments were
ligated, and the ligation reaction mixture was used to

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trans~orm E. coli K-12 strain JM101. Transformant bacteria
were selected on ampicillin-containing plates. Plasmid DNA
was isolated and analyzed by restriction analysis to confirm
the correct insert.
F.XAMPT,~. 46
Con~truction o~ ~MON15981
Construction o~ pMON15981, a plasmid cont~in~n~ DNA
sequences encoding a multi-~unctional hematopoietic receptor
agonist. Plasmid, pMON15960, DNA was digested with
restriction enzyme SmaI and used as template in a PCR
reac~ion using synthetic DNA oligonucleotides 38 stop (SEQ
ID NO:65) and 39 start (SEQ ID NO:64) as primers, resulting
in the ampli~ication o~ a DNA ~ragment o~ 576 base pairs.
The amplified ~ragment was digested with restriction en~ymes
HindIII and NcoI, resulting in a HindIII, NcoI ~ragment o~
558 base pairs. Plasmid, pMON13181, DNA was digested with
HindIII and A~lIII, resulting in a HindIII, AflIII fragment
of 4068 base pairs. The restriction ~ragments were ligated,
and the ligation reaction mixture was used to trans~orm E.
coli K-12 strain JM101. Trans~ormant bacteria were selected
on ampicillin-containing plates. Plasmid DMA was isolated,
analyzed by restriction analysis, and sequenced to confirm
the correct insert. The plasmid, pMON15981, contains the
DNA sequence o~ (SEQ ID NO:155) which encodes the ~ollowing
amlno acld se~uence:
MetAlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAla
ProLeuLeuAspProAsnAsn~euAsnAspGluAspValSerIleLeuMetAspArgAsn
LeuArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSer
GlyIleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro
SerArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThr
PheTyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaTyrLysLeuCysHisProGluGluLeuValLeuLeu
GlyHisSerLeuGlyIleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGln
LeuAlaGlyCysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGln
AlaLeuGluGlyIleSerProGlu~euGlyProThrLeuAspThrLeuGlnLeuAspVal

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AlaAspPheAlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAlaProAlaLeu
GlnProThrGlnGlyAlaMetProAlaPheAlaSerAlaPheGlnArgArgAlaGlyGly
ValLeuValAlaSerHisLeuGlnSerPheLeuGluValSerTyrArgValLeuArgHis
LeuAlaGlnProGlyGlyGlySerAspMetAlaThrProLeuGlyProAlaSerSerLeu
ProGlnSerPheLeuLeuLysSerLeuGluGlnValArgLysIleGlnGlyAspGlyAla
AlaLeuGlnGluLysLeuCysAlaThr (SEQ ID NO:195)
MPT.F. 47
constructiGn of DMON15982
Construction of pMON15982, a plasmid containing DNA
sequences encoding a multi-functional hematopoietic receptor
agonist. Plasmid, pMON15960, DNA was digested with
restriction enzyme SmaI and used as template in a PCR
reaction using synthetic DNA oligonucleotides 96 stop (SEQ
ID NO:67) and 97 start (SEQ ID NO: 66) as primers, resulting
in the amplification of a DNA fragment of 576 base pairs.
The amplified fragment was digested with restriction enzymes
HindIII and NcoI, resulting in a HindIII~ NcoI fragment of
558 base pairs. Plasmid, pMON13181, DNA was digested with
HindIII and AflIII, resulting in a HindIII, AflIII fragment
of 4068 base pairs. The restriction fragments were ligated,
and the ligation reaction mixture was used to transform E.
coli K-12 strain JM101. Transformant bacteria were selected
on ampicillin-containing plates. Plasmid DNA was isolated,
analyzed by restriction analysis, and sequenced to confirm
the correct insert. The plasmid, pMON15982, contains the
DNA sequence of (SEQ ID NO:157) which encodes the following
amino acid sequence:
MetAlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAla
ProLeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsn
LeuArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSer
GlyIleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro
SerArgHisproIleIleIleLysAlaGlyAspTrpGlnGlupheArgGluLysLeuThr
PheTyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaProGluLeuGlyProThrLeuAspThrLeuGlnLeu
AspValAlaAspPheAlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAlaPro
AlaLeuGlnProThrGlnGlyAlaMetProAlaPheAlaSerAlaPheGlnArgArgAla
i

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GlyGlyValLeuValAlaSerHisLeuGlnSerPheLeuGluValSerTyrArgValLeu
ArgHisLeuAlaGlnProGlyGlyGlySerAspMetAlaThrProLeuGlyProAlaSer
SerLeuProGlnSerPheLeuLeuLysSerLeuGluGlnValArgLysIleGlnGlyAsp
GlyAlaAlaLeuGlnGluLysLeuCysAlaThrTyrLysLeuCysHisProGluGluLeu
ValLeuLeuGlyHisSerLeuGlyIleProTrpAlaProLeuSerSerCysProSerGln
AlaLeuGlnLeuAlaGlyCysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGly
LeuLeuGlnAlaLeuGluGlyIleSer (SEQ ID NO:196)
~XAMPLE 48
Co~truct;on of ~MQN15965
Construction of pMON15965, a plasmid containing DNA
sequences encoding a multi-~unctional hematopoietic receptor
agonist. Plasmid, pMON15960, DNA was digested with
restriction enzyme SmaI and used as template in a PCR
reaction using synthetic DNA oligonucleotides 142 stop (SEQ
ID NO:73) and 141 start (SEQ ID NO:72) as primers, resulting
in the amplification o~ a DNA ~ragment of 576 base pairs.
The amplified fragment was digested with restriction enzymes
HindIII and NcoI, resulting in a HindIII, NcoI ~ragment of
558 base pairs. Plasmid, pMON13181, DNA was digested with
HindIII and AflIII, resulting in a HindIII, A~lIII ~ragment
o~ 4068 base pairs. The restriction fragments were ligated,
and the ligation reaction mixture was used to transform E.
coli K-12 strain JM101. Transformant bacteria were selected
on ampicillin-containing plates. Plasmid DNA was isolated,
analyzed by restriction analysis, and sequenced to confirm
the correct insert. The plasmid, pMON15965, contains the
DNA sequence of (SEQ ID NO:157) which encodes the following
amino acid sequence:
MetAlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAla
ProLeuLeuAspProAsnAsnLeuAsnAspGluASpValSerIleLeuMetAspArgAsn
LeuArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSer
GlyIleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro
SerArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThr
PheTyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHi~LysSerProAsnMetAlaSerAlaPheGlnArgArgAlaGlyGlyValLeuVal

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AlaSerHisLeuGlnSerPheLeuGluValSerTyrArgValLeuArgHisLeuAlaGln
ProGlyGlyGlySerAspMetAlaThrProLeuGlyProAlaSerSerLeuProGlnSer
PheLeuLeuLysserLeuGluGlnvalArgLysIleGlnGlyAspGlyAlaAlaLeuGln
GluLysLeuCysAlaThrTyrLysLeuCysHisProGluGluLeuValLeuLeuGlyHis
SerLeuGlyIleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGlnLeuAla
GlyCysLeuSe~GlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGlnAlaLeu
GluGlyIleSerProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspValAlaAsp
PheAlaThrThrIleTrpGlnGlnMetGluGluLeuGlyMetAlaProAlaLeuGlnPro
ThrGlnGlyAlaMetProAlaPheAla (SEQ ID NO:196)
F~AMPL~ 49
Construction of ~MON15966
~onstruction of pMON15966, a plasmid containing DNA
sequences encoding a multi-functional hematopoietic receptor
agonist. Plasmid, pMON15960, DNA was digested with
restriction enzyme SmaI and used as template in a PCR
reaction using synthetic DNA oligonucleotides 126 stop (SEQ
ID NO:68) and 125 start (SEQ ID NO:69) as primers,
resulting in the amplification of a DNA fragment o~ 576 base
pairs. The amplified fragment was digested with restriction
enzymes HindIII and NcoI, resulting in a HindIII, NcoI
fragment of 558 base pairs. Plasmid, pMON13181, DNA was
digested with HindIII and AflIII, resulting in a HindIII,
AflIII fragment of 4068 base pairs. The restriction
fragments were ligated, and the ligation reaction mixture
was used to transform E. coli K-12 strain JM101.
Transformant bacteria were selected on ampicillin-containing
plates. Plasmid DNA was isolated, analyzed by restriction
analysis, and sequenced to confirm the correct insert. The
plasmid, pMON15966, contains the DNA sequence of (SEQ ID
NO:158) which encodes the following amino acid sequence:
MetAlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysArgProProAla
ProLeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsn
LeuArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSer
GlyIleGluAlaIleLeuArgAsnLeuGlnProCySLeuProSerAlaThrAlaAlaPro
: SerArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThr
PheTyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGly

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SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaMetAlaProAlaLeuGlnProThrGlnGlyAlaMet
ProAlaPheAlaSerAlaPheGlnArgArgAlaGlyGlyValLeuValAlaSerHisLeu
GlnSerPheLeuGluValSerTyrArgValLeuArgHisLeuAlaGlnProGlyGlyGly
SerAspMetAlaThrProLeuGlyProAlaSerSerLeuProGlnSerPheLeuLeuLys
SerLeuGluGlnValArgLysIleGlnGlyAspGlyAlaAlaLeuGlnGluLysLeuCys
AlaThrTyrLysLeuCysHisProGluGluLeuValLeuLeuGlyHisSerLeuGlyIle
ProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGlnLeuAlaGlyCysLeuSer
GlnLeuHisserGlyLeupheLeuTyrGlnGlyLeuLeuGlnAlaLeuGluGlyIleser
ProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspValAlaAspPheAlaThrThr
IleTrpGlnGlnMetGluGluLeuGly (SEQ ID NO:198
~x~MpT~F~ 50
Construction of ~MON15967
Construc~ion of pMON15967, a plasmid containing DNA
sequences encoding a multi-functional hematopoietic receptor
agonist. Plasmid, pMON15960, DNA was digested with
restriction enzyme SmaI and used as template in a PCR
reaction using synthetic DNA oligonucleotides 132 stop (SEQ
ID NO:71) and 133 start (SEQ ID NO:70) as primers, resulting
in the ampli~ication of a DNA ~ragment o~ 576 base pairs.
The amplified fragment was digested with restriction enzymes
HindIII and NcoI, resulting in a HindIII, NcoI fragment of
558 base pairs. Plasmid, pMON13181, DNA was digested with
HindIII and AflIII, resulting in a HindIII, AflIII fragment
o~ 4068 base pairs. The restriction fragments were ligated,
and the ligation reaction mixture was used to trans~orm E.
coli K-12 strain JM101. Transformant bacteria were selected
on ampicillin-containing plates. Plasmid DNA was isolated,
analyzed by restriction analysis, and sequenced to confirm
the correct insert. The plasmid, pMON15967, contains the DNA
sequence of (SEQ ID NO: ~59) which encodes the following
amino acid sequence:
MetAlaAsnCysSerIleMetIleAspGluIleIleHisHisLeuLysAr~ProProAla
ProLeuLeuAspProAsnAsnLeuAsnAspGluAspValSerIleLeuMetAspArgAsn
LeuArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSer
GlyIleGluAlaIleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro

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SerArgHisProIleIleIleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThr
PheTyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGly
SerProGlyGluProSerGlyProIleSerThrIleAsnProSerProProSerLysGlu
SerHisLysSerProAsnMetAlaThrGlnGlyAlaMetProAlaPheAlaSerAlaPhe
GlnArgArgAlaGlyGlyValLeuValAlaSerHisLeuGlnSerPheLeuGluValSer
TyrArgValLeuArgHisLeuAlaGlnProGlyGlyGlySerAspMetAlaThrProLeu
GlyProAlaSerSerLeuProGlnSerPheLeu~euLysSerLeuGluGlnValArgLys
IleGlnGlyAspGlyAlaAlaLeuGlnGluLysLeucysAlaThrTyrLysLeucysHis
ProGluGluLeuValLeuLeuGly~isSerLeuGlyIleProTrpAlaProLeuSerSer
CysProSerGlnAlaLeuGlnLeuAlaGlyCysLeuSerGlnLeuHisSerGlyLeuPhe
LeuTyrGlnGlyLeuLeuGlnAlaLeuGluGlyIleSerProGluLeuGlyProThrLeu
AspThrLeuGlnLeuAspValAlaAspPheAlaThrThrIleTrpGlnGlnMetGluGlu
LeuGlyMetAlaProAlaLeuGlnPro
~X~MpLE 51
Con~truction of ~MON13180, an intermediate ~l~smid used for
constructina ~lasmids that contain DNA sequence encodina
multi-functional hemato~oietic rece~tor a~onists.
Plasmid, pMON13046 (WO 95/21254), DNA was digested with
restriction endonucleases XmaI and SnaBI, resulting in a
4018 base pair vector fragment. The 4018 base pair XmaI-
SnaBI fragment was puri~ied using a Magic DNA Clean-up
System kit (Promega, Madison, WI) in which the 25 base pair
XmaI-SnaBI insert fragment is not retained. The
complimentary pair of synthetic oligonucleotides, glyxal
(SEQ ID MO:74) and glyxa2 (SEQ ID NO:75), were designed to
remove sequence encoding a factor Xa cleavage site. When
properly assembled these oligonucleotides also result in
XmaI and ~naBI ends. The primers, Glyxal and glyxa2, were
annealed in annealing buffer (20mM Tris-HCl pH7.5, 10 mM
MgCl2, 50 mM NaCl) by heating at 70~C for ten minutes and
allowed to slow cool. The 4018 base pair XmaI-~naBI
fragment from pMON13046 was ligated with the assembled
oligonucleotides using T4 DNA~ligase (Boehringer Mannheim,
Indianapolist IN). A portion of the ligation reaction was
used to transform E. coli strain DH5~ cells (Life
Technologies, Gaithersburg, MD). Transformant bacteria were

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selected on ampicillin-containing plates. Plasmid DNA was
isolated from the transformants and analyzed using a PCR
based assay. Plasmid DNA from selected transformants was
sequenced to confirm the correct insertion of the
oligonucleotides. The resulting plasmid was designated
pMON13180 and contains the DNA sequence of (SEQ ID NO:**).
E:XAMPT,~. 52
Co~truction of pMON13181, an intermediate ~ m;d used for
construct:~n~ };)lasmids that contain DNA se~uences encodina
mult;-functional hemato~oietic rece~tor a~onists.
Plasmid, pMON13047 (WO 95/21254), DNA was digested with
restriction endonucleases XmaI and SnaBI, resulting in a
4063 base pair vector fragment. The 4063 base pair XmaI-
SnaBI fragment was purified using a Magic DNA Clean-up
~ystem kit (Promega, Madison, WI) in which the 25 base pair
XmaI-SnaBI insert fragment is not retained. The
complimentary pair of synthetic oligonucleotides, glyxal
(SEQ ID NO:74) and glyxa2 (SEQ ID NO:75), were designed to
remove se~uence encoding the factor Xa cleavage site. When
properly assembled these oligonucleotides also result in
XmaI and SnaBI ends. Glyxal and glyxa2 were annealed in
annealing buffer by heating at 70~C for ten minutes and
allowed to slow cool. The 4063 base pair XmaI-SnaBI
fragment ~rom pMOM13047 was ligated with the assembled
oligonucleotides using T4 DN~ ligase (Boehringer Mannheim,
Indianapolis, IN). A portion of the ligation reaction was
used to transform E. coli strain DH5a cells (Life
Technologies, Gaithersburg, MD). Transformant bacteria were
selected on ampicillin-containing plates. Plasmid DNA was
isolated from the transformants and analyzed using a PCR
based assay. Plasmid DNA from selected transformants was
sequenced to confirm the correct insertion of the

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173
oligonucleotides. The resulting plasmid was designated
pMON13181 and contains the DNA sequence of (SEQ ID NO:**).
E:x~MpT~F~ 53
Construction of pMON13182
The new N-terminus/C-terminus gene in pMON13182 was
created using Method I as described in Materials and
Methods. Fragment Start was created and amplified from G-
CSF Serl7 sequence in pMON13037 using the primer set, 39
start (SEQ ID NO:64) and L-ll start (SEQ ID NO:60).
Fragment Stop was created and amplified from G-CSF Serl7
sequence i. pMON13037 using the primer set, 38 stop (SEQ ID
NO:65) and L-ll stop (SEQ ID NO:61). The full-length new N
terminus/C-terminus G-CSF Serl7 gene was created and
amplified from the annealed Fragments Start and Stop using
primers 39 start and 38 stop.
The resulting DNA fragment which contains the new gene
was digested with restriction endonucleases NcoI and HindIII
and puri~ied using a Magic DNA Clean-up System kit (Promega,
Madison, WI). The intermediate plasmid, pMON13180, was
digested with restriction endonucleases HindIII and AflIII,
resulting in a 4023 base pair vector fragment, and purified
using a Magic DNA Clean-up System kit (Promega, Madison,
WI). The purified restriction fragments were combined and
ligated using T4 DNA ligase (Boehringer Mannheim,
Indianapolis, IN). A portion of the ligation reaction was
used to transform E. coli strain DH5~ cells ~Life
Technologies, Gaithersburg, MD). Transformant bacteria were
selected on ampicillin-containing plates. Plasmid DNA was
isolated and sequenced to confirm the correct insert. The
resulting plasmid was designated pMON13182.

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E. coli strain JM101 was transformed with pMON13182 for
protein expression and protein isolation from inclusion
bodies.
The plasmid, pMON13182, contains the DNA sequence of
(SEQ ID No:a4) which encodes the following amino acid
~equence:
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile ~is His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu &lu
Ser Phe val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met ~la Tyr Lys Leu Cys
His Pro Glu Glu Leu Val Leu Leu Gly ~Iis Ser Leu Gly Ile Pro
Trp Ala Pro ~eu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala
Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly
Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr
Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile
Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro
Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu
Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly
Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val
Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys
Ala Thr (SEQ ID NO:166)
F~.~Al~qpr.~. 54
C~n~truction of pMON13183
The new N-terminus/C-terminus gene in pMON13183
was created using Method I as described in Materials and
Methods. "Fragment Start" was created and amplified from G-
CSF Serl7 sequence in pMON13037 using the primer set, 39
start (SEQ ID NO:64) and L-ll start (SEQ ID NO:60).
Fragment Stop was created and amplified from G-CSF Serl7
sequence in pMON13037 using the primer set, 38 stop (SEQ ID
No:65) and L-ll stop (SEQ I~ NO:61). The full-length new N

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terminus/C-terminus G-CSF Ser17 gene was created and
ampli~ied ~rom the annealed Fragments Start and Stop using
39 start and 38 stop.
The resulting DNA ~ragment which contains the new gene
was digested with restriction endonucleases NcoI and HindIII
and purified using a Magic DNA Clean-up System kit (Promega,
Madison, WI). The intermediate plasmid, pMON13181, was
digested with restriction endonucleases HindIII and A~lIII,
resulting in a 4068 base pair vector ~ragment, and puri~ied
using a Magic DNA Clean-up System kit (Promega, Madison,
WI). The puri~ied restriction ~ragments were combined and
ligated using T4 DNA ligase (Boehringer Mannheim,
Indianapolis, IN). A portion o~ the ligation reaction was
used to transform E. coli strain DH5OC cells (Li~e
Technologies, Gaithersburg, MD). Trans~ormant bacteria were
selected on ampicillin-containing plates. Plasmid DNA was
isolated and sequenced to confirm the correct insert. The
resulting plasmid was designated pMON13183.
E. coli strain JM101 was trans~ormed with pMON13183 ~or
protein expression and protein isolation from inclusion
bodies.
The plasmid, pMON13183, contains the DMA ses~uence of
(SEQ ID NO:95) which encodes the ~ollowing amino acid
sequence:
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Tyr Lys Leu Cys
His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro
Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala
Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly
Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr
Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile
.

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Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro
Thr Gln Gly Ala Me~ Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe I~eu Glu
Val Ser l~rr Arg Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly
Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val
Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys ~eu Cys
Ala Thr (SEQ ID No:167)
F~MPLE 55
~onstruction of ~MON~3184
The new N-terminus/C-terminus gene in pMON13184 was
created using Method I as described in Materials and
Methods. Fragment Start was crea~ed and amplified from G-
CSF Ser17 sequence in pMON13037 using the primer set, 97
start (SEQ ID NO:66) and L-11 start (SEQ ID NO:60).
Fragment Stop was created and amplified from G-CSF Ser17
sequence in pMOM13û37 using the primer set, 96 stop (SEQ ID
No:67) and L-11 stop (SEQ ID NO:61). The full-length new N
terminus/C-terminus G-CSF Ser17 gene was created and
amplified from the annealed Fragments Start and Stop using
97 start and 96 stop.
The resulting DNA fragment which contains the new gene
was digested with restriction endonucleases NcoI and HindIII
and purified using a Magic DNA Clean-up System kit (Promega,
Madison, WI). The intermediate plasmid, pMOM13180, was
digested with restriction endonucleases HindIII and AflIII,
resulting in a 4023 base pair vector fragment, and purified
using a Magic DMA Clean-up System kit (Promega, Madison,
WI). The purified restriction fragments were combined and
ligated using T4 DNA ligase (Boehringer Mannheim,
Indianapolis, IN). A portion of the ligation reaction was
used to transform ~. coli strain DH5a cells (Life
Technologies, Gaithersburg, MD). Transformant bacteria were
selected on ampicillin-containing plates. Plasmid DNA was

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isolated and sequenced to confirm the correct insert. The
resulting plasmid was designated pMON13184.
E . col i strain JM101 was transformed with pMON13184 for
S protein expression and protein isolation from inclusion
bodies.
The plasmid, pMON13184, contains the DNA sequence of
(SEQ ID NO:96) which encodes the following amino acid
se~uence:
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Pro Glu Leu Gly
Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr
Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu
Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln
Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe
Leu Glu Val Ser Tyr Arg Val Leu Arg ~is Leu Ala Gln Pro Ser
Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu
Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys
Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu
Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys
Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His
Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly
Ile Ser (SEQ ID NO:168)
EX~MPLE 56
cQnstruction of ~MON13185
The new N-terminus/C-terminus gene in pMON13185 was
created using Method I as described in Materials and
Methods. Fragment Start was created and amplified from G-
CSF Serl7 sequence in pMON13037 using the primer set, 97
start (SEQ ID No:66) and L-ll start (SEQ ID Mo:60).
Fragment Stop was created and ampli~ied from G-CSF Serl7

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178
sequence in pMON13037 using the primer set, 96 stop (SEQ ID
NO:67 and L-~l stop (SEQ ID NO:61). The ~ull-length new N
terminus/C-terminus G-CSF Ser17 gene was created and
ampli~ied ~rom the annealed Fragments Start and Stop using
97 start and 96 stop.
The resulting DNA ~ragment which contains the new gene
was digested with restriction endonucleases NcoI and HindIII
and purified using a Magic DNA Clean-up System kit (Promega,
Madison, ~I). The intermediate plasmid, pMON13181, was
digested with restriction endonucleases HindIII and AflIII,
resulting in a 4068 base pair vector fragment, and puri~ied
using a Magic DNA Clean-up System kit (Promega, Madison,
WI). The puri~ied restriction ~ragments were combined and
ligated using T4 DNA ligase (Boehringer Mannheim,
Indianapolis, IN). A portion of the ligation reaction was
used to transform E. coli strain DH5~ cells (Life
Technologies, Gaithersburg, MD). Transformant bacteria were
selected on ampicillin-containing plates. Plasmid DNA was
isolated and sequenced to con~irm the correct insert. The
resulting plasmid was designated pMON13185.
E. col i strain JM101 was trans~ormed with pMON13185 for
protein expression and protein isolation ~rom inclusion
bodies.
The plasmid, pMON13185, contains the DNA se~uence o~
(SEQ ID Mo:67) which encodes the following amino acid
sequence:
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ald Pro Leu Leu Asp Pro Asn Asn Leu Asn As~ Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gl~ Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Pro Glu Leu Gly
Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr

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Thr Ile Trp Gln Gln Met Glu Giu ~eu Gly Met Ala Pro Ala Leu
Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln
r Arg Arg Ala Gly Gly Val Leu ~al Ala Ser His Leu Gln Ser Phe
Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser
Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu
Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys
Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu val Leu
Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys
Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His
Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly
Ile Ser (SEQ ID NO:169)
EXAMPT.F. 57
Construction of ~MON13186
The new N-terminus/C-terminuS gene in pMON13186 was
created using Method I as described in Materials and
Methods. Fragment Start was created and ampli~ied from G-
CSF Ser17 sequence in pMON13037 using the primer set, 126
start (SEQ ID NO:68) and L-11 start (SEQ ID No:60).
Fragment Stop was created and ampli~ied ~rom G-CSF Ser17
sequence in pMON13037 using the primer set, 125 stop (SEQ ID
NO:69) and k-11 stop (SEQ ID NO:61). The full-length new N
terminus/C-terminus G-CSF Ser17 gene was created and
ampli~ied ~rom the annealed Fragments Start and Stop using
126 start and 125 stop.
The resulting DNA fragment which contains the new gene
was digested with restriction endonucleases NcoI and HindIII
and purified using a Magic DNA Clean-up System kit (Promega,
Madison, WI). The intermediate plasmid, pMON13180, was
digested with restriction endonucleases HindIII and AflIII,
resulting in a 4023 base pair vector ~ragment, and purified
using a Magic DNA Clean-up System kit (Promega, Madison,
WI). The purified restriction fragments were combined and
ligated using T4 DNA ligase (Boehringer Mannheim,
Indianapolis, IN). A portion of the ligation reaction was
used to transform E. coli strain DH5~ cells (Life

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180
Technologies, Gaithersburg, MD). Trans~ormant ~acteria were
selected on ampicillin-containing plates. Plasmid DMA was
isolated and sequenced to confirm the correct insert. The
resulting plasmid was desi~nated pMON13186.
E. coli strain JM101 was transformed with pMOM13186 for
protein expression and protein isolation from inclusion
bodies.
The plasmid, pMON13186, contains the DNA sequence o~
(SEQ ID Mo:98) which encodes the following amino acid
sequence:
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Met Ala Pro Ala
Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe
Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser
Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro
Ser Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu
Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu
Lys Leu Cys Ala Thr Ty~ Lys Leu Cys His Pro Glu Glu Leu Val
Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser
Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu
His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu
Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu
Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu
Leu Gly ~SEQ ID NO:170)
E~MPTIF 58
Constructio~ of ~MON13187
The new N-terminus/C-terminus gene in pMON13187 was
created using Method I as described in Materials and
Methods. Fragment Start was created and ampli~ied from G-
CSF Serl7 sequence in pMoNl3o37 using the primer set, 126
start (SEQ ID NO:68) and L-ll start (SEQ ID NO:60).
-

CA 02234061 1998-04-06
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Fragment Stop was created and amplified ~rom G-CSF Ser17
sequence in pMON13037 using the primer set, 125 stop (SEQ ID
NO:69) and L-11 stop (SEQ ID NO:61). The full-length new N
terminus/C-terminus G-CSF Ser17 gene was created and
amplified ~rom the annealed Fragments Start and Stop using
126 start and 125 stop.
The resulting DNA ~ragment which contains the new gene
was digested with restriction endonucleases NcoI and HindIII
and purified using a Magic DNA Clean-up System kit (Promega,
Madison, WI). The intermediate plasmid, pMON13181, was
digested with restriction endonucleases HindIII and AflIII,
resulting in a 4068 base pair vector fragment, and purified
using a Magic DNA Clean-up System kit (Promega, Madison,
WI). The purified restriction ~ragments were combined and
ligated using T4 DNA ligase (Boehringer Mannheim,
Indianapolis, IN). A portion of the ligation reaction was
used to transform E. coli strain DH5a cells (Li~e
Technologies, Gaithersburg, MD). Transformant bacteria were
selected on ampicillin-containing plates. Plasmid DNA was
isolated and se~uenced to confirm the correct insert. The
resulting plasmid was designated pMON13187.
E. coli strain JM101 was transformed with pMON13187 for
protein expression and protein isolation ~rom inclusion
bodies.
The plasmid, pMON13187, contains the DNA se~uence o~
(SEQ ID NO:99) which encodes the following amino acid
sequence:
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro

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Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Met Ala Pro Ala
Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe
Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser
Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro
Ser Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu
Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu
Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val
Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser
Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu
His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu
Gly Ile Ser Pro Glu Leu Gly Pro Thr ~eu Asp Thr Leu Gln Leu
Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu
Leu Gly ~SEQ ID NO:171)
~.XAMP~E 59
Construction o~ ~MON13188
The new ~-terminus/C-terminus gene in pMON13188 was
created using Method I as described in Materials and
Methods. Fragment Start was created and amplified ~rom G-
CSF Ser17 sequence in pMON13037 using the primer set, 133
start tSEQ ID MO:70) and L-11 start (SEQ ID NO:60).
Fragment Stop was created and amplified ~rom G-CSF Ser17
sequence in pMON13037 using the primer set, 132 stop (SEQ ID
NO:71) and L-11 stop (SEQ ID NO:61). The full-length new N
terminus/C-terminus G-CSF Ser17 gene was created and
amplified from the annealed Fragments Start and Stop using
133 start and 132 stop.
The resulting DNA fragment which contains the new gene
was digested with restriction endonucleases NcoI and HindIII
and purified using a Magic DNA Clean-up System kit (Promega,
Madison, WI). The intermediate plasmid, pMON13180, was
digested with restriction endonucleases HindIII and AflIII,
resulting in a 4023 base pair vector fragment, and purified
using a Magic DNA Clean-up System kit (Promega, Madison,
WI). The purified restriction fragments were combined and
ligated using T4 DNA ligase (Boehringer Mannheim,
Indianapolis, IN). A portion of the ligation reaction was
used to transform E. coli strain DH5~ cells (Life

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183
Technologies, Gaithersburg, MD). Transformant bacteria were
selected on ampicillin-containing plates. Plasmid DNA was
isolated and sequenced to con~irm the correct insert. The
resulting plasmid was designated pMON13188.
E. coli strain JM101 was transformed with pMON13188 ~or
protein expression and protein isolation ~rom inclusion
bodies.
The plasmid, pMON13188, contains the DNA sequence of
(SEQ ID MO:100) which encodes the following amino acid
sequence:
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg HiS Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Glr- Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Thr Gln Gly Ala
Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val
Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg
Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly Ser Gly Gly Ser
Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val Arg Lys Ile Gln
Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys
Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly
Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln
Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr
Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly
Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr
Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu
Gln Pro (SEQ ID NO:172)
~ P~ 60
Con~truction o~ pMON13189
The new N-terminus/C-terminus gene in pMON13189 was
created using Method I as described in Materials and
Methods. Fragment Start was created and amplified ~rom G-
CSF Serl7 sequence in pMON13037 using the primer set, 133
start (SEQ ID NO:70) and L-ll start (SEQ ID No:60).

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Fragment Stop was created and amplified ~rom G-CSF Ser17
sequence in pMOM13037 using the primer set, 132 stop (SEQ ID
~0:71) and L-11 stop (SEQ ID NO:61). The ~ull-length new N
terminus/C-terminus G-CSF Ser17 gene was created and
amplified ~rom the annealed Fragments Start and Stop using
133 start and 132 stop.
The resulting DNA ~ragment which contains the new gene
was digested with restriction endonucleases NcoI and HindIII
and puri~ied using a Magic DNA Clean-up System kit (Promega,
Madison, WI). The intermediate plasmid, pMON13181, was
digested with restriction endonucleases HindIII and A~lIII,
resulting in a 4068 base pair vector fragment, and puri~ied
using a Magic DNA Clean-up System kit (Promega, Madison,
WI). The purified restriction ~ragments were combined and
ligated using T4 DNA ligase (Boehringer Mannheim,
Indianapolis, IN). A portion o~ the ligation reaction was
used to transform E. coli strain DH50~ cells ~Life
Technologies, Gaithersburg, MD). Transformant bacteria were
selected on ampicillin-containing plates. Plasmid DMA was
isolated and se~uenced to confirm the correct insert. The
resulting plasmid was designated pMON13189.
E. coli strain JM101 was transformed with pMON13189 for
protein expression and protein isolation ~rom inclusion
bodies.
The plasmid, pMON13189, contains the DNA sequence of
(SEQ ID NO:101) which encodes the ~ollowing amino acid
sequence:
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro

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Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Thr Gln Gly Ala
Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val
Leu val Ala Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg
Val Leu Arg His Leu Ala Gln Pro Ser Gly Gly Ser Gly Gly Ser
Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val Arg Lys Ile Gln
Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys
Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly
Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln
Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr
Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly
Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr
Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu
Gln Pro (SEQ ID NO:173)
F.~MPT.~ 61
Construction of pMON13190
The new N-terminus/C-terminus gene in pMON13190 was
created using Method I as described in Materials and
Methods. Fragment Start was created and amplified from G-
CSF Serl7 sequence in pMON13037 using the primer set, 142
start (SEQ ID NO:72) and L-ll start (SEQ ID NO:60).
Fragment Stop was created and amplified from G-CSF Serl7
se~uence in pMON13037 using the primer set, 141 stop (SEQ ID
NO:73) and L-ll stop (SEQ ID NO:61). The full-length new N
terminus/C-terminus G-CSF Serl7 gene was created and
amplified from the annealed Fragments Start and Stop using
142 start and 141 stop.
The resulting DNA fragment which contains the new gene
was digested with restriction endonucleases NcoI and HindIII
and purified using a Magic DNA Clean-up System kit (Promega,
Madison, WI). The intermediate plasmid, pMON13180, was
digested with restriction endonucleases HindIII and AflIII,
resulting in a 4023 base pair vector fragment, and purified
using a Magic DNA Clean-up System kit (Promega, Madison,
WI). The purified restriction fragments were combined and
ligated using T4 DNA ligase (Boehringer Mannheim,
Indianapolis, IN). A portion of the ligation reaction was
used to transform E. coli strain DH5~ cells (Life

CA 02234061 1998-04-06
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~86
Technologies, Gaithersburg, MD). Trans~ormant bacteria were
selected on ampicillin-containing plates. Plasmid DNA was
isolated and se~uenced to confirm the correct insert. The
resulting plasmid was designated pMON13190.
E. coli strain JM101 was transformed with pMON13190 for
protein exLression and protein isolation from inclusion
bodies.
The plasmid, pMON13190~ contains the DNA sequence o~
(SEQ ID NO:102) which encodes the following amino acid
sequence:
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Ser Ala Phe Gln
Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe
Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser
Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu
Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys
Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu
Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys
Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His
Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly
Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp
Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu
Gly Met Ala Pro Ala Leu Gln Pro Thr Gln G1~ Ala Met Pro Ala
Phe Ala (SEQ ID NO:174)
FX~MP~E 62
Construction of pMON13191
The new N-terminuS/C-terminus gene in pMON13191 was
created using Method I as described in Materials and
Methods. Fragment Start was created and amplified from G-
CSF Ser17 sequence in pMON13037 using the primer set, 142

CA 02234061 1998-04-06
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187
start (SEQ ID NO:72) and L-11 start (SEQ ID NO:60).
Fragment Stop was created and amplified from G-CSF Ser17
sequence in pMON13037 using the primer set, 141 stop (SEQ ID
NO:73) and L-11 stop ~SEQ ID NO:61). The full-length new N
terminus/C-terminus G-CSF Ser17 gene was created and
ampli~ied ~rom the annealed Fragments Start and Stop using
142 start and 141 stop.
The resulting DNA fragment which contains the new gene
was digested with restriction endonucleases NcoI and HindIII
and purified using a Magic DNA Clean-up System kit (Promega,
Madison, WI). The intermediate plasmid, pMON13181, was
digested with restriction endonucleases HindIII and AflIII,
resulting in a 4068 base pair vector fragment, and purified
using a Magic DNA Clean-up System kit (Promega, Madison,
WI). The puri~ied restriction fragments were combined and
ligated using T4 DNA ligase (Boehringer Mannheim,
Indianapolis, IN). A portion o~ the ligation reaction was
used to trans~orm E. coli strain DH5Oc cells (Life
Technologies, Gaithersburg, MD). Transformant bacteria were
selected on ampicillin-containing plates. Plasmid DNA was
isolated and sequenced to confirm the correct insert. The
resulting plasmid was designated pMON13191.
E. coli strain JM101 was transformed with pMON13191 for
protein expression and protein isolation from inclusion
bodies.
The plasmid, pMOM131~1, contains the DNA sequence of
(SEQ ID NO:103) which encodes the following amino acid
sequence:
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
- Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
'~ Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro

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Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Ser Ala Phe Gln
Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe
~eu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Ser
Gly Gly Ser Gly Gly Ser Gln Ser Phe Leu Leu Lys Ser Leu Glu
Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys
Leu Cys Ala Thr Tyr Lys Leu Cys Xis Pro Glu Glu I,eu Val Leu
Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys
Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His
Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly
Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp
Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu
Gly Met Ala Pro Ala Leu Gln Pro Thr Gln Gly Ala Met Pro Ala
Phe Ala (SEQ ID NO:175)
l~XAl'qPLE 63
Construction of l?MQN131~2
20 The new N-terminus/C-terminus gene in pMOM13192 was
created using Method II as described in Materials and
Methods. Fragment Start was created and aInpli~ied from G-
CSF sequence in pMON13037 using the primer set, 3g start
(SEQ ID No:64) and P-bl start (SEQ ID NO:62). Fragment Stop
was created and amplified ~rom G-CSF Serl7 seguence in
pMON13037 using the primer set, 38 stop (SEQ ID NO:65) and
P-bl stop (SEQ ID No:63). Frayment Start was digested with
restriction endonuclease NcoI, and Fragment Stop was
digested with restriction endonuclease HindIII. After
purification, the digested Fragments Start and Stop were
combined with and ligated to ~he approximately 3800 base
pair NcoI-HindIII vector ~ragment of pMON3934.
The intermediate plasmid described above contained the
~ull length new N-terminus/C-terminus G-CSF Serl7 gene and
was digested with restriction endonucleases McoI and
HindIII. The digested DNA was resolved on a 1% TAE gel,
stained with ethidium bromide and the ~ull-length new N-
terminus/C-terminus G-CSF Serl7 gene was isolated using
Geneclean (BiolOl, Vista, CA). The intermediate plasmid,

CA 0223406l l998-04-06
W O 97/12985 PCTAUS96~1~774 189
pMON13180, was digested with restric~ion endonucleases
HindIII and A~lIII, resulting in a 4023 base pair vector
~ragment, and purified using a Magic DNA Clean-up System kit
(Promega, Madison, WI). The puri~ied restriction ~ragments
were combined and ligated using T4 DNA ligase (Boehringer
Mannheim, Indianapolis, IN). A portion of the ligation
reaction was used to trans~orm E. col i strain DH5~ cells
(Li~e Technologies, &aithers~urg, MD). Transformant
bacteria were selected on ampicillin-containing plates.
Plasmid DNA was isolated and sequenced to con~irm the
correct in,sertion of the new gene. The resulting plasmid
was designated pMON13192.
E. coli strain JM101 was transformed with pMON13192 for
protei~ expression and protein isolation from inclusion
bodies.
The plasmid, pMON13192, contains the DNA sequence o~
(SEO ID NO:104) which encodes the ~ollowing amino acid
se~uence:
13192.Pept
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp &lu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val ~lu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Tyr Lys Leu Cys
His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro
Trp Ala Pro ~eu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala
Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly
Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr
Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile
Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro
Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
Ala Gly Gly Val Leu Val Ala ~er His Leu Gln Ser Phe Leu Glu
Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Thr Pro Leu
Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys Ser Leu
Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu
Lys Leu Cys Ala Thr (SEQ ID NO:176)

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190
~XAMPLE 64
Construction of ~MON13193
5 The new N-terminus/C-terminuS gene in pMON13193 was
created usiny Method II as described in Materials and
Methods. Fragment Start was created and amplified from G-
CSF Ser17 sequence in pMON13037 using the primer set, 39
start (SEQ ID No:64) and P-bl start (SEQ ID NO:62).
10 Fragment Stop was created and amplified from G-CSF Ser17
sequence in pMON13037 using the primer set, 38 stop ~SEQ ID
NO:65) and P-bl stop (SEQ ID No:63). Fragment Start was
digested with restriction endonuclease NcoI, and Fragment
Stop was digested with restriction endonuclease HindIII.
15 After purification, the digested Fragments Start and Stop
were combined with and ligated to the approximately 3800
base pair NcoI-HindIII vector fragment of pMON3934.
The intermediate plasmid described above contained the
full length new N-terminus/C-terminus G-CSF Ser17 gene and
20 was digested with restriction endonucleases NcoI and
HindIII. The digested DNA was resolved on a 1% TAE gel,
stained with ethidium bromide and the full-length new N-
terminus/C-terminus G-CSF Ser17 gene was isolated using
Geneclean (BiolO1, Vista, CA). The intermediate plasmid,
25 pMON13181, was digested with restriction endonucleases
HindIII and AflIII, resulting in a 4068 base pair vector
fragment, and purified using a Magic DNA Clean-up System kit
(Promega, Madison, WI). The purified restriction fragments
were combined and ligated using T4 DNA ligase (Boehringer
30 Mannheim, Indianapolis, IN). A portion of the ligation
reaction was used to transform E. coli strain DH50C cells
(Life Techrlologies, Gaithersburg, MD). Transformant
bacteria were selected on ampicillin-containing plates.
Plasmid DNA was isolated and sequenced to confirm the

CA 02234061 1998-04-06
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191
correct insertion of the new gene. The resulting plasmid
was designated pMON13193.
E. coli strain JM101 was transformed with pMON13193 for
protein expression and protein isolation ~rom inclusion
bodies.
~.
The plasmid, pMON13193, contains the DNA sequence of
(SEQ ID NO:105~ encodes the following amino acid se~uence:
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His HiS Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
~lu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg ~is Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala ~ln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Tyr Lys Leu Cys
His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro
Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala
Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly
Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr
Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile
Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro
Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg
Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu
Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Thr Pro Leu
Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys Ser Leu
Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu
Lys Leu Cys Ala Thr (SEQ ID NO:177)
E~MP~E 65
Construction of ~MON25190
The new N-terminus/C-terminus gene in pMON25190 was
created using Method II as described in Materials and
Methods. Fragment Start was created and amplified from G-
CSF se~uence in pMON13037 using the primer set, 97 start
(SEQ ID Mo:66) and P-~l start (SEQ ID Mo:62). Fragment Stop
~, was created and amplified from G-CSF Ser17 sequence in

CA 02234061 1998-04-06
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192
pMON13037 using the primer set, 96 stop (SEQ ID No:67) and
P-bl stop (SEQ ID No:63)~ Fragment Start was digested with
restriction endonuclease NcoI, and Fragment S~op was
digested with restriction endonuclease HindIII. After
purification, the digested Fragments Start and Stop were
combined with and ligated to the approximately 3800 base
pair NcoI-HindIII vector fragment of pMON3934.
The intermediate plasmid described above contained the
full length new N-terminus/C-terminuS G-CSF Serl7 gene and
was digested with restriction endonucleases NcoI and
HindIII. The digested DNA was resolved on a 1% TAE gel,
stained with ethidium bromide and the full-length new N-
terminus/C-terminus G-CSF Serl7 gene was isolated using
Geneclean (BiolOl, Vista, CA). The intermediate plasmid,
pMON13180, was digested with restriction endonucleases
HindIII and AflIII, resulting in a 4023 base pair vector
fragment, and puri~ied using a Magic DNA Clean-up System kit
(Promega, Madison, WI). The purified restriction fragments
were combined and ligated using T4 DNA ligase (soehringer
Mannheim, Indianapolis, IN). A portion of the ligation
reaction was used to transform E. coli strain DH5a cells
(Life Technologies, Gaithersburg, MD). Transformant
bacteria were selected on ampicillin-containing plates.
Plasmid DNA was isolated and sequenced to confirm the
correct insertion of the new gene. The resulting plasmid
was designated pMON25190.
E. coli strain JM101 was transformed with pMON25190 for
protein expression and protein isolation from inclusion
bodies.
The plasmid, pMON25190, contains the DNA sequence of
(SEQ ID NO:106) which encodes the following amino acid
sequence: ~
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg ~7
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp

CA 02234061 1998-04-06
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193
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Pro Glu Leu Gly
Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr
Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu
Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln
Arg Arg Ala Gly Gly Val ~eu Val Ala Ser Xis Leu Gln Ser Phe
Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Thr
Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys
Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp (~ly Ala Ala Leu
Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu
I eu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu
Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser
Gln l:,eu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala
~eu Glu Gly Ile Ser (SEQ ID NO:178)
F.~MpT.F. 66
Construction of pMON25191
The new M-terminus/C-terminuS gene in pMON25191 was
created using Method II as described in Materlals and
Methods. Fragment Start was created and amplified from G-
CSF Serl7 se~uence in pMON13037 using the primer set, 97
start (SEQ ID NO:66) and P-bl start (SEQ ID NO:62).
Fragment Stop was created and amplified from G-CSF Serl7
se~uence in pMON13037 using the primer set, 96 stop (SEQ ID
NO:9 8) and P-bl stop (SEQ ID NO:63). Fragment Start was
digested with restriction endonuclease NcoI, and Fragment
Stop was digested with restriction endonuclease HindIII~
After purification, the digested Fragments Start and Stop
were combined with and ligated to the approximately 3800
base pair NcoI-HindIII vector fragment of pMON3934.
The intermediate plasmid described above contained the
full length new N-terminus/C-terminus G-CSF Se:rl7 gene and
was digested with restriction endonucleases NcoI and

CA 02234061 1998-04-06
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194
HindIII. The digested DNA was resolved on a 1% TAE gel,
stained with ethidium bromide and the ~ull-length new N-
terminus/C-terminus G-CSF Ser17 gene was isolated using
Geneclean (BiolO1, Vista, CA). The intermediate plasmid,
pMON13181, was digested with restriction endonucleases
HindIII and AflIII, resulting in a 4068 base pair vector
~ragment, and puri~ied using a Magic DNA Clean-up System kit
(Prome~a, Madison, WI). The puri~ied restriction ~ragments
were combined and ligated using T4 DNA ligase (Boehringer
Mannheim, Indianapolis, IN). A portion o~ the ligation
reaction was used to t~ansform ~. coli strain DH5a cells
(Life Technologies, Gaithersburg, MD). Transformant
bacteria were selected on ampicillin-containing plates.
Plasmid ~NA was isolated and sequenced to con~irm the
correct insertion of the new gene. The resulting plasmid
was designated pMON25191.
E. coli strain JM101 was transformed with pMON251~1 for
protein expression and protein isolation ~rom inclusion
bodies.
The plasmid, pMON25191, contains the DMA se~uence o~
(SEQ ID NO:107) which encodes the ~ollowing amino acid
sequence:
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His Xis Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Pro Glu Leu Gly
Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr
Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu
Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln
Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe
Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro Thr
Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys
Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu
-

CA 02234061 1998-04-06
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195
Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu
Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu
Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser
Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala
Leu Glu Gly Ile Ser (SEQ ID NO:179)
~XA~PLE 67
Construction of pMO~13194
The new N-terminus/C-terminus gene in pMON13194 was
created using Method II as described in Materials and
Methods. Fragment Start was created and amplified from G-
CSF ~er17 sequence in pMON13037 using the primer set, 126
start (SEQ ID NO:68) and P-bl start (SEQ ID NO:62).
Fragment Stop was created and amplified from G-CSF Ser17
sequence in pMON13037 using the primer set, 125 stop (SEQ ID
NO:67) and P-bl stop (SEQ ID NO:63). Fragment Start was
digested with restriction endonuclease McoI, and Fragment
Stop was digested with restriction endonuclease HindIII.
After purification, the digested Fragments Start and Stop
were combined with and ligated to the approximately 3800
base pair NcoI-HindIII vector fragment of pMON3934.
The intermediate plasmid described above contained the
full length new N-terminus/C-terminus G-CSF Ser17 gene and
was digested with restriction endonucleases NcoI and
HindIII. The digested DNA was resolved on a 1% TAE gel,
stained with ethidium bromide and the full-length new N-
terminus/C-terminus G-CSF Ser17 gene was isolated using
Geneclean (BiolO1, Vista, CA). The intermediate plasmid,
pMON13180, was digested with restriction endonucleases
HindIII and AflIII, resulting in a 4023 base pair vector
fragment, and purified using a Magic DNA Clean-up System kit
(Promega, Madison, WI). The purified restriction ~ragments
were combined and ligated using T4 DNA ligase (Boehringer

CA 02234061 1998-04-06
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196
Mannheim, Indianapolis, IN). A portion of the ligation
reaction was used to trans~orm E. coli strain DH5~ cells
(Li~e Technologies, Gaithersburg, MD). Transformant
bacteria were selected on amplcillin-containing plates. t
Plasmid DMA was isolated and sequenced to con~irm the
correct insertion o~ the new gene. The resulting plasmid r
was designated pMON13194.
E. coli strain JM101 was transformed with pMON13194 for
protein expression and protein isolation ~rom inclusion
bodies.
The plasmid, pMON13194, contains the DNA sequence of
(SEQ ID NO:108) which encodes the ~ollowing amino acid
sequence:
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg HiS Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Met Ala Pro Ala
Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe
Gln Arg Arg Ala Gly Gly Val Leu val Ala Ser His Leu Gln Ser
Phe Leu Glu Val Ser Tyr Ary Val Leu Arg His Leu Ala Gln Pro
Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu
Lys Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala
Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu
Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro
Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu
Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln
Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr
Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln
Met Glu Glu Leu Gly (SEQ ID NO:180)
FXAMPT~ 68
Construct;on o~ ~MON13195
The new N-terminus/C-terminus gene in pMON13195 was
created using Method II as described in Materials and

CA 02234061 1998-04-06
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197
Methods. Fragment Start was created and amplified from G-
CSF Serl7 sequence in pMOM13037 using the primer set, 126
start (SEQ ID NO:68) and P-bl start (SEQ ID NO:62).
Fragment S~op was created and amplified from G-CSF Serl7
sequence in pMOM13037 using the primer set, 125 stop (SEQ ID
No:69) and P-bl stop (SEQ ID NO:63). Fragment Start was
digested with restriction endonuclease McoI, and Fragment
Stop was digested with restriction endonuclease HindIII.
After purification, the digested Fragments Start and Stop
were combined with and ligated to the approximately 3800
base pair NcoI-HindIII vector fragment of pMOM3934.
The intermediate plasmid described above contained the
~ull length new M-terminus/C-terminus G-CSF Serl7 gene and
was digested with restriction endonucleases NcoI and
HindIII. The digested DNA was resolved on a 1% TAE gel,
stained with ethidium bromide and the full-length new M-
terminus/C-terminus G-CSF Serl7 gene was isolated using
Geneclean (BiolOl, Vista, CA). The intermediate plasmid,
pMOM13181, was digested with restriction endonucleases
HindIII and AflIII, resulting in a 4068 base pair vector
fragment, and purified using a Magic DNA Clean-up System kit
(Promega, Madison, WI). The purified restriction fragments
were combined and ligated using T4 DNA ligase (Boehringer
Mannheim, Indianapolis~ IN). A portion of the ligation
reaction was used to transform E. col i strain DH5a cells
(Life Technologies, Gaithersburg, MD). Transformant
bacteria were selected on ampicillin-containing plates.
Plasmid DNA was isolated and sequenced to confirm the
correct insertion of the new gene. The resulting plasmid
was designated pMON13195.
E. coli strain JM101 was transformed with pMOM13195 for
protein expression and protein isolation from inclusion
bodies.

CA 02234061 1998-04-06
W O 97/12985 PC~US96/15774 198
The plasmid, pMON13195, contains the DNA se~uence of
(SEQ ID NO:109) which encodes the ~ollowing amino acid
sequence:
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn ~eu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn ~eu Gln Pro Cys Leu Pro Ser Ala ~hr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Ser Pro Pro
Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Met Ala Pro Ala
Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe
Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser
Phe Leu Glu Val Ser Tyr Arg Val Leu Arg Hls Leu Ala Gln Pro
Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu
Lys Ser Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala
Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu
Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro
Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu
Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln
Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr
Leu Gln Leu Asp Val Ala Asp Phe Ala Thr ~hr Ile Trp Gln Gln
Met Glu Glu Leu Gly (SEQ ID NO:181)
F.~MP~E 69
Construction of ~MON13196
The new N-terminus/C-terminus gene in pMON13196 was
created uslng Method II as described in Materials and
Methods. Fragment Start was created and amplified from G-
CSF sequence in pMOM13037 using the primer set, 133 start
(SEQ ID NO:70) and P-bl start (SEQ ID NO:62). Fragment Stop
was created and amplified from G-CSF Serl7 sequence in
pMON13037 using the primer set, 132 stop (SEQ ID NO:71) and
P-bl stop (SEQ ID No:63)~ Fragment Start was digested with
restriction endonuclease McoI, and Fragment Stop was
digested with restriction endonuclease HindIII~ After
puri~ication, the digested Fragments Start and Stop were

CA 02234061 1998-04-06
W O 97~12g8~ PCT~US96flS774
lg9
combined with and ligated to the approximate~y 3800 base
pair NcoI-HindIII vector fragment of pMON3934.
The intermediate plasmid described above contained the
full length new N-terminus/C-terminus G-CSF Serl7 gene and
was digested with restriction endonucleases McoI and
HindIII. The digested DNA was resolved on a 1% TAE gel,
stained with ethidium bromide and the full-length new N-
terminus/C-terminus G-CSF Serl7 gene was isolated using
Geneclean (BiolOl, Vista, CA). The intermediate plasmid,
pMON13180, was digested with restriction endonucleases
HindIII and AflIII, resulting in a 4023 base pair vector
fragment, and purified using a Magic DNA Clean-up System kit
(Promega, Madison, WI). The purified restriction fragments
were combined and ligated using T4 DNA ligase (Boehringer
Mannheim, Indianapolis, IN). A portion of the ligation
reaction was used to transform E. col i strain DH5~ cells
(Life Technologies, Gaithersburg, MD). Transformant
bacteria were selected on ampicillin-containing plates.
Plasmid DNA was isolated and sequenced to con~irm the
correct insertion of the new gene. The resulting plasmid
was designated pMON13196.
~ . coli strain JM101 was transformed with pMON13196 for
protein expression and protein isolation from inclusion
bodies.
The plasmid, pMON13196, contains the DNA sequence of
(SEQ ID NO:110) which encodes the following amino acid
sequence:
Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg
Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp
Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu
Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile
Glu Ala Ile Leu Arg Asn Leu Gln Pro Cys Leu Pro Ser Ala Thr
Ala Ala Pro Ser Arg His Pro Ile Ile Ile Lys Ala Gly Asp Trp
Gln Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu
Gln Ala Gln Glu Gln Gln Tyr Val Glu Gly Gly Gly Gly Ser Pro
Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Thr Gln Gly Ala

CA 02234061 1998-04-06
W O 97/12985 PCT~US96/15774
200
Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val
Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg
Val Leu Arg His Leu Ala Gln Pro Thr Pro Leu Gly Pro Ala Ser
Ser Leu Pro Gln Ser Phe Leu Leu Lys Ser Leu Glu Gln Val Arg
Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys ~eu Cys Ala
Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His
Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln
Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu
Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro
Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp
Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala
Pro Ala Leu Gln Pro (SEQ ID NO-182)
F.~PT.F~ 70
Construction of ~MQN13197
The new M-terminus/C-terminus gene in pMON13197 was
created using Method II as described in Materials and
Methods. Fragment Start was created and amplified from G-
CSF Serl7 sequence in pMON13037 using the primer set, 133
start (SEQ ID NO:70) and P-bl start (SEQ ID NO:62).
Fragment Stop was created and amplified from G-CSF Serl7
25 sequence in pMON13037 using the primer set, 132 stop (SEQ ID
NO:71) and P-bl stop (SEQ ID No:63). Fragment Start was
digested with restriction endonuclease NcoI, and Fragment
Stop was digested with restriction endonuclease HindIII.
After purification, the digested Fragments Start and Stop
30 were combined with and ligated to the approximately 3800
base pair NcoI-HindIII vector fragment of pMON3934.
The intermediate plasmid described above contained the
full length new N-terr~inus/C-terminus G-CSF Serl7 gene and
was digested with restriction endonucleases NcoI and
35 HindIII. The digested DNA was resolved on a 1% TAE gel,
stained with ethidium bromide and the full-length new N-
terminus/C-terminus G-CSF Serl7 gene was isolated using
Geneclean (BiolOl, Vista, CA). The intermediate plasmid, ,~
pMON13 181, was digested with restriction endonucleases

CA 0 2 2 3 4 0 61 19 9 8 - 0 4 - 0 6 . .
- - - - . - ,
.
DEMANDES OU E3R~V~TS VOLUMINEIJX
LA PRES~YTE PARTIE DE CEI IE DEMANDE OU CE~ BREVET
COMPRE~YD PLUS D'UN TOME.
CECI EST LE TOME / ~DE Z_
NOTE: Pour les ~omes additionels, ve~ ez c~ntacter le {3ureau c~nadien -des
brevets
z~3y~
JUIVIBO APPLICATIONSIPA~NTS
rHIS SECTION OF THE APPLICAT~ONIPATENT CONTAINS MORE
THAN ONE VOLUME
.
T~S IS VOLUME 1 OF '2
.
P~O~E: For additional v{~umes-please c~ntact~~h~e Canadian Patent ~ff~ce
.
, . .,. :, ::' ' . ,. . ,'
... . .; .. ~, . . .. ..

Dessin représentatif

Une figure unique qui représente un dessin illustrant l'invention.

États administratifs

2024-08-01 : Dans le cadre de la transition vers les Brevets de nouvelle génération (BNG), la base de données sur les brevets canadiens (BDBC) contient désormais un Historique d'événement plus détaillé, qui reproduit le Journal des événements de notre nouvelle solution interne.

Veuillez noter que les événements débutant par « Inactive : » se réfèrent à des événements qui ne sont plus utilisés dans notre nouvelle solution interne.

Pour une meilleure compréhension de l'état de la demande ou brevet qui figure sur cette page, la rubrique Mise en garde , et les descriptions de Brevet , Historique d'événement , Taxes périodiques et Historique des paiements devraient être consultées.

Historique d'événement

Description	Date
Inactive : CIB expirée	2015-01-01
Inactive : CIB en 1re position	2012-11-01
Inactive : CIB attribuée	2012-11-01
Inactive : CIB expirée	2010-01-01
Inactive : CIB expirée	2010-01-01
Inactive : CIB enlevée	2009-12-31
Inactive : CIB enlevée	2009-12-31
Le délai pour l'annulation est expiré	2007-10-04
Demande non rétablie avant l'échéance	2007-10-04
Réputée abandonnée - omission de répondre à un avis sur les taxes pour le maintien en état	2006-10-04
Inactive : CIB de MCD	2006-03-12
Inactive : CIB de MCD	2006-03-12
Inactive : CIB de MCD	2006-03-12
Inactive : CIB de MCD	2006-03-12
Lettre envoyée	2001-10-31
Exigences pour une requête d'examen - jugée conforme	2001-10-01
Requête d'examen reçue	2001-10-01
Toutes les exigences pour l'examen - jugée conforme	2001-10-01
Inactive : Correspondance - Formalités	1998-10-05
Symbole de classement modifié	1998-07-09
Inactive : CIB attribuée	1998-07-09
Inactive : CIB attribuée	1998-07-09
Inactive : CIB attribuée	1998-07-09
Inactive : CIB attribuée	1998-07-09
Inactive : CIB attribuée	1998-07-09
Inactive : CIB attribuée	1998-07-09
Inactive : CIB attribuée	1998-07-09
Inactive : CIB en 1re position	1998-07-09
Inactive : CIB attribuée	1998-07-09
Inactive : Notice - Entrée phase nat. - Pas de RE	1998-06-16
Demande reçue - PCT	1998-06-15
Demande publiée (accessible au public)	1997-04-10

Historique d'abandonnement

Date d'abandonnement	Raison	Date de rétablissement
2006-10-04

Taxes périodiques

Le dernier paiement a été reçu le 2005-10-03

Avis : Si le paiement en totalité n'a pas été reçu au plus tard à la date indiquée, une taxe supplémentaire peut être imposée, soit une des taxes suivantes :

taxe de rétablissement ;
taxe pour paiement en souffrance ; ou
taxe additionnelle pour le renversement d'une péremption réputée.

Les taxes sur les brevets sont ajustées au 1er janvier de chaque année. Les montants ci-dessus sont les montants actuels s'ils sont reçus au plus tard le 31 décembre de l'année en cours.
Veuillez vous référer à la page web des taxes sur les brevets de l'OPIC pour voir tous les montants actuels des taxes.

Historique des taxes

Type de taxes	Anniversaire	Échéance	Date payée
Enregistrement d'un document			1998-04-06
Taxe nationale de base - générale			1998-04-06
TM (demande, 2e anniv.) - générale	02	1998-10-05	1998-09-30
TM (demande, 3e anniv.) - générale	03	1999-10-04	1999-09-23
TM (demande, 4e anniv.) - générale	04	2000-10-04	2000-09-20
TM (demande, 5e anniv.) - générale	05	2001-10-04	2001-09-27
Requête d'examen - générale			2001-10-01
TM (demande, 6e anniv.) - générale	06	2002-10-04	2002-09-30
TM (demande, 7e anniv.) - générale	07	2003-10-06	2003-10-01
TM (demande, 8e anniv.) - générale	08	2004-10-04	2004-10-01
TM (demande, 9e anniv.) - générale	09	2005-10-04	2005-10-03

Titulaires au dossier

Les titulaires actuels et antérieures au dossier sont affichés en ordre alphabétique.

Titulaires actuels au dossier
G.D. SEARLE & CO.

Titulaires antérieures au dossier
BARBARA KURE KLEIN
CHARLES A. MCWHERTER
CHARLES M. BAUM
JOHN P. MCKEARN
JUDITH G. GIRI
LINDA L. ZURFLUH
MAIRE H. CAPARON
NEENA L. SUMMERS
NICHOLAS R. STATEN
S. C. BAUER
STEPHEN C. LEE
YIQING FENG

Les propriétaires antérieurs qui ne figurent pas dans la liste des « Propriétaires au dossier » apparaîtront dans d'autres documents au dossier.

Documents

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Liste des documents de brevet publiés et non publiés sur la BDBC .

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Description du Document	Date (aaaa-mm-jj)	Nombre de pages	Taille de l'image (Ko)
Dessin représentatif	1998-07-12	1	6
Description	1998-10-04	308	9 226
Description	1998-04-05	308	9 225
Revendications	1998-04-05	104	5 263
Description	1998-04-05	202	11 537
Abrégé	1998-04-05	1	72
Dessins	1998-04-05	4	60
Rappel de taxe de maintien due	1998-06-15	1	111
Avis d'entree dans la phase nationale	1998-06-15	1	193
Courtoisie - Certificat d'enregistrement (document(s) connexe(s))	1998-06-15	1	117
Courtoisie - Certificat d'enregistrement (document(s) connexe(s))	1998-06-15	1	116
Rappel - requête d'examen	2001-06-04	1	118
Accusé de réception de la requête d'examen	2001-10-30	1	179
Courtoisie - Lettre d'abandon (taxe de maintien en état)	2006-11-28	1	175
PCT	1998-04-05	17	649
Correspondance	1998-10-04	2	67

Listes de séquence biologique

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Soyez avisé que les fichiers avec les extensions .pep et .seq qui ont été créés par l'OPIC comme fichier de travail peuvent être incomplets et ne doivent pas être considérés comme étant des communications officielles.

Fichiers LSB

Nom de fichier	Reçu	Grosseur (octets)
C-2910C.SEQ	1998-10-05	129 963
C-2910C.TXT	1998-10-05	471 749
C-2910C.PEP	1998-10-05	82 622

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Les informations demandèes seront
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Merci de patienter.

Sommaire du brevet 2234061

Abrégé français

Abrégé anglais

Historique d'événement

Historique d'abandonnement

Taxes périodiques

Historique des taxes

Votre demande est en traitement.Les informations demandèes serontaccessibles dans quelques instants.Merci de patienter.

Votre demande est en traitement.

Les informations demandèes seront
accessibles dans quelques instants.

Merci de patienter.