Note: Descriptions are shown in the official language in which they were submitted.
CA 0220~i648 1997-0~i-20
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WO96/15801PCT~S95/15203
HUMAN CALCIUM SENSOR PROTEIN,
. FRAGMENTS THEREOF AND DNA ~ODING SAME
This application is a continuation-in-part of 08/487,314
filed June 7,1995, which is a continuation-in-part of 08/344,836
filed November 23, 1994, which is a continuation-in-part of
PCT/SE94/00483 filed May 24, 1994.
BACKGROUND OF THE INVENTION
. The present invention relates tG a cDNA clone encoding a
human calcium sensor protein of parathyroid, placental, and
kidney tubule cells.
In WO 88/03271 there is described monoclonal
antiparathyroid antibodies identifying a parathyroid cell
membrane-bound calcium receptor or sensor, crucially involved in
calcium regulation of the parathyroid hormone (PTH) release
(1,2). The receptor function is essential for maintenance of
normal plasma calcium concentrations, and reduced receptor
expression within proliferating parathyroid cells of patients
with hyperparathyroidism (HPT) results in calcium insensitivity
of the PTH secretion and variably severe hypercalcemia (3-6).
Reactivity with the antiparathyroid antibodies was also
demonstrated for proximal kidney tubule cells and
cytotrophoblast cells of the human placenta, and the
cytotrophoblasts were ~m~n~trated to exhibit an almost
parathyroid-identical regulation of cytoplasmic calcium
[Ca2+i](7,8). The antibody-reactive structure was found to exert
calcium sensing function also in the cytotrophoblasts, and as
these cells constitute part of the syncytium, the calcium sensor
was suggested to be actively involved in the calcium homeostasis
of the fetus (7,8). It was proposed that the antibody-reactive
structure of the proximal kidney tubule cells exerts a similar
calcium sensing function, and that the calcium sensor, thus,
plays a more universal role in calcium regulation via different
organ systems (1,7,9,10).
On HPT patients with hypercalcemia, surgery is performed to
remove one or more of the parathyroid glands. It would be
greatly desirable to have alternatives to this surgical
procedure as HPT has proven to be a very common disorder and
SU~STITUTE S~EET (RUL ~ Jj
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wos6/ls8ol PCT~S95/15203
surgery is a relatively costly procedure and sometimes even
entails some risks for the patients.
I~
The calcium sensor/receptor has been revealed as a 500 kDa
single chain glycoprotein (7~. However, the amino acid sequence
as well as the correspon~;ng DNA se~uences thereof are hitherto
unknown.
SUMMARY OF THE INVENTION
Therefore, an object of the present invention was to
provide sufficient structural data of the calcium
sensor/receptor to enable complete characterization thereof.
In one embodiment, the present invention provides complete
amino acid sequence of the human calcium sensor protein of
parathyroid, placental and kidney tubule cells.
In another embodiment the invention provides nucleic acid
sequence encoding the human calcium sensor and nucleic acid
probes for identifying other novel calcium sensor proteins.
Another object is to use said structural data to design
novel treatment methods as well as compounds and compositions
for treating calcium related disorders.
In other embodiments, the present invention provides
identification of peptide regions within the calcium sensor
protein cytoplasmic ~om~ in which are homologous to SH2 and SH3
b;n~;~g motifs involved in signal transduction pathways.
Two important human diseases associated with perturbations
of the calcium ion homeostasis are hyperthyroidism and
osteoporosis. Thus, in one embodiment cells expressing the
calcium sensor protein or a fragment thereof or comprising the
cDNA encoding the calcium sensor protein of the present
invention may be utilized in an assay to identify molecules
which block or ~nhAnce the activity of the calcium sensor
protein, including signal transduction pathways associated with
the activity of the sensor. These molecules will be useful in
the treatment of mAmmAlian pathological conditions associated
with perturbations in the levels of PTH, vitAmi n~ D3 production,
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WO96/15801 PCT~S9Sl15203
estrogen, osteoclast activity or osteoblast activity (there~ore,
bone resorption and/or ~ormation), calcium secretion and calcium
ion homeostasis.
J 5 The present invention describes the isolation and
characterization of cDNA clones encoding the calcium sensor/-
receptor in human placenta and Northern blots verifying the
presence o~ the correspo~;n~ mRNA within the parathyroid and
kidney. Close se~uence similarity between the calcium sensor and
a rat Heymann nephritis antigen, gp330 (ll, 67), suggests that
the common calcium sensor o~ the placenta, the parathyroid and
kidney tubule is related to this antigen, represents the human
homologue of gp330, and belongs to a family of large
glycoproteins with receptor function and calcium b;n~;ng
ability. There~ore, a ~urther object of this invention is to
provide diagnostic assays and therapeutic methods based on human
gp330.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig l. Isolation by HPLC of peptides obtained after digestion
of the calcium sensor protein with Lys-C endoprotease (solid
line). Dashed line represents the chromatography of an identical
reaction where the calcium-sensor was omitted. The flow rate was
kept at l00 ~l/min. Two peptide ~ractions which gave easily
interpretable se~uences are denoted by arrows.
Fig 2. Sequences of two Lys-C peptides ( SEQ ID Nos. 1 and 2)
isolated by HPLC of the calcium-sensor protein.
Fi~ 3. Partial nucleotide sequence (SEQ ID No. 3) and deduced
amino acid seguence ( SEQ ID No. 4) of the-cDNA clone, pCAS-2,
encoding part of the calcium-sensor protein. Portions of the
deduced amino acid sequence identical to the peptides 292 and
293 are underlined.
Fi~ 4. Alignment of the amino acid sequence o~ the
calcium-sensor protein ( SEQ ID No. 4) to correspon~; ng portions
of the Heymann antigen (HEYMANN, SEQ ID No. 5), low density
lipoprotein receptor (LDL-RC, SEQ ID No. 6), and LDL related
receptor protein (LDLRRP, SEQ ID No. 7). Stars denote residues
identical between the calcium sensor protein and any of the
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WO96/15801 PCT~S95/15203
other sequences. X denotes a position in the Heymann antigen
sequence where identity has not been published.
Fig 5. Northern blot analysis of total RNA from parathyroid
5 ~nom~ ( 1 ), kidney (2), liver (3), placenta (4), pancreas (5),
adrenal gland (6), small gut (7). Filters were hybridized with
the 2. 8 kb pCAS-2 insert probe, and reactions visualized b~ a
phosphorimager. Locations of 28S and 18S ribosomal RNA are
inaicated .
- Fis. 6. Complete nucleotide (SEQ ID No. ll) and amino acid (SEQ
ID No. 12) sequence of the human calcium sensor 2.8 kb cDNA
clone. The tr~ncm~mhrane ~om~;n of the sensor is shown in bold
type. The three SH3 b; n~; ~g regions are underlined or overlined
and the SH2 b;n~;n~ region is shown in strikethru.
Fig 7. Amino acid sequence of the calcium sensor cytoplasmic
~om~; n ( SEQ ID No. 13) and com.~arison of the three calcium
sensor SH3 b; n~ i ng regions (SEQ ID Nos. 14-16) to known SH3
binding motifs (SEQ ID Nos. 20-37).
Fis. 8. Comparison of relative b;n~;ng strengths between a
calcium sensor SH3 b;n~;n~ region and various GST fusion
proteins comprising an SH3 ~om~; n
Fis. 9. Comparison of the calcium sensor SH2 b;n~; n~ region
(SEQ ID No. l9) with amino acid sequence requirements necessary
for interaction with the SH2 region of the p85 regulatory
subunit of PI3K (SEQ ID Nos. 38-78).
Fig. l0. Structure of human gp330, including the EGF repeat,
growth factor repeats and YWTD spacer regions. N depicts the
amino terminus of the protein and C the carboxyl-terminus. The
arrow indicates the location of the tr~nsm~mhrane region.
Fig. ll. Strategy for extending CAS sequence from pCAS-2.
Fig.l2. Comparison of the same region within different CAS
cDNA sequences revealing amino acid sequence differences.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Unless indicated otherwise herein, the following terms have
the indicated m~ningS
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The term "polypeptide" means a linear array of amino acids
connected one to the other by peptide bonds between the a-amino
and carboxy groups of adjacent amino acids.
"Substantially purified" is used herein to mean
"substantially homogeneous", which is defined as a material
which is substantially free of compounds normally associated
with it in its natural state (e.g., other proteins or peptides,
carbohydrates, lipids). "Substantially purified" is not meant to
exclude artificial or synthetic mixtures with other compounds.
The term is also not meant to exclude the presence of impurities
which do not interfere with biological activity, and which may
be present, for example, due to incomplete purification or
compounding with a ph~rmAceutically acceptable preparation.
The term "biologically active polypeptide~ means the
naturally occurring polypeptide ~er se as well as biologically
active analogues thereof, including synthetically produced
polypeptides and analogues thereof, as well as natural and
ph~rmAceutically acceptable salts and ph~rm~ceutiCally
acceptable derivatives thereof. The term "biologically active
polypeptide" also encompasses biologically active fragments
thereof, as well as "biologically active sequence analogues"
thereof. Different forms of the peptide may exist. These
variations may be characterized by difference in the nucleotide
sequence of the structural gene coding for proteins of identical
biological function.
The term "biologically active sequence analogue" includes
nonnaturally occurring analogues having single or multiple amino
acid substitutions, deletions, additions, or replacements. All
such allelic variations, modifications, and analogues resulting
in derivatives which retain one or more of the native
biologically active properties are included within the scope of
, 35 this invention.
In this application, nucleotides are indicated by their
bases using the following standard one-letter abbreviations:
Gl1~n;ne G
4 0 A~n lne A
Thymine T
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WO96/15801 PCT~S95/15203
Cytosine C
Unknown N
In this application, amino acid residues are indicated
using the following st~n~rd one-letter abbreviations:
;n~ A
Cysteine C
Aspartic Acid D
Glutamic Acid E
Phenylalanine F
Glycine G
Histidine H
Isoleucine
Lysine K
l5 Leucine L
Methionine M
Asparagine N
Proline P
Glut~m;ne Q
20 Arginine R
Serine S
Threonine T
Valine V
Tryptophan W
25 Tyrosine Y
Unknown X
The term "amino acid" as used herein is meant to denote the
above recited natural amino acids and functional e~uivalents
thereof.
This invention provides isolated nucleic acid molecules
encoding a common calcium sensor protein of parathyroid,
placental and kidney tubule cells and comprising a coding
se~uence selected from the group consisting of SEQ ID No. 3, SEQ
ID No. ll, SEQ ID No. 83, SEQ ID No. 85, SEQ ID No. 87, and SEQ
ID No. 89. r
Furthermore, this invention provides a vector comprising an
isolated nucleic acid molecule encoding the calcium sensor
protein or a fragment thereof which encodes functional regions
of the sensor.
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Moreover, the invention provides a method of preparing
calcium sensor protein which comprises inserting a nuleic acid
encoding the calcium sensor or a ~ragment thereo~ in a suitable
-~ vector, inserting the resulting vector in a suitable host cell,
recovering the calcium sensor protein produced by the resulting
cell, and purifying the calcium sensor protein so recovered.
This method for preparing a calcium sensor protein or fragment
t~ereof uses recombinant DNA technology methods which are well
known in the art. Alternatively, the calcium sensor protein or
a fragment thereof may be prepared using stAn~Ard solid phase
methodology of peptide synthesis.
The present invention also provides antisense nucleic acids
which can be used to down regulate or block the expression of
the calcium sensor protein either in vitro, ex vivo or in vivo.
The down regulation of gene expression can be made at both
translational or transcriptional levels. Antisense nucleic acids
of the invention are more preferentially RNA fragments capable
of specifically hybridizing with all or part of the sequence
selected from the group consisting of SEQ ID No. 3, SEQ ID No.
11, SEQ ID No. 83, SEQ ID No. 85, SEQ ID No. 87, and SEQ ID No.
89 or the correspo~ ng messenger RNA. These antisense can be
synthetic oligonucleotides prepared based on the sequence
selected ~rom the group consisting of SEQ ID No. 3, SEQ ID No.
ll, SEQ ID No. 83, SEQ ID No. 85, SEQ ID No. 87, and SEQ ID No.
89, optionally modi~ied to improve their stability of
selectivity, as disclosed for instance in EP 92574. They can
also be DNA sequences whose expression in the cell produces RNA
complementary to all or part of the calcium sensor protein mRNA.
These antisenses can be prepared by expression o~ all or part o~
the sequence selected from the group consisting Of SEQ ID No. 3,
SEQ ID No. ll, SEQ ID No. 83, SEQ ID No. 85, SEQ ID No. 87, and
SEQ ID No. 89 in the opposite orientation (EP 140 308).
3~
Material and Methods
Ti~sue ~pec;me~C~ Samples of human parathyroid glands were
obtained at surgery of patients with primary HPT. Other human
tissue specimens (kidney, epididymis, liver, pancreas, adrenal
gland, small gut, spleen, lung and striated muscle) were sampled
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~ rom organs ~uvv~d at surgery. Human placental tissue was
collected in conjunction with uncomplicated pre~n~ncies at full
term. All specimens were ;mmP~l;Ately ~auick-frozen in isopentane
and stored at -70C.
Isolation of the calcium sensor ~rotein from hum~n
~lacenta. I~e 500 kDa calcium sensor protein was isolated and
purified, frsm altogether 25 human placentas, by ;mm~nosorbent
and ion exch~nge chromatographies, following a previously
desc~ibed protocol (7). The procedure utilizes two different
monoclonal antiparathyroid antibodies (1,7), Ell and Gll, known
to bind dif~erent epitopes of the calcium sensing protein; Ell
has displayed no functional ef~ect, while Gll ef~iciently blocks
calcium regulation in both parathyroid and placental cells
(1,7). After purification, the calcium sensor protein
preparation was subjected to gel chromatography on a Zorbax GF25
gel column (9.2 x 250 mm), prior to enzymatic digestion.
me biologically active calcium sensor protein of the
present invention has been isolated as described. It can also be
prepared by chemical synthesis in a recombinant DWA biosystem.
Biologically active fragments of the calcium sensor protein can
also be prepared using synthetic or recombinant technologies
which are known in the art.
Cleavage and sequence dotermination of isolated
~e~ti~les. Cleavage of the 500 kDa protein with endoprotease Lys
C from Achromobacter lyticus generated peptides, which were
subjected to separation on a Brownlee microbore C4 column (2.2 x
30 mm), equilibrated in 5% acetonitrile in 0.02~6 trifluoroacetic
acid. A l;ne~r gradient of 5 to 6096 acetonitrile in 0.02%
trifluoroacetic acid was employed for peptide elution, monitored
at 214 nm using Waters 990 diod-array detector (Millipore
Corporation, Millford, Mass). Amino te~inAl sequences of the
peptides were det~rm;ne~ in an ABI 470A gas-phase se~uenator,
eguipped with an ABI 120A PTH-amino acid chromatograph (Applied
Biosystems, Foster City, Ca., USA).
Oli5~onucleotide synthesis. Oligonucleotides were synthesized
40 using an ABI 381 oligonucleotide synthesizer (Applied Biosys-
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tems). The following oligonucleotide mixture was utilized as a
probe for screening of the placental cDNA library:
,.
CCA ATA IAG CTG ATC CTC AAA GAT ATC IAG IGA ATA IGG ATT CAT IGC
G G G G G G
(SEQ ID No. 8)
The ~ollowing two oligonucleotides were synthesized ~or use in
PCR reactions:
GCG GAATTC GTA ATG CAA CCA GAC GG
C G C T
G G
T T
(SEQ ID No. 9)
ATA GGATCC TG ATC CTC AAA AAT ATC
G T G G G
(SEQ ID No. 10)
The first nine nucleotides contain an EcoR I and a BamH I
site, respectively, and the r~A;n;ng nucleotides correspond to
amino acid residues 1 to 6 of peptides 293 and to residues 8 to
13 of peptide 292.
Screening of a placental CDNA library with a mixed
oligonucleotide probe. A placental l gt 11 CDNA library
(Clontech, Ca., USA) was plated out to a density of
approximately 2 x 105 plaques within a 20x25 cm agar plate.
Replicate filters (Hybond-N+, Amersham~ of ten plates were
prehybridized in 5 x SSPE (SSPE; 120 mM NaCl, 8 mM NaH2P04, 0.8
mM EDTA, pH 7.4), 5 x Denhart~s solution (12), 0.5% SDS, 20~1g~ml
single stranded salmon sperm DNA (Sigma Chemical Co., S:t Louis,
Ohio). The mixed oligonucleotide probe, endlabeled with y-
~ [32p]-ATP and polynucleotide kinase (Amersham), was added to the
hybridization mixture (30 x 106 cpm in 50 ml), and hybridization
was carried out o~er night at 42C. The filter was washed twice
in 2 x SSPE and once in 0.1 x SSPE, exposed to an
autoradiography screen and analysed by a phosphorimager
(Molecular Dynamics, Image Count S.W, Sun Valley Ca).
PCR reaction. Part of the ~ gt 11 cDNA clone CAS-1 was
CA 02205648 1997-OS-20
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lo
amplified by PCR using two degenerated probes correspon~;ng to
portions of peptides 292 and 293. The following conditions were
used: 170 ng template DNA, l pmol of each oligonucleotide
mixture as primers, dNTP 3mM, Taq-polymerase 0.75 u. The
reaction was carried out in 20 ~l of lOmM Tris-HCl, pH 8.0, 1.5
mM MgC12, 50mM KCl in a Perkin-Elmer 9600 PCR-m~c~i ne
(Perkin-Elmer, Norwalk, USA). Two cycles of denaturation at 94C
for 2 min. ~nne~l ;n~ at 47C for 1 min and extension at 72C for
1 min 30 sec were followed by 33 cycles of 94C for 1 min. 54C
for 45 sec. 72C for l min and a final extension at 72C for 10
min.
Screeniny of a ~lacental CDNA library with a
PCR-fraçJment aE~ ~7robe. A placental ~ ZAP-II cDNA library, was
screened with the PCR-fragment from the cDNA clone CAS-1 labeled
by random priming as the probe. The Screening was carried out as
above. 2 x 106 pla~ues distributed on ten 20 x 25 cm agar plates
were screened.
Nucleoti~le sequence aete ;~tion. The insert of the phage
clone CAS-2 was released from the phage vector in the
Bluescript vector using a helper phage (Stratagene, La Jolla,
Ca.). Nucleotide sequence reactions were carried out according
to the cycle sequencing procedure, utilizing a kit from Applied
Biosystems. Sequences were analyzed in an ABI 373 A DNA
sequenator using the Data Collection Program VIII software
(Applied Biosystems). Completion of the CAS-2 2.8 kb cDNA
sequence was accomplished by the dideoxynucleotide chain-
termination method with Sequenase (United States Biochemical)
and is shown in Figure 6(SEQ ID No. 11). Multiple sequencing
analyses were performed on both strands of CAS-2 to confirm the
sequence. Amino acid sequence deduced from the cDNA sequence
was analyzed by a Macvector DNA/RNA software analysis package
(Macintosh).
Reverse transcriptase PCR amplification and st~n~d 32p_
labeled probe screening of human lambda kidney cDNA libraries
were used to complete the cloning of the CAS cDNA (SEQ ID No.
83).
Full-length human placental (SEQ ID No. 85), kidney (SEQ ID
No. 87) and parathyroid (SEQ ID No. 89) CAS cDNA sequences were
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obtA;ne~ from PCR amplified buman placental, kidney and
parathyroid cDNA libraries as follows. Speci~ically primed
first-strand cDNA was prepared using oligonucleotide primers
designed off SEQ ID No. 83, total RNA RNAzol B method (Tel-
Test), and a cDNA synthesis kit (Promega). The ~ollowingprimers with indicated sequence positions were used in the
reactions:
Fls GCAGACCTAAAGGAGCGTT 1 SEQ ID No.91
G7as CCCGACCATTGGAGAAGATA 1311 SEQ ID No.92
G20s GCCAGTACCAGTGCCATGA 1054 SEQ ID No.93
G29as CCTCATGACACTGATACTCTT 2540 SEQ ID No.94
G26s GGCTGTGAGCAGGl~l~l 2109 SEQ ID No.95
G16as CGACCACTAATTGAATCAAAATC 4540 SEQ ID No.96
G16s CGGTG~'l~'l~'l~ATACAG 4338 SEQ ID No.97
E2as ATCCACATCCACATGCAG 6413 SEQ ID No.98
E4s CCTCAAATGGCTGTAGCAACAA 6157 SEQ ID No.99
B9as CTGCTGCTGCACGTGTGA 8704 SEQ ID No.100
B5s CCAGTCTGGATACACAAAATGT 8570 SEQ ID No.101
23.5 GGCGCACTGCCATTC 10,910 SEQ ID No.102
G19s CTCAGATGGCTCTGATGAACT 10,718 SEQ ID No.103
G36as G~llll~l~lll~lll~CTT 13,026 SEQ ID No.104
G35s GAGAGTCATTGCA~AGGAAGCA 12,893 SEQ ID No.105
G31as AATATATGTGCA~AA~l~l~lll 14,120 SEQ ID No.106
Four separate reverse trancriptase (RT) reactions were performed
using the ~ollowing primers:
RT reaction 1 (RT1) primer G29as
" (RT2) primer E2as
" (RT3) primer 23.5
" (RT4) primer G3las
The following primers were used for PCR with listed RT reaction:
Drimer RT reaction
Fls/G7as RT1
G20s/G29as RT1
G26s/G16as RT2
G16s/E2as RT2
E4s/B9as RT3
B5s/23.5 RT3
G19s/G36as RT4
G35s/G3las RT4
PCR ampli~ication of first-strand cDNA was per~ormed in a
Perkin-Elmer 9600 Thermal Cycler using the ~ollowing program: 1
cycle of denaturation at 94C for 2 min., followed by 40 cycles
of denaturation at 94C for 15 sec., annealing at 51C for 10
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sec., and extension at 72C for 3 min., after which, the
products of the reactions were separated by electrophoresis and
gel purified (QIAGEM). PCR reagents were purchased from Perkin-
Elmer and used according to manufacturer's suggestions. PCR
fragments were then nucleotide sequenced using a
dideoxynucleotide chain-termination method (Perkin-Elmer Prism
Dye Deoxy T~rm;n~tor Cycle Sequencing Kit), and an ABI 373
automated DNA sequencer (Applied Biosystems). PCR fragments
from four separate reactions were sequenced on both strands to
confirm sequence data. Computer generated DNA se~uence
analysis was performed using Auto-Assembler and Factura (Applied
Biosystems), and MacVector and AssemblyLIGN (Eastman Kodak
Company) software programs.
Database search. The EMBL-31 database in the Intelligenetics
format (Intelligenetics Rel.5.4), was searched for se~uence
similarities to the placental cDNA sequence using the FAST DB
algorithm (13).
Immunosta;n;n57 an~l Northern blot. Tm~mlnohistochemical
studies were performed on acetone-fixed, 6 ~m thick frozen
sections, utilizing the monoclonal antiparathyroid antibodies
Ell and Gll, at concentrations of 5 ~g/ml, together with a mouse
peroxidase antiperoxidase technique on human placental,
parathyroid, kidney, and epididymis specimens as well as on the
other human tissues - see above (1,7). Monoclonal antibodies to
collagen-type II were used as negati~Te controls (14).
Total RNA was extracted from tissue samples by the acid
phenol/chloroform method. ~or Northern blot analysis
approximately 10 ~g of total RNA was electrophoresed in a
1.5%/37% agarose/formaldehyde gel, blotted onto nylon membranes
(Qiabrane, Diagen GmbH, Dusseldorf, Germany) and probed with the
2.3 kb clone (see results) labeled by the random priming method.
Hybridizations were performed at 42C for 18-24 h in 50%
formamide, 4 x saline sodium citrate (SSC; 300 mM NaCl, 30 mM
Na-citrate, pH 7.0), 2 X Denhart's solution, 10% dextran sulfate
(Kabi-Pharmacia, Uppsala, Sweden) and lO0 ~g/ml salmon sperm
DNA. Filters were washed at a final stringency of 1 x SSC/0.1%
CA 0220~648 1997-0~-20
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SDS for 30 sin at 42C, and exposed within a phosphorimager as
above.
CAS P~pti~e Bin~ing Analy~is: A peptide correspon~;~g to
one putative CAS SH3 bin~;ng region (ATPPPSPSLPAKPKPPSRR) (SEQ
ID No. 18) was synthesized on an ABI model 430A synthesizer
using FastMoctm chemistry. The peptide was HPLC purified and
analyzed by ~ass spectroscopy. 5 mg of the peptide was coupled
to 500 ul of Amino Link (Pierce) agarose as described by the
supplier. Efficiency of coupling was checked by RP-HPLC of
peptide solution before and after coupling and
spectrophotometrically at a wavelength of 220 nm. Both methods
indicated a coupling efficiency of >70%. The coupled peptide
was reacted with 5 ug aliquots of various GST-SH3 fusion
proteins at room temperature ~or l hour before the resin was
washed extensively with ll'~S. The resin was boiled in SDS
loading dye and electrophoresed on an SDS-PAGE gel. B;n~;ng
ability of the various SH3 proteins for the peptide was judged
by the relative intensity of the Coomassie blue-st~;n~hle bands
on the SDS gel. GST protein alone was used alone as a control.
Expression and Purification of GST-SH3 fusion Proteins: Various
GST-SH3-cont~;n;ng fusion clones were kind gifts from Dr. I.
Gout, Ludwig Inst. for Cancer Research, To~on, UK. The fusion
proteins were all produced by inducing their expression in XLl-
blue E. coli using 1 mM IPTG. Cells containing the fusion
proteins were sonicated in PBS cont~' n i ng 10 mM EDTA and 1%
Triton-X lO0. After pelleting cell debris, the cleared lysate
was applied to a glutathione-Sepharose column (Pharmacia), and
the bound fusion protein was eluted with lO mM reduced
glutathione in 50 mM Tris pH 8Ø These purified fusion
proteins were then dialyzed extensively against PBS before being
used in all subsequent experiments. Protein was quantified by
measuring the absorbance at 280 nm followed by characterization
by SDS polyacrylamide gel electrophoresis.
RESULTS
Isolation of the calcium sensor protein, peptide
clea~age and ~equence determination.
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The calcium sensor protelY was purified from placental
tissue ~y means of Pectin chromatography, immunosorbent
chromatography utilizing the immobilized monoclonal anti-
parathyroid antibodies, and ~inally ion exc~Ange chromatography
(1,7). The same antibodies were used in a sandwich ELISA to
monitor- the purification (7). In order to avoid contamination
with low molecular peptides, the whole inal preparation,
consisting of 200 ~g of the 500 kDa protein chain (7), was made
6 M with regard to guanidine-HCl and applied to a gel
chromatography column, equilibrated with 2 M guanidine-HCl, 0.1
M Tris-~l, pH 8.5. The column was eluted with the same buffer.
Virtually all protein material emerged close to the void volume
at the expected position for a protein with a molecular mass of
500 kDa. Separate fractions cont~;n;ng this material were
combined and endoproteinase Lys C ( 1 ~g ) was added. The
digestion was allowed to proceed over night at 37C. The
fragmented protein was reduced by incubation with 0.1% B-
mercaptoethanol at 37C for 30 min and subse~uently alkylated
with 4-vinyl pyridine (0.3%) at room temperature for 2 h. The
peptide mixture was then applied to a reversed phase C4 column
equilibrated in 5% acetonitrile in 0.2% trifluoroacetic acid.
Peptides were eluted by a l;ne~ gradient of 5 - 60%
acetonitrile in 0.02% trifluoracetic acid (Fig 1). Due to the
large number of peptides, the elution pattern was complex.
Several peptide fractions were sequenced in a gas phase
se~uenator and easily interpretable se~uences were obtained for
two fractions (Fig 2, SEQ ID Nos. 1 and 2).
Isolation of a cDNA clone encoding the 500 kDa calcium
sensor.
An oligonucleotide mixture (48 bp) was constructed to encode
amino acid residues 2 to 17 of the sequenced peptide 292. To
reduce the complexity of the oligonucleotide mixture, five
inosine bases were inserted at degenerated positions where no
guidance could be obtained from the codon usage in ~llm~ns At
nine positions, where two bases were possible, one of the bases
was suggested with a likelihood exceeding 70% from codon usage,
and was therefore used in the oligonucleotide mixture.
The mixed oligonucleotide was radioactively labelled and
CA 02205648 1997-05-20
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used as a probe to screen a human placental ~ gt 11 cDNA
library Approximately 2 x 106 plaques were screened and a
single positive clone, CAS-l, was found. The insert of this
clone was estimated to 2.3 kb, by restriction mapping. To oht~;n
a recognizable se~uence of the clone in a rapid way, an attempt
was made to PCR amplify part of the sequence using degenerated
oliogonucleotides correspon~' ng to part of peptides 292 and 293
as primers. A distinct DNA fragment of approximately 430 bp-was
obt~ne~ assuming that the peptide 292 is located carboxy-
terminal to peptide 293. The fragment was partially seguencedusing the oligonucleotide mixture correspon~;ng to peptide 293
as the primer. In one re~d;ng frame from the obtained se~uence,
the se~uence VGRHI could be deduced, in excellent agreement with
the carboxyte~m;nAl 5 amino residues of peptide 293. To obtain a
clone with a larger insert a human placental ~ ZAP-II cDNA
library reported to contain clones with large inserts was
screened with the PCR fragment as the probe. From 2 x 106
pla~ues a single clone, CAS-2, was found. The insert of this
clone, estimated to 2.8 kb, was released in the Bluescript +
vector, using a helper phage. Part of the insert of this clone,
pCAS-2, was sequenced using synthetic oligonucleotides as
primers (Fig 3, SEQ ID No. 3). An open reA~;n~ frame was found
cont~;n;ng both peptide 292 and 293. There was perfect agreement
between the peptide se~uences and the predicted amino acid
se~uence (SEQ ID No. 4) from the cDNA clone. The complete
se~uence of the 2.8 kb CAS-2 is shown in Figure 6 (SEQ ID No.
11) .
The CAS-2 sequence was extended using st~n~d methodology.
Reverse transcriptase PCR amplification and st~n~rd 32P-labeled
probe screening of human lambda kidney cDNA libraries were used
to complete the cloning of the CAS cDNA (SEQ ID No. 83). Probe
fragments were designed off appropriate clones, starting with
clone pCAS-2 (Figure 11), to allow isolation of overlapping but
5'-extended clones from these libraries. This cDNA walking
procedure was used for the isolation of all cDNA clones except
clones pMeg2, pHPlC8, pHPlBl, and pM4Bl. These clones were
isolated from human kidney cDNA libraries using rat gp330 PCR
amplified probe fragments (nts. 148-1249, 2892-3873, 4553-5693,
and 5868-6968) obtained with rat cDNA prepared from rat kidney
CA 02205648 1997-05-20
WO 96115801 PCT/US9S/lS203
total RNA. Three small cloning gaps (aa 564-997, 1622-1836, and
2212-2312;) were completed by direct PCR amplification through
these regions using speci~ic human gp330 oligonucleotide primers
and cDNA prepared from human kidney total RNA (CAS-1750, -1210,
and -700).
An ext~n~ calcium sensor sequence is shown in SEQ ID No.
17. A complete human calcium sensor sequence in shown in SEQ ID
Nos. 83 and 84. Based on the above cloning procedure amino
acids 1-3711 of SEQ ID No. 84 were determ; ne~ from human kidney
cDNA whereas amino acids 3712-4655 were identified from the CAS-
2 placental cDNA clone (Figure 11).
Full-length human placental (SEQ ID Nos. 85 and 86), kidney
(SEQ ID Nos. 87 and 88) and parathyroid (SEQ ID Nos. 89 and 90)
CAS cDNA and amino acid sequences have been det~rm;ne~ by
se~uencing PCR fragments from specifically primed first-strand
human placental, kidney and parathyroid cDNA, prepared using
oligonucleotide primers designed o$f SEQ ID No. 83, total RN~
RNAzol B method, and a cDNA synthesis kit as described in
Material and Methods.
Comparison of all CAS sequences obt~; n~ so far reveals
only four potential differences throughout the complete amino
acid sequence: Ala1287 to Ala/Pro, Ala2872 to Thr, Lys4094 to
Lys/Glu, and Ile4210 to Ile/Leu (Figure 12). The a-m-biguous
positions and the minor amino acid differences are most likely
associated with normal ethnic and/or allelic variation
differences being reflected in the cDNA sources used in
constructing the cDWA libraries.
The 500 kDa ~lacental calcium sensor belon~s to the LD~-
receptor su~erfamily.
A search in a database with the predicted amino acid sequence
from Figure 3 (SEQ ID No 3) revealed that the placental 500 kDa
protein is homologous to receptors belonging to the LDL-receptor
superfamily. The highest s;m; 1 ~rity was found with the rat
He~mann nephritis antigen (11, 67). Fig 4 shows an alignment of
placental 500 kDa protein se~uence to the se~uence of the
Heymann antigen (SEQ ID No~ 5) as well as to two other members
of the same protein superfamily, the LDL-receptor (SEQ ID No. 6)
CA 02205648 1997-05-20
WO96115801 PCT~S95/15203
and the LDLreceptor-related protein (identical to the a2-
- macroglobulin receptor, (11,15,16), SEQ ID No. 7). The se~uence
identity between the placental calcium-sensor and the Heymann
antigen gp330 was estimated to be 82% in the region of
comparison (236 amino acid residues). A complete se~uence of
the human calcium sensor protein is shown in SEQ ID No. 83.
Overall, the identity between rat gp330 and the human homolog is
77%. The structure of human gp330 iS shown in Figure 10. The
protein is 4655 amino acids in length and comprises an N-
t~m~nAl signal peptide of 25 amino acids, a 4398 amino acid
extracellular ~om~i n, a tr~n~m~mhrane region of 23 amino acids
and a C-termlnAl ~m~;n of 209 amino acids. As shown in Figure
10, the structure of human gp330 closely correlates with that of
the rat homolog (Figure 3 of ref. 67).
T ~Qhigto~h~ ;stry ~nd Northern blot.
The close similarity between the placental 500 kDa calcium-
sensor protein and the rat Heymann nephritis antigen promptedthe expanded ; ~ lnohistochemical investigation of the present
study. The antiparathyroid antibodies (Ell and G11) were found
to stain not only parathyroid, placental and proximal kidney
tubule cells but also epididymal cells, as previously
demonstrated for antibodies reactive with the Heymann antigen
(17-20).
Northern blot analysis of total RNA (approximately 10 ~g/lane)
from human kidney, placenta and parathyroid glands with the
identified 2.8 kb clone as the probe, revealed one major
hybridizing RNA species of approximately 15,000 bases in all
these tissues (Fig 5). Human liver, pancreas, adrenal gland, and
small gut (Fig 5) as well as spleen, lung and striated muscle
(not shown) lacked hybridizing species.
Identification o~ SH2 and S~3 binding regions in the
cytoplasmic domain of the calcium sensor:
Src-homology regions 2 and 3 (SH2 and SH3) are conserved
seguence motifs consisting of approximately 100 and 60 amino
acid residues, respectively, and are found in many eukaryotic
proteins with diverse function (42-44). SH3 ~om~; n.s have been
CA 0220~648 l997-0~-20
WO96/15801 PCT~S95/152Q3
identified in several cytoskeleton-associated proteins, such as
p80/p85, myosinlb, spectrin, neutrophil NADPH oxidase-associated
proteins p47 and p67, and in several yeast proteins important
for morphogenesis (i.e., Bemlp and ABP-1), mating (FUS1) or for
regulation o~ ras activity (cdc25 and ste6 (for review see
Mussachio et al. (45)). The observation that many SH3-
cont~; n; ng proteins are cytoskeleton-associated led to the
suggestion that SH3 ~m~; n~ play a role in multimeric proteln
complex formation at or near cytoplasmic membranes. Some
proteins that contain both SH2 and SH3 ~nm~;n~ perform the
function of adaptor molecules by joining activated receptor
tyrosine kinases with p21 ras g~ni~e nucleotide-releasing
protein (GNRP). For example, Grb2 and its homologues bind to
phosphotyrosine on activated membrane-anchored receptor tyrosine
kinases through their SH2 ~om~;~ and to SOS through their amino-
and carboxyt~m;n~l SH3 ~om~;n~ (46-50). These processes lead
to translocation of SOS to the plasma ...~..~.ane where ras
proteins are interacted with and conseguently activated. Thus,
SH2/SH3-cont~;n;ng and SH2/SH3-b;n~;ng proteins are involved in
a highly conserved signal transduction pathways from activated
receptors.
Complete nucleic acid sequencing and translation of the 2.8
kb human cDNA clone CAS-2 (Figure 6) (SEQ ID Nos. 11 and 12)
demonstrate the existence of at least three potential SH3
b;nA;ng regions denoted as CAS-PEP1 (SEQ ID No. 14), CAS-PEP2
(SEQ ID No. 15), and CAS-PEP3 (SEQ ID No. 16) (Figure 7). All
three of these CAS-2 cytoplasmic peptide regions have the
required consensus sequence of a SH3-b;n~;ng region, which is
shown together with the CAS peptides in Figure 7 (53). Further
support that the cytoplasmic ~om~; n of CAS-2 binds SH3 regions
is shown in the evidence in Figure 8. A region of the CAS-2
cytoplasmic ~om~n (ATPPPSPSLPAKPKPPSRR) (SEQ ID No. 18) that
included CAS-PEP1 (PSLPAKP, Figure 7) was synthesized. The
peptide was incubated with various purified GST-SH3 fusion
proteins and the relative b;n~;ng strengths of the fusion
proteins was assayed by SDS-PAGE (Figure 8). The data clearly
indicate that several of the SH3-region cont~;n; ng proteins had
an affinity for the peptide cont~;n;ng CAS-PEP1, with the
following relative order of decreasing affinities: LANE 6: SH3-
CA 0220~648 1997-0~-20
.
WO96/15801 PCT~S95/15203
PI3K (SH3 of p85 subunit of phosphoinositol-3 kinase, (54,55)) >
LANE 7: SH3-PLC-gamma, (phospholipase-C gamma, (56)) > LANE 2:
SH3-FYN (src-~amily soluble tyrosine kinase, (57), ~ LANE 4:
SH3-GRB2, (growth factor receptor bin~ing protein N-t~rmlnAl
SH3) and LANE 5 (C-terminal SH3 of GRB2) (58,59).
Significantly, all of the positive reacting SH3-cont~;n;n~
proteins shown in Figure 8 are intim.ately associated with signal
transduction and st;m~ tion of cell growth (54-59). PI3K
contains two SH2 regions and one SH3 region. PI3K is relatively
new to the fam.ily of signal transducing molecules, but appears
to be involved with insulin signaling through the glucose
transporter, and is believed to associate directly with the ras
protein. PLC-gamma is a well known signaling molecule also
cont~;n;n~ two SH2 regions and one SH3 region, and is known to
hydrolyze membrane lipids to other powerful downstream signaling
molecules (eg. IP3 and diacylglycerol) when st;mlll~ted by ligand
activated growth factor receptors. FYN is a highly
characterized member of the src-family of soluble tyrosine
kinases known to be intimately associated with cell growth and
differentiation. FYN contains one SH2 and one SH3 region, is
also known to be st;m~ ted by ligand activated growth factor
receptors. GRB2 contains two SH3 regions and one SH2 region,
and is known as an adaptor molecule in that it has no known
intrinsic enzymatic capabilities. GRB2 molecules are also
stimulated by ligand activated growth factor receptors. It is
also worth noting that SH3-GAP (GTP-ase activating protein, LANE
3, (60, 61)), and SH3-NCF (neutrophil cytotoxic factor-type l,
LANE 8, or -type 2, lane 9, (62, 63)) had little or no affinity
for the peptide cont~;n;ng CAS-PEPl. This evidence supports the
specificity of the interaction between the CAS-PEPl and various
SH3 ~m~;n~. In addition, CAS-PEPl does not bind a control GST
fusion protein as shown in lane l of Fig. 8.
The cytoplasmic ~om~;n of CAS-2 also comprises a p85-SH2
b;n~;ng region. Though different SH2 cont~;n;ng proteins all
require phosphorylated tyrosine residues for an interaction, it
is well established that the amino acid residues surrolln~;ng the
tyrosine residue dictate the specificity and strength of the
interaction (64). Figure 9 defines those amino acid sequence
requirements that are necessary for interaction with the SH2
CA 0220~648 1997-OS-20
W O96/158~1 PCTrUS95/15203
region of the p85 regulatory s ~unit of PI3K. The evIdence
clearly shows that for a bi~in~ interaction to take place with
the SH2 region of p85, the tyrosine residue must be inclùded in
the amino acid sequence motif YXXM (where "x~ can be any amino
acid), and must have an acidic amino acid residue (D or E)
approximately 3-5 residues in either direction o~ the YXXM
motif. This exact amino acid sequence requirement exists in the
.cytoplasmic ~m~;n of CAS-2 (FENPIYAQMENE) (SEQ ID No. 19), and
is underlined in the CAS-2 cytoplasmic sequences at the top of
Figure 9.
Altogether, the evidence demonstrates that the cytoplasmic
~m~ i n of the calcium sensor protein of the invention contains
three consensus SH3 bi n~i ng regions and one potential SH2
recognition region of the type recognized by the SH2 region of
p85 and supports an involvment of SH2 and SH3 mediated signal
transduction for biological activity of the calcium sensor
protein, possibly through PI3K. The potential interaction of
PI3K with the calcium sensor protein is even more interesting in
light of recent evidence linking the CAS-2 protein to calcium
sensing in human parathyroid tissue, given that calcium sensing
appears to involve G-protein activation, PKC activation, and
inositol phosphate generation, all of which are activities that
can be associated with PI3K signal transduction cascades.
Therefore, these regions provide useful tools in assays for the
identification of compounds that either stimulate or inhibit the
signal transduction pathways used by the calcium sensor protein.
Using assay techniques known to those skilled in the art,
agonists or antagonists which mimic or inhibit the activity of
the calcium sensor protein SH2/SH3 regions will be useful for
the treatment of diseases that are intimately associated with
the sensor, such as primary hyperparathyroidism (HPT) (52) and
osteoporosis.
The relation of the calcium sensor protein to the LDL-
receptor superfamily of proteins was noted above. All of the
members of the LDL-receptor superfamily are ~scavenger~
proteins. None of these scavenger proteins have recognized
signal transduction regions, and specifically, none of these
scavenger proteins contain SH regions. Therefore it was
CA 0220~648 1997-0~-20
Wo 96/15801 PCT/USs5/1s203
entirely unexpected to identify SH2 and SH3 b; n~i n~ regions
active in signal transduction in the calcium sensor protein.
The occurrence of these regions is a further indication that the
calcium sensor protein is not a scavenger protein, even though
5 it has regions of homology with the LDL-receptor superfamily of
scavenger proteins.
.
Rat Heymann nephritis antigen, gp330, belongs to the LDL
receptor superfamily -of largej multifunctional glycoproteins
lO (68, 69, 70). Identification of the calcium sensor protein as
the human homolog of rat gp330 enables new diagnostic and
therapeutic agents for human disease.
Examples of diagnostic and therapeutic uses for gp330, or
15 biologically active fragments thereof, are disclosed in EP
358,977, the entire contents of which are incorporated herein by
reference. For example, human gp330, or fragment thereof, may
be used in assays for detecting autoantibodies associated with
human merLLl La~lous glomerulonephritis. Examples of suitable
20 assays include immunoassays, such as ELISA. Alternatively,
synthetic peptides based on the human gp330 sequence may be used
to localize immunodominent B- or T-lymphocyte recognition sites.
Therefore, the invention enables detection of gp330 specific
autoantibodies and helper, cytotoxic or suppressor T-cells. The
25 invention permits identification of patients who may develop
idiopathic auto;mmllne membranous glomerulonephritis and patients
susceptible to auto;mmlln~ membranous glomerulonephritis
following a renal allograft.
Human gp330 is useful for treatment of human membranous
glomerulonephritis according to a variety of methods, For
example, gp330 may be coupled to a polyphenol followed by
;mmlln;zation of a patient according to U.S. Patent 4,702,907,
the entire contents of which are incorporated herein by
reference. Treatment in this m~nn~r results in selective
immunosupression of antibodies specific for gp330. As an
alternative method of treatment, it is also possible to
selectively remove gp330-reactive autoantibodies from sera by
i~nobilizing gp330, or fragment thereof, on a solid support and
CA 0220~648 1997-0~-20
WO96/15801 PCT~S95/15203
o;?~2
pass the sera over the support, thereby effectively removing
autoantibodies characteristic of human membranous
glomerulonephritis. Alternatively, human gp330, or a fragment
thereof, can be directly A~m;n;~tered to a patient in order to
perturb formation of immune complexes. Synthetic peptides based
on the se~uence of human gp330 are also useful therapetically.
~m; n; stration of ; ~ lnogenic peptides inhibits activation or
function of gp330 specific helper and cytotoxic T-cells.
The structure of human gp330 includes 16 growth factor
repeats separated by 8 YWTD spacer regions and 1 epi~rm~l
growth factor repeat in the immediate extracellular
juxt~m~mhrane region (Figure 11). Therefore, ~m;n;~tration of
gp330, or a fragment thereof having growth factor activity, is
useful in the treatment of wounds, such as burns and abrasions.
Epi~m~l growth factor is also a potent inhibitor of gastric
acid secretion. Therefore, gp330, or a fragment thereof having
epidermal growth factor activity, is useful for treatment or
~Levention of gastric ulcers. DetPrm;n~tion of effective
amounts of therapeutic agent for administration is within the
skill of the practitioner.
Discus~ion
The important role of the parathyroid as key regulator of
the calcium homeostasis has been related to its ex~uisite
capacity to sense and respond to variation in the extracellular
Ca2+ ion concentration. Essential for recognition of changes in
external calcium is a cation receptor or sensor of the
parathyroid cell me,--~La~e, the presence of which was implicated
by a series of in vitro studies on parathyroid cell regulation
(9, 10, 21-24). The concept of a cell membrane receptor was
further substantiated when monoclinal antiparathyroid antibodies
were found to recognize and interfere with the calcium sensing
of parathyroid cells (1-6). Another crucial piece of evidence
was obtained when cytotrophoblast cells of the human placenta,
selected by their reactivity with the antiparathyroid
antibodies, displayed parathyroid-like sensing of changes in
external calcium, a function which also could be blocked by one
of the anti-parathyroid antibodies (7, 8) . The calcium sensor of
CA 0220~648 1997-0~-20
WO96/15801 PcT~S95/15203
the placenta was subseguently isolated by ;mml~nQsorbent and ion
ex~hAn~e chroma~ographies and shown to -consist of a large
glycoprotein of approximately 500 kDa molecular size (7). It was
y also ~m~n~trated by ;mm1l~oprecipitation that a protein of the
5 same size reacted with the antiparathyroid antibodies within the
. parathyroid and kidney tubule cells (to be published, (25).
The parathyroid calcium sensor or receptor is known to have
features in common with most other classical receptors for
10 cellular activation, although it exhibits the unusual ability to
bind and be activated by divalent cations. Cation bi n~i ng
triggers biphasic rise in [Ca2+i] and concomittant activation of
phospholipase C, possibly via a coupled G-protein, with a
resulting accumulation of inositol phosphates (2,5,9,lO). An
15 initial transient rise in [Ca~+i] is due to
inositoltrisphosphate ( Ip3 ) induced mobilization of Ca2+ from
intracellular sources, while an ensuing steady-state elevation
in [Ca2+i] is caused by calcium gating through plasma membrane
ch~nn~l s, possibly mediated by increase in inositol-
20 tetraphosphate (Ip4) (9,lO, 23 ) .
Sequence analysis of a partial cDNA clone and data-base
comparison of the deduced amino acid sequence showed that the
placental calcium sensor protein belongs to the LDL-receptor
25 superfamily of proteins, and available sequences showed close
similarity with the rat Heymann nephritis antigen (ll,15,16).
This antigen was originally described in the rat as a 330 kDa
glycoprotein (gp 330), present within the proximal kidney tubule
brush border, and in placental and epididymal cells, but by
30 special st~;n; ng techniques also demonstrated to occur sparsely
on rat kidney glomerular cells, as well as on pneumocytes II in
the lung and sporadic cells of the liver and small intestine
(17-l9). It has later been proposed that the molecular size of
the protein was underestimated and actually should be in the
range of 500 kDa (20). The Heymann antigen has been revealed as
the ~om;n~ting antigen causing membranous, autoimmune
glomerulonephritis in the rat after ;mmlln;zation with a crude
tubular protein fraction (17,l9). Using anti-gp 330 antibodies a
protein with an estimated molecular size larger than 400 kDa has
40 been identified in man (20). The sequence identity of 77~
CA 0220~648 1997-0~-20 -
WO 96/1!;801 PCT~US95/15203
between the human placental 500 kDa calcium sensor protein and
the rat Heymann nephritis antigen indicates that they represent
related forms of the calcium sensor protein in two different
species. This view is supported by close similarities in tissue
distribution of the two proteins, as revealed by the
;mml~nohlstochemistry of the present study. The antibodies E11
and G11, reacting with the calcium sensor protein, thus stain
parathyroid cells, proximal kidney tubule cells, placental
cytotrophoblasts and also epididymal cells. Fur~h~rmQre, we have
recently reported st~; n; n~ with one of the antiparathyroid
antibodies preferentially within coated pits and the base o~ the
proximal tubule microvilli, which equals that previously
described with antibodies against the gp 330 protein (19,26). A
reco~nized glycoprotein of similar size within the tubule brush
border, renal maltase, has been located mainly to microvillar
membranes and not within the coated invaginations (18).
Thus far recognized members of the LDL-receptor
superfamily, the LDL-receptor, the LDL-receptor-related protein
and the Heymann antigen, have been thought to function as
receptors ~or proteins, but all exhibit functionally important
Ca2+-bin~ ability (16,27,28). Thus, Ca2+ b;n~;ng is necessary
for the interaction of the LDL-receptor with apo-B (27). The
LDL-receptor related protein (a2-macroglobulin receptor) is also
known to bind Ca2+, which induces conformational changes, and
Ca2+ is necessary for b;n~;ng of activated a2-macroglobulin to
the receptor t16). Recently, the rat Heymann antigen was shown
by a blotting technique to interact with Ca2+ (28).
The Ca2+ b;n~;ng motifs of the calcium sensor protein
remain to be identi~ied. The sensor protein (as well as the
Heym~nn antigen) contains EGF-like modules, like other members
of the LDL-receptor superfamily (11,16,27), which may represent
putative Ca2+ b;n~;n~ sites. Thus, when present in the
coagulation ~actors IX, X and protein C, each EGF-like module is
known to bind one Ca2+ ion (29-34), ànd the EGF-like modules
have also been demonstrated to mediate Ca2+dependent
protein/protein interaction (35). Kinetic data have suggested
that the calcium sensor displays positive cooperativity in its
interaction with Ca2+, a phenomenon which appears essential-for
CA 0220~648 1997-0~-20
WO96/15801 PCT~S9511S203
~_
the sigmoidal regulation of [Ca2+i] and PTH release, with a
steep relation within the physiological range of extracellular
calcium (9,lO). rrhe positive cooperativity should re~uire
multiple b; n~l n~ sites for Ca2+, possibly resulting from the
repetitive EGF-like modules, generally present in molecules of
the LDL-receptor superfamily (ll,16,27). However, Ca2+ bin~;ng
to EGF-like ~m~ in.~ are known to induce only minor, localized
pertubations of the three-~;m~n~ional structure (32), and it is
possible that the calcium sensor contains also other Ca2+
bin~in~ sites.
A 43 kDa membrane protein (~2-macroglobulin receptor-
associated protein, or Heparin-b;n~'n~ protein) (28,36) is known
to interact both with the LDL-receptor-related protein and with
the rat Heymann antigen in a Ca2+dependent m~nner (28). No
physiological function has yet been assigned to this protein,
but it appears also in tissues where the Heymann antigen and the
LDL-receptorrelated proteins are not expressed (28). An
intriguing observation is the presence of a putative leucine-
zipper motif in the aminot~rmln~l part of the 43 kDa protein(36), considering that such motifs have been suggested to
influence the opening and closure of membrane ion ~hAnn~l,5 (37).
Since the 43 kDa protein interacts with the Heymann antigen, it
can be assumed to form a complex also with the calcium sensor
protein in a Ca2+-dependent m~nn~. Interaction with the 43 kDa
protein might be important for the tr~n~mlssion of Ca2+induced
conformational changes within the extracellular portion of the
molecule to the cell interior. It is also possible that
additional proteins interact with the calcium sensor in a
Ca2+dependent manner, and that such an interaction is important
for the modulation of the sensor response. The mechanisms b~
which an activated calcium sensor triggers further signalling to
the cell interior is unknown, although we have in prel;m;n~ry
experiments utilized ;mm~lnoprecipitation to
isolate a phosphorylated form of the sensor protein in dispersed
parathyroid cells loaded with [32p]-orthophosphate (unpublished
observation).
The calcium sensor protein o~ the placenta may be involved
CA 02205648 1997-05-20
WO96/15801 PCT~S95/15203
in maintenance of a feto-maternal Ca2+ gradient and placental
Ca2+ transport, possibly by mediating calcium regulation of the
parathyroid hormone related peptide (PTHrP) production and/or
l,25 (OH)2D3 metabolism (8). Its presence already within the
blastocyst (unpublished o~servation) may indicate a function
also as adhesion molecule, or implicate involvement in
dif~erentiation or growth regulation, as suggested for the
Heymann antigen (38). The function of a calcium sensor within
the kidney tu~ule brush border is less well explored. However,
it should be noted that the enzyme l-~-hydroxylase present in
the placenta and proximal kidney tubule, is regulated by
extracellular calcium, and the calcium sensor might accordingly
regulate l,25 (OH)2D3 metabolism, but it may possibly also
influence Ca2+ reabsorption from the glomerular ~iltrate (7-9).
The significance of the presence of the calcium sensor protein
on epididymal cells, as well as rat pneumocytes, liver and
intestinal cells as implicated by the distribution of the
Heymann antigen (18,l9), yet rem~ins unknown. It has, however,
been proposed that several cell types may exhibit Ca2+ sensing
ability for regulation of various functions, separate from the
general calcium homeostasis, either during development or in the
differentiated state (l0).
The association with auto;mmlln~ nephritis substantiates
that the Heymann antigen is an ;mmllnogen molecule. This may have
implication also in parathyroid disorder, as we have recently
reported the presence of circulating parathyroid autoantibodies
and induction of class II transplantation antigen in the
pathological parathyroid tissue of patients with primary HPT.
These f;n~;ngs suggested that autoimmune phenomena may be
involved in HPT (39) and autoimmllnity has also been implicated
in the pathogenesis of rare idiopathic hypoparathyroidism (l0).
The availability of cDNA clones for the calcium sensor should,
enable extended studies on the pathophysiology in parathyroid
disorder, and also in vestigation of a possible genetic
abberration affecting the calcium sensing function of the
parathyroid and ki & ey tubule in kindreds with familial
hypocalciuric hypercalcemia (FHH) (40,41).
The skilled person within this art realizes that the in~ormation
CA 02205648 1997-05-20
WO96/15801 PCT~S95/1~203
obtainable from the nucleotide se~uences of SEQ ID No. 3, SEQ ID
No. 11, SEQ ID No. 83, SEQ ID No. 85, SEQ ID No. 87, and SEQ ID
No. 89 can be used for isolating the genomic sequence encoding
tthe calcium sensor. Preferablyj an analysis of overlapping cDNA
5 clones in conjunction with PCR techniques is used. The genomic
sequence can be obtained from the analysis of overlapping
.genomic cosmid and/or lambda phage clones.
CA 0220~648 l997-0~-20
WO96/15801 PCT~S95/lS203
Referenco~
l.Juhlin, C., Holm~hl, R., Johansson, H., Rastad, J.,
Akerstrom, G., Klareskog, L., (1987) Proc. Natl. A~ad. Sci. USA.
84, 2990-2994.
2.Juhlin, C., Johansson, H., Holm~l, R., Gylfe, E., Larsson,
R., Rastad, J., Akerstrom, G., Klareskog, L., (1987) Biochem.
B;ophys. Res. Commun. 143, 570-574.
3.Juhlin, C., Klareskog, L., Nygren, P., Gylfe, E., Ljunghall,
S., Rastad, J., Akerstrom, G., (1988) Endocrinol. 122,
2g99-3001.
4.Juhlin, C., Akerstrom, G., Klareskog, L., Gylfe, E., Holm~
R., Johansson, H., Ljlln~h~ll, S., Larsson, R., Nygren, P.,
Rastad, J., (1988) World. J. Surg. 12, 552-558.
5.Gyl~e, E., Juhlin, C., Akerstrom, G., Klareskog, L., Rask, L.,
Rastad, J., (1990) Cell Calcium. 11, 329-332.
6.Juhlin, C., Rastad, J., Klareskog, L., Grimelius, L.,
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Stanley, K. K.,(1988) EMBO. J. 7, ~119-4127.
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~o
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CA 02205648 l997-05-20
WO96/15801 PCT~S95/15203
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CA 02205648 1997-05-20
W O96/15801 PCTrUS95/1S203
33
SEQUENCE LISTING
(1) GENERAL INFORMATION:
(i) APPLICANT:
f NAME: RHONE-POULENC RORER PHARMACEUTICALS INC.
STREET: 500 Arcola Road
CITY: Collegeville
STATE: Pennsylvania
COUNTRY: USA
POSTAL CODE: 19426
(i) APPLICANT:
NAME: AKERSTROM, Goran
STREET: S. Rudbecksgatan l0
CITY: S-752 36 Uppsala
STATE:
CoUNTRY: Sweden
POSTAL CODE:
(i) APPLICANT:
NAME: JUHLIN, Claes
STREET: Ralsvagen 69
CITY: S-752 52 Uppsala
STATE:
COUNTRY: Sweden
POSTAL CODE:
(i) APPLICANT:
NAME: RASK, Lars
STREET: Saves vag 14
CITY: S-752 63 Uppsala
STATE:
COUNTRY: Sweden
POSTAL CODE:
(i) APPLICANT:
NAME: HJALM, Goran
STREET: Student Vigem l
CITY: F5234 Uppsala
STATE:
COUNTRY: Sweden
POSTAL CODE:
(i) APPLICANT:
NAME: MORSE, Clarence C.
STREET: 34 Buckwalter Road
CITY: Royersford
STATE: Pennsylvania
COUNTRY: USA
POSTAL CODE: l9468
(i) APPLICANT:
NAME: MURRAY, Edward M.
STREET: 9ll Anderson Avenue
CITY: Drexel Hill
STATE: Pennsylvania
COUNTRY: USA
POSTAL CODE: l9026
(i) APPLICANT:
NAME: CRUMLEY, Greg R.
STREET: 620 Christian Stree~, Apt. lA
CA 0220~648 l997-0~-20
W O96/1~801 PCTÇUS95/lS203
~Y
CITY: Philadelphia
STATE: Pennsylvania
COUNTRY: USA
POSTAL CODE: 19147
(ii) TITLE OF lNV~'~'l'lON: Human Calcium Sensor Protein, Fragments
Thereof and DNA Encoding Same
(iii) NUMBER OF SEQUENCES: 106
(iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: Rhone-Poulenc Rorer Inc.
~B) STREET: 500 Arcola Rd., 3C~3
(C) CITY: Collegeville
(D) STATE: PA
(E) COUNTRY: USA
(F) ZIP: 19426-0107
(v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk
(B) COMPUTER: Macintosh
(C) OPERATING SYSTEM: System 7.1
(D) SOFTWARE: Word 5.1 (Patentin)
(vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER: PCT
(B) FILING DATE:
(C) CLASSIFICATION:
(vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: US 08/344,836
(B) FILING DATE: 23-NOV-1994
(vii) PRIOR APPLICATION DATA
(A) APPLICATION NUMBER: US 08/487,314
(B) FILING DATE: 07-JUNE-1995
(viii) ATTORNEY/AGENT INFORMATION:
(A) NAME: Savitzky, Martin
(B) REGISTRATION NUMBER: 29,699
(C) REFERENCE/DOCKET NUMBER- A1355B-WO
(ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: 610-454-3816
(B) TELEFAX: 610-454-3808
(2) INFORMATION FOR SEQ ID NO:l:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids
(B) TYPE: amino acid
(C) STRAN~N~S:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE peptide
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:l:
Xaa Ala Met Asn Pro Tyr Ser Leu Asp Ile Phe Glu Asp Gln Leu Tyr
CA 02205648 1997-05-20
WO 96/15801 PCT/US95/15203
3~
Trp
s
(2) INFORMATION FOR SEQ ID NO:2:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 13 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(~) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:
Xaa Val Met Gln Pro Asp Gly Ile Ala Xaa Asp Trp Val
1 5 10
(2) INFORMATION FOR SEQ ID NO:3:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 804 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: double
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 1..804
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:
AAA TAC GTA ATG CAG CCA GAT GGA ATA GCA GTG GAC TGG GTT GGA AGG 48
Lys Tyr Val Met Gln Pro Asp Gly Ile Ala Val Asp Trp Val Gly Arg
1 5 10 15
CAT ATT TAC TGG TCA GAT GTC AAG AAT AAA CGC ATT GAG GTG GCT AAA 96
His Ile Tyr Trp Ser Asp Val Lys Asn Lys Arg Ile Glu Val Ala Lys
20 25 30
CTT GAT GGA AGG TAC AGA AAG TGG CTG ATT TCC ACT GAC CTG GAC CAA 144
Leu Asp Gly Arg Tyr Arg Lys Trp Leu Ile Ser Thr Asp Leu Asp Gln
35 40 45
55 CCA GCT GCT ATT GCT GTG AAT CCC AAA CTA GGG CTT ATG TTC TGG ACT 192
Pro Ala Ala Ile Ala Val Asn Pro Lys Leu Gly Leu Met Phe Trp Thr
50 55 60
GAC TGG GGA AAG GAA CCT AAA ATC GAG TCT GCC TGG ATG AAT GGA GAG 240
60 Asp Trp Gly Lys Glu Pro Lys Ile Glu Ser Ala Trp Met Asn Gly Glu
65 70 75 80
GAC CGC AAC ATC CTG GTT TTC GAG GAC CTT GGT TGG CCA ACT GGC CTT 288
Asp Arg Asn Ile Leu Val Phe Glu Asp Leu Gly Trp Pro Thr Gly Leu
CA 0220~648 l997-0~-20
WO 96/lS801 PCT/US95/lS203
36
TCT ATC GAT TAT TTG AAC AAT GAC CGA ATC TAC TGG AGT GAC TTC AAG 336
Ser Ile Asp Tyr Leu Asn Asn Asp Arg Ile Tyr Trp Ser Asp Phe Lys
100 105 110
GAG GAC GTT ATT GAA ACC ATA AAA TAT GAT GGG ACT GAT AGG AGA GTC 384
Glu Asp Val Ile Glu Thr Ile Lys Tyr Asp Gly Thr Asp Arg Arg Val
115 120 125
ATT GCA AAG GAA GCA ATG AAC CCT TAC AGC CTG GAC ATC TTT GAA GAC 432
Ile Ala Lys Glu Ala Met Asn Pro Tyr Ser Leu Asp Ile Phe Glu Asp
130 135 140
CAG TTA TAC TGG ATA TCT AAG GAA AAG GGA GAA GTA TGG AAA CAA AAT 480
Gln Leu Tyr Trp Ile Ser Lys Glu Lys Gly Glu Val Trp Lys Gln Asn
145 150 155 160
AAA TTT GGG CAA GGA AAG AAA GAG AAA ACG CTG GTA GTG AAC CCT TGG 528
2 0 Lys Phe Gly Gln Gly Lys Lys Glu Lys Thr Leu Val Val Asn Pro Trp
165 170 175
CTC ACT CAA GTT CGA ATC TTT CAT CAA CTC AGA TAC AAT AAG TCA GTG 576
Leu Thr Gln Val Arg Ile Phe His Gln Leu Arg Tyr Asn Lys Ser Val
180 185 190
CCC AAC CTT TGC AAA CAG ATC TGC AGC CAC CTC TGC CTT CTG AGA CCT 624
Pro Asn Leu Cys Lys Gln Ile Cys Ser His Leu Cys Leu Leu Arg Pro
195 200 205
GGA GGA TAC AGC TGT GCC TGT CCC CAA GGC TCC AGC TTT ATA GAG GGG 672
Gly Gly Tyr Ser Cys Ala Cys Pro Gln Gly Ser Ser Phe Ile Glu Gly
210 215 220
3 5 AGC ACC ACT GAG TGT GAT GCA GCC ATC GAA CTG CCT ATC AAC CTG CCC 720
Ser Thr Thr Glu Cys Asp Ala Ala Ile Glu Leu Pro Ile Asn Leu Pro
225 230 235 240
CCC CCA TGC AGG TGC ATG CAC GGA GGA AAT TGC TAT TTT GAT GAG ACT 768
Pro Pro Cys Arg Cys Met His Gly Gly Asn Cys Tyr Phe Asp Glu Thr
245 250 255
GAC CTC CCC AAA TGC AAG TGT CCT AGC GGC TAC ACC 804
Asp Leu Pro Lys Cys Lys Cys Pro Ser Gly Tyr Thr
260 265
(2) INFORMATION FOR SEQ ID NO: 4:
5 0 ( i ) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 268 amino acids
(B) TYPE: amino acid
( D ) TOPOLOGY: l inear -,
( ii ) MOLECULE TYPE: protein
(xi ) SEQUENCE DESCRIPTION: SEQ ID NO: 4:
Lys Tyr Val Met Gln Pro Asp Gly Ile Ala Val Asp Trp Val Gly Arg
1 5 10 15
His Ile Tyr Trp Ser Asp Val Lys Asn Lys Arg Ile Glu Val Ala Lys
CA 0220S648 l997-05-20
W O 96/15801 PCTrUS9Sl15203
~eu Asp Gly Arg Tyr Arg Lys Trp Leu Il?Ser Thr Asp Leu Asp Gln
35 40 45
Pro Ala Ala Ile Ala Val Asn Pro Lys Leu Gly Leu Met Phe Trp Thr
50 S5 60
f Asp Trp Gly I-ys Glu Pro Lys Ile Glu Ser Ala Trp Met Asn Gly Glu
65 70 75 80
Asp Arg Asn Ile Leu Val Phe Glu Asp Leu Gly Trp Pro Thr Gly Leu
85 90 95
Ser Ile Asp Tyr Leu Asn Asn Asp Arg Ile Tyr Trp Ser Asp Phe Lys
100 105 110
Glu Asp Val Ile Glu Thr Ile Lys Tyr Asp Gly Thr Asp Arg Arg Val
115 120 125
Ile Ala Lys Glu Ala Met Asn Pro Tyr Ser Leu Asp Ile Phe Glu Asp
130 135 140
Gln Leu Tyr Trp Ile Ser Lys Glu Lys Gly Glu Val Trp Lys Gln Asn
145 150 155 160
Lys Phe Gly Gln Gly Lys Lys Glu Lys Thr Leu Val Val Asn Pro Trp
165 170 175
Leu Thr Gln Val Arg Ile Phe His Gln Leu Arg Tyr Asn Lys Ser Val
180 185 190
Pro Asn Leu Cys Lys Gln Ile Cys Ser His Leu Cys Leu Leu Arg Pro
195 200 205
Gly Gly Tyr Ser Cys Ala Cys Pro Gln Gly Ser Ser Phe Ile Glu Gly
210 215 220
Ser Thr Thr Glu Cys Asp Ala Ala Ile Glu Leu Pro Ile Asn Leu Pro
225 230 235 240
40 Pro Pro Cys Arg Cys Met His Gly Gly Asn Cys Tyr Phe Asp Glu Thr
245 250 255
Asp Leu Pro Lys Cys Lys Cys Pro Ser Gly Tyr Thr
260 265
(2) INFORMATION FOR SEQ ID NO: 5:
( i ) SEQUENCE CHARACTERISTICS:
( A ) LENGTH: 269 amino ac ids
(8) TYPE: amino acid
( C ) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
( xi ) SEQUENCE DESCRIPTION: SEQ ID NO: 5:
Xaa Xaa Xaa Xaa Xaa Pro Asp Gly Leu Ala Val Asp Trp Val Gly Arg
1 5 lQ 15
His Ile Tyr Trp Ser Asp Ala Asn Ser Gln Arg Ile Glu Val Ala Thr
CA 0220~648 l997-0~-20
WO 96/1580 l PCT/US9S/lS203
3~
Leu Asp Gly Arg Tyr Arg Lys Trp Leu Ile Thr Thr Gln Leu Asp Gln
Pro Ala Ala Ile Ala Val Asn Pro Lys Leu Gly Leu Met Phe Trp Thr
50 55 . 60
Asp Gln Gly Lys Gln Pro Lys Ile Glu Ser Ala Trp Met Asn Gly Glu
65 70 75 80
His Arg Ser Val Leu Val Ser Glu Asn Leu Gly Trp Pro Asn Gly Leu
85 90 95
Ser Ile Asp Tyr Leu Asn Asp Asp Arg Val Tyr Trp Ser Asp Ser Lys
100 105 110
Glu Asp Val Ile Glu Ala Ile Lys Tyr Asp Gly Thr Asp Arg Arg Leu
115 120 125
Ile Ile Asn Glu Ala Met Lys Pro Phe Ser Leu Asp Ile Phe Glu Asp
130 135 140
Lys Leu Tyr Trp Val Ala Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Arg Gln
145 150 155 160
Asn Lys Phe Gly Lys Glu Asn Lys Glu Lys Val Leu Val Val Asn Pro
165 170 175
Trp Leu Thr Gln Val Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
180 185 190
Xaa Xaa Xaa Xaa Cys Lys Gln Val Cys Ser His Leu Cys Leu Leu Arg
195 200 205
3 5 Pro Gly Gly Tyr Ser Cys Ala Cys Pro Gln Gly Ser Asp Phe Val Thr
210 215 220
Gly Ser Thr Val Gln Cys Xaa Xaa Xaa Xaa Xaa Xaa Pro Val Thr Met
225 230 235 240
Pro Pro Pro Cys Arg Cys Met His Gly Gly Asn Cys Tyr Phe Asp Glu
245 250 255
Asn Glu Leu Pro Lys Cys Lys Cys Ser Ser Gly Tyr Ser
260 265
(2) INFORMATION FOR SEQ ID NO: 6:
( i ) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 280 amino acids
(B) TYPE: amino acid
( C ) STRANDEDNESS:
(D) TOPOLOGY: linear
55 (ii) MOLECULE TYPE: protein
(xi ) SEQUENCE DESCRIPTION: SEQ ID NO: 6:
Arg Asp Ile Gln Ala Pro Asp Gly Leu Ala Val Asp Trp Ile His Ser
Asn Ile Tyr Trp Thr Asp Ser Val Leu Gly Thr Val Ser Val Ala Asp
CA 0220~648 1997-0~-20
W O96/15801 PCTrUS95/15203
3q
20 25 30
Thr Lys Gly Val Lys Arg Lys Thr Leu Phe Arg Glu Asn Gly Ser Lys
. 35 40 45
Pro Arg Ala Ile Val Val Asp Pro Val His Gly Phe Met Tyr Trp Thr
50 55 60
Asp Trp Gly Thr Pro Ala Lys Ile Lys Lys Gly Gly Leu Asn Gly Val
65 70 75 80
Asp Ile Tyr Ser Leu Val Thr Glu Asn Ile Gln Trp Pro Asn Gly Ile
Thr Leu Asp Leu Leu Ser Gly Arg Leu Tyr Trp Val Asp Ser Lys Leu
100 105 110
His Ser Ile Ser Ser Ile Asp Tyr Asn Gly Gly Asn Arg Lys Thr Ile
115 120 125
Leu Glu Asp Glu Lys Arg Leu Ala His Pro Phe Ser Leu Ala Val Phe
130 135 140
Glu Asp Lys Val Phe Trp Thr Asp Ile Ile Asn Glu Ala Ile Phe Ser
145 150 155 160
Ala Asn Arg Leu Thr Gly Ser Asp Val Asn Leu Leu Ala Glu Asn Leu
165 170 175
Leu Ser Pro Glu Asp Met Val Leu Phe His Asn Leu Thr Gln Pro Arg
180 185 190
Gly Val Asn Trp Cys Glu Arg Thr Thr Leu Ser Asn Gly Gly Cys Gln
195 200 205
Tyr Leu Cys Leu Pro Ala Pro Gln Ile Asn Pro His Ser Pro Lys Phe
210 215 220
Thr Cys Ala Cys Pro Asp Gly Met Leu ~eu Ala Arg Asp Met Arg Ser
225 230 235 240
Cys Leu Thr Glu Ala Glu Ala Ala Val Ala Thr Gln Glu Thr Ser Thr
245 250 255
Val Arg Leu Lys Val Ser Ser Thr Ala Val Arg Thr Gln His Thr Thr
260 265 270
Thr Arg Pro Val Pro Asp Thr Ser
275 280
.50
(2) INFORMATION EOR SEQ ID NO:7:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 281 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID No:7:
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
4'~)
Thr Gly Leu Ser Asn Pro Asp Gly Leu Ala Val Asp Trp Val Gly Gly
5 10 15
Asn Leu Tyr Trp Cys Asp Lys Gly Arg Asp Thr Ile Glu Val Ser Lys
20 25 30
Leu Asn Gly Ala Tyr Arg Thr Val Leu Val Ser Ser Gly Leu Arg Glu
Pro Arg Ala Leu Val Val Asp Val Gln Asn Gly Tyr Leu Tyr Trp Thr
50 55 60
Asp Trp Gly Asp His Ser Leu Ile Gly Arg Ile Gly Met Asp Gly Ser
65 70 75 80
Ser Arg Ser Val Ile Val Asp Thr Lys Ile Thr Trp Pro Asn Gly Leu
85 90 95
Thr Leu Asp Tyr Val Thr Glu Arg Ile Tyr Trp Ala Asp Ala Arg Glu
100 105 110
Asp Tyr Ile Glu Phe Ala Ser Leu Asp Gly Ser Asn Arg His Val Val
115 120 125
Leu Ser Gln Asp Ile Pro His Ile Phe Ala Leu Thr Leu Phe Glu Asp
130 135 140
Tyr Val Tyr Trp Thr Asp Trp Glu Thr Lys Ser Ile Asn Arg Ala His
145 150 155 160
Lys Thr Thr Gly Thr Asn Lys Thr Leu Leu Ile Ser Thr Leu His Ar~
165 170 175
Pro Met Asp Leu His Val Phe His Ala Leu Arg Gln Pro Asp Val Pro
180 185 190
Asn His Pro Cys Lys Val Asn Asn Gly Gly Cys Ser Asn Leu Cys Leu
195 200 205
Leu Ser Pro Gly Gly Gly His Lys Cys Ala Cys Pro Thr Asn Phe Tyr
210 215 220
Leu Gly Ser Asp Gly Arg Thr Cys Val Ser Asn Cys Thr Ala Ser Gln
225 230 235 240
Phe Val Cys Lys Asn Asp Lys Cys Ile Pro Phe Trp Trp Lys Cys Asp
245 250 255
Thr Glu Asp Asp Cys Gly Asp His Ser Asp Glu Pro Pro Asp Cys Pro
260 265 270
Glu Phe Lys Cys Arg Pro Gly Gln Phe .
275 280
5 5 (2) INFORMATION FOR SEQ ID NO: 8:
( i ) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 48 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
( D ) TOPOLOGY: l inear
( ii ) MOLECULE TYPE: other nucleic acid
CA 02205648 1997-05-20
W O96/15801 PCTrUS95/15203
~//
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(ix) FEATURE:
(A) NAME/KEY: modi~ied_base
(B) LOCATION: 7
(D) OTHER INFORMATION: /mod_base= i
(ix) FEATURE:
(A) NAME/KEY: modified_base
(B) LOCATION: 28
(D) OTHER INFORMATION: /mod_base= i
(ix) FEATURE:
(A) NAME/KEY: modi~ied_base
(B) LOCATION: 31
(D) OTHER INFORMATION: /mod_base= i
(ix) FEATURE:
(A) NAME/KEY: modi~ied_base
(B) LOCATION: 37
(D) OTHER INFORMATION: /mod_base= i
(ix) FEATURE:
(A) NAME/KEY: modified_base
(B) LOCATION: 46
(D) OTHER INFORMATION: /mod_base= i
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:
CCARTANAGC TGRTCCTCRA AGATRTCNAG NGARTANGGR TTCATNGC 48
(2) INFORMATION FOR SEQ ID NO:9:
(i) SEQUENCE CHARACTERISTICS:
~ (A) LENGTH: 26 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: other nucleic acid
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:
GCGGAATTCG TNATGCARCC NGAYGG 26
(2) INFORMATION FOR SEQ ID NO:l0:
QU~:N~: CHARACTERISTICS:
(A) LENGTH: 26 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) ~OLECULE TYPE: other nucleic acid
CA 0220~648 l997-0~-20
WO 96/1~801 PCT/US95/15203
(iii) HYPOTHETICAL: NO
( iv) ANTI-SENSE: NO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:
ATAGGATCCT GRTCYTCRAA DATRTC 26
(2) INFORMATION FOR SEQ ID NO: 11:
( i ) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2835 base pairs
(B) TYPE: nucleic acid
( C ) STRAMDEDNESS: s ing l e
( D ) TOPOLOGY: l inear
2 0 ( i i ) MOIIECULE TYPE: cDNA
(iii) HYPOTHETICAL: NO
( iv) ANTI-SENSE: NO
( ix ) FEATURE:
( A ) NAME / KEY: CDS
(B) LOCATION: 1. .2835
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:
CAA GGC TGT GAG GAG AGG ACA TGC CAT CCT GTG GGG GAT TTC CGC TGT 48
3 5 Gln Gly Cys Glu Glu Arg Thr Cys His Pro Val Gly Asp Phe Arg Cys
5 10 15
AAA ACT CAC CAC TGC ATC CCT CTT CGT TGG CAG TGT GAT GGG CAA AAT 96
Lys Thr His His Cys Ile Pro Leu Arg Trp Gln Cys Asp Gly Gln Asn
20 25 30
GAC TGT GGA GAT AAC TCA GAT GAG GAA AAC TGT GCT CCC CGG GAG TGC 144
Asp Cys Gly Asp Asn Ser Asp Glu Glu Asn Cys Ala Pr~ Arg Glu Cys
35 40 45
ACA GAG AGC GAG TTT CGA TGT GTC AAT CAG CAG TGC ATT CCC TCG CGA 192
Thr Glu Ser Glu Phe Arg Cys Val Asn Gln Gln Cys Ile Pro Ser Arg
50 55 60
5 0 TGG ATC TGT GAC CAT TAC AAC GAC TGT GGG GAC AAC TCA GAT GAA CGG 240
Trp Ile Cys Asp His Tyr Asn Asp Cys Gly Asp Asn Ser Asp Glu Arg
65 70 75 80
GAC TGT GAG ATG AGG ACC TGC CAT CCT GAA TAT TTT CAG TGT ACA AGT 288
Asp Cys Glu Met Arg Thr Cys His Pro Glu Tyr Phe Gln Cys Thr Ser
85 90 95
GGA CAT TGT GTA CAC AGT GAA CTG AAA TGC GAT GGA TCC GCT GAC TGT 336
Gly His Cys Val His Ser Glu Leu Lys Cys Asp Gly Ser Ala Asp Cys
100 105 110
TTG GAT GCG TCT GAT GAA GCT GAT TGT CCC ACA CGC TTT CCT GAT GGT 384
Leu Asp Ala Ser Asp Glu Ala Asp Cys Pro Thr Arg Phe Pro Asp Gly
115 120 125
CA 0220~648 l997-0~-20
WO 96/15801 - PCT/US95/15203
GCA TAC TGC CAG GCT ACT ATG TTC GAA TGC AAA AAC CAT GTT TGT ATC 432
Ala Tyr Cys Gln Ala Thr Met Phe Glu Cys Lys Asn His Val Cys Ile
130 135 140
CCG CCA TAT TGG AAA TGT GAT GGC GAT GAT GAC TGT GGC GAT GGT TCA 480
Pro Pro Tyr Trp Lys Cys Asp Gly Asp Asp Asp Cys Gly Asp Gly Ser
145 150 155 160
0 GAT GAA GAA CTT CAC CTG TGC TTG GAT GTT CCC TGT AAT TCA CCA AAC 528
Asp Glu Glu Leu His Leu Cys Leu Asp Val Pro Cys Asn Ser Pro Asn
165 170 175
CGT TTC CGG TGT GAC AAC AAT CGC TGC ATT TAT AGT CAT GAG GTG TGC 576
Arg Phe Arg Cys Asp Asn Asn Arg Cys Ile Tyr Ser His Glu Val Cys
180 185 190
AAT GGT GTG GAT GAC TGT GGA GAT GGA ACT GAT GAG ACA GAG GAG CAC 624
Asn Gly Val Asp Asp Cys Gly Asp Gly Thr Asp Glu Thr Glu Glu His
195 200 205
TGT AGA AAA CCG ACC CCT AAA CCT TGT ACA GAA TAT GAA TAT AAG TGT 672
Cys Arg Lys Pro Thr Pro Lys Pro Cys Thr Glu Tyr Glu Tyr Lys Cys
210 215 220
GGC AAT GGG CAT TGC ATT CCA CAT GAC AAT GTG TGT GAT GAT GCC GAT 720
Gly Asn Gly His Cys Ile Pro His Asp Asn Val Cys Asp Asp Ala Asp
225 230 235 240
3 0 GAC . TGT GGT GAC TGG TCC GAT GAA CTG GGT TGC AAT AAA GGA AAA GAA 768
Asp Cys Gly Asp Trp Ser Asp Glu Leu Gly Cys Asn Lys Gly Lys Glu
245 250 255
AGA ACA TGT GCT GAA AAT ATA TGC GAG CAA AAT TGT ACC CAA TTA AAT 816
3 5 Arg Thr Cys Ala Glu Asn Ile Cys Glu Gln Asn Cys Thr Gln Leu Asn
260 265 270
GAA GGA GGA TTT ATC TGC TCC TGT ACA GCT GGG TTC GAA ACC AAT GTT 864
Glu Gly Gly Phe Ile Cys Ser Cys Thr Ala Gly Phe Glu Thr Asn Val
275 280 285
TTT GAC AGA ACC TCC TGT CTA GAT ATC AAT GAA TGT GAA CAA TTT GGG 912
Phe Asp Arg Thr Ser Cys Leu Asp Ile Asn Glu Cys Glu Gln Phe Gly
290 295 300
ACT TGT CCC CAG CAC TGC AGA AAT ACC AAA GGA AGT TAT GAG TGT GTC 960
Thr Cys Pro Gln His Cys Arg Asn Thr Lys Gly Ser Tyr Glu Cys Val
305 310 315 320
TGT GCT GAT GGC TTC ACG TCT ATG AGT GAC CGC CCT GGA AAA CGA TGT 1008
Cys Ala Asp Gly Phe Thr Ser Met Ser Asp Arg Pro Gly Lys Arg Cys
325 330 335
GCA GCT GAG GGT AGC TCT CCT TTG TTG CTA CTG CCT GAC AAT GTC CGA 1056
Ala Ala Glu Gly Ser Ser Pro Leu Leu Leu Leu Pro Asp Asn Val Arg
340 345 350
ATT CGA AAA TAT AAT CTC TCA TCT GAG AGG TTC TCA GAG TAT CTT CAA 1104
Ile Arg Lys Tyr Asn Leu Ser Ser Glu Arg Phe Ser Glu Tyr Leu Gln
355 360 365
GAT GAG GAA TAT ATC CAA GCT GTT GAT TAT GAT TGG GAT CCC AAG GAC 1152
Asp Glu Glu Tyr Ile Gln Ala Val Asp Tyr Asp Trp Asp Pro Lys Asp
370 375 380
.CA 0220~648 l997-0~-20
e~ ~
W O96/lS801 PCTrUS95115203
ATA GGC CTC AGT GTT GTG TAT TAC ACT GTG CGA GGG GAG GGC TCT AGG 1200
Ile Gly Leu Ser Val Val Tyr Tyr Thr Val Arg Gly Glu Gly Ser Arg
385 390 395 400
TTT GGT GCT ATC AAA CGT GCC TAC ATC CCC AAC TTT GAA TCC GGC CGC 1248
Phe Gly Ala Ile Lys Arg Ala Tyr Ile Pro Asn Phe Glu Ser Gly Arg
405 410 415
10 AAT AAT CTT GTG CAG GAA GTT GAC CTG AAA CTG AAA TAC GTA ATG CAG 1296
Asn Asn Leu Val Gln Glu Val Asp Leu Lys Leu Lys Tyr Val Met Gln
420 425 430
CCA GAT GGA ATA GCA GTG GAC TGG GTT GGA AGG CAT ATT TAC TGG TCA 1344
15 Pro Asp Gly Ile Ala Val Asp Trp Val Gly Arg His Ile Tyr Trp Ser
435 440 445
GAT GTC AAG AAT AAA CGC ATT GAG GTG GCT AAA CTT GAT GGA AGG TAC 1392
Asp Val Lys Asn Lys Arg Ile Glu Val Ala Lys Leu Asp Gly Arg Tyr
450 455 460
AGA AAG TGG CTG ATT TCC ACT GAC CTG GAC CAA CCA GCT GCT ATT GCT 1440
Arg Lys Trp Leu Ile Ser Thr Asp Leu Asp Gln Pro Ala Ala Ile Ala
465 470 475 480
GTG AAT CCC AAA CTA GGG CTT ATG TTC TGG ACT GAC TGG GGA AAG GAA 1488
Val Asn Pro Lys Leu Gly Leu Met Phe Trp Thr Asp Trp Gly Lys Glu
485 490 495
30 CCT AAA ATC GAG TCT GCC TGG ATG AAT GGA GAG GAC CGC AAC ATC CTG 1536
Pro Lys Ile Glu Ser Ala Trp Met Asn Gly Glu Asp Arg Asn Ile Leu
500 505 510
GTT TTC GAG GAC CTT GGT TGG CCA ACT GGC CTT TCT ATC GAT TAT TTG 1584
35 Val Phe Glu Asp Leu Gly Trp Pro Thr Gly Leu Ser Ile Asp Tyr Leu
515 520 525
AAC AAT GAC CGA ATC TAC TGG AGT GAC TTC AAG GAG GAC GTT ATT GAA 1632
Asn Asn Asp Arg Ile Tyr Trp Ser Asp Phe Lys Glu Asp Val Ile Glu
530 535 540
ACC ATA AAA TAT GAT GGG ACT GAT AGG AGA GTC ATT GCA AAG GAA GCA 1680
Thr Ile Lys Tyr Asp Gly Thr Asp Arg Arg Val Ile Ala Lys Glu Ala
545 550 555 560
ATG AAC CCT TAC AGC CTG GAC ATC TTT GAA GAC CAG TTA TAC TGG ATA 1728
Met Asn Pro Tyr Ser Leu Asp Ile Phe Glu Asp Gln Leu Tyr Trp Ile
565 570 575
50 TCT AAG GAA AAG GGA GAA GTA TGG AAA CAA AAT AAA TTT GGG CAA GGA 1776
Ser Lys Glu Lys Gly Glu Val Trp Lys Gln Asn Lys Phe Gly Gln Gly
580 585 590
AAG AAA GAG AAA ACG CTG GTA GTG AAC CCT TGG CTC ACT CAA GTT CGA 1824
55 Lys Lys Glu Lys Thr Leu Val Val Asn Pro Trp Leu Thr Gln Val Arg
595 600 605
ATC TTT CAT CAA CTC AGA TAC AAT AAG TCA GTG CCC AAC CTT TGC AAA 1872
Ile Phe His Gln Leu Arg Tyr Asn Lys Ser Val Pro Asn Leu Cys Lys
610 615 620
CAG ATC TGC AGC CAC CTC TGC CTT CTG AGA CCT GGA GGA TAC AGC TGT 1920
Gln Ile Cys Ser His Leu Cys Leu Leu Arg Pro Gly Gly Tyr Ser Cys
625 630 635 640
CA 0220~648 1997-0~-20
W O96/15801 PCTruS95/l5203
y~
GCC TGT CCC CAA GGC TCC AGC TTT ATA GAG GGG AGC ACC ACT GAG TGT 1968
Ala Cys Pro Gln Gly Ser Ser Phe Ile Glu Gly Ser Thr Thr Glu Cys
645 650 655
GAT GCA GCC ATC GAA CTG CCT ATC AAC CTG CCC CCC CCA TGC AGG TGC 2016
Asp Ala Ala Ile Glu Leu Pro Ile Asn Leu Pro Pro Pro Cys Arg Cys
660 665 670
10 ATG CAC GGA GGA AAT TGC TAT TTT GAT GAG ACT GAC CTC CCC AAA TGC 2064
Met His Gly Gly Asn Cys Tyr Phe Asp GlU Thr Asp Leu Pro Lys Cys
675 680 685
AAG TGT CCT AGC GGC TAC ACC GGA AAA TAT TGT GAA ATG GCG TTT TCA 2112
15 Lys Cys Pro Ser Gly Tyr Thr Gly Lys Tyr Cys Glu Met Ala Phe Ser
690 695 700
AAA GGC ATC TCT CCA GGA ACA ACC GCA GTA GCT GTG CTG TTG ACA ATC 2160
Lys Gly Ile Ser Pro Gly Thr Thr Ala Val Ala Val Leu Leu Thr Ile
20 705 710 715 720
CTC TTG ATC GTC GTA ATT GGA GCT CTG GCA ATT GCA GGA TTC TTC CAC 2208
Leu Leu Ile Val Val Ile Gly Ala Leu Ala Ile Ala Gly Phe Phe His
725 730 735
TAT AGA AGG ACC GGC TCC CTT TTG CCT GCT CTG CCC AAG CTG CCA AGC 2256
Tyr Arg Arg Thr Gly Ser Leu Leu Pro Ala Leu Pro Lys Leu Pro Ser
740 745 750
30 TTA AGC AGT CTC GTC AAG CCC TCT GAA AAT GGG AAT GGG GTG ACC TTC 2304
Leu Ser Ser Leu Val Lys Pro Ser Glu Asn Gly Asn Gly Val Thr Phe
755 760 765
AGA TCA GGG GCA GAT CTT AAC ATG GAT ATT GGA GTG TCT GGT TTT GGA 2352
35 Arg Ser Gly Ala Asp Leu Asn Met Asp Ile Gly Val Ser Gly Phe Gly
770 775 780
CCT GAG ACT GCT ATT GAC AGG TCA ATG GCA ATG AGT GAA GAC TTT GTC 2400
Pro Glu Thr Ala Ile Asp Arg Ser Met Ala Met Ser Glu Asp Phe Val
40 785 790 795 800
ATG GAA ATG GGG AAG CAG CCC ATA ATA TTT GAA AAC CCA ATG TAC TCA 2448
Met Glu Met Gly Lys Gln Pro Ile Ile Phe Glu Asn Pro Met Tyr Ser
805 810 815
GCC AGA GAC AGT GCT GTC AAA GTG GTT CAG CCA ATC CAG GTG ACT GTA 24g6
Ala Arg Asp Ser Ala Val Lys Val Val Gln Pro Ile Gln Val Thr Val
820 825 830
50 TCT GAA AAT GTG GAT AAT AAG AAT TAT GGA AGT CCC ATA AAC CCT TCT 2544
Ser Glu Asn Val Asp Asn Lys Asn Tyr Gly Ser Pro Ile Asn Pro Ser
835 840 845
GAG ATA GTT CCA GAG ACA AAC CCA ACT TCA CCA GCT GCT GAT GGA ACT 2592
55 Glu Ile Val Pro Glu Thr Asn Pro Thr Ser Pro Ala Ala Asp Gly Thr
~ 850 855 860
CAG GTG ACA AAA TGG AAT CTC TTC AAA CGA AAA TCT AAA CAA ACT ACC 2640
Gln Val Thr Lys Trp Asn Leu Phe Lys Arg Lys Ser Lys.Gln Thr Thr
60 865 870 875 880
AAC TTT GAA AAT CCA ATC TAT GCA CAG ATG GAG AAC GAG CAA AAG GAA 2688
Asn Phe Glu Asn ~ro Ile Tyr Ala Gln Met Glu Asn Glu Gln Lys Glu
885 890 895
.
CA 0220~648 l997-0~-20
WO 96/15801 PC'r/USg~1152U3
AGT GTT GCT GCG ACA CCA CCT CCA TCA CCT TCG CTC CCT GCT AAG CCT 2736
Ser Val Ala Ala Thr Pro Pro Pro Ser Pro Ser Leu Pro Ala Lys Pro
900 905 910
AAG CCT CCT TCG AGA AGA GAC CCA ACT CCA ACC TAT TCT GCA ACA GAA 2784
Lys Pro Pro Ser Arg Arg Asp Pro Thr Pro Thr Tyr Ser Ala Thr Glu
915 920 925
GAC ACT TTT AAA GAC ACC GCA AAT CTT GTT AAA GAA GAC TCT GAA GTA 2832
Asp Thr Phe Lys Asp Thr Ala Asn Leu Val Lys Glu Asp Ser Glu Val
~30 935 940
TAG 2835
*
945
(2) INFORMATION FOR SEQ ID NO:12:
( i ) SEQUENCE CHARACTERISTICS:
( A ) LENGTH: 945 amino ac ids
(B) TYPE: amino acid
( D ) TOPOLOGY: 1 inear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:
3 0 Gln Gly Cys Glu Glu Arg Thr Cys His Pro Val Gly Asp Phe Arg Cys
5 10 15
Lys Thr His His Cys Ile Pro Leu Arg Trp Gln Cys Asp Gly Gln Asn
'~O 25 30
Asp Cys Gly Asp Asn Ser Asp Glu Glu Asn Cys Ala Pro Arg Glu Cys
35 40 45
Thr Glu Ser Glu Phe Arg Cys Val Asn Gln Gln Cys Ile Pro Ser Arg
50 55 60
Trp Ile Cys Asp His Tyr Asn Asp Cys Gly Asp Asn Ser Asp Glu Arg
65 70 75 80
Asp Cys Glu Met Arg Thr Cys His Pro Glu Tyr Phe Gln Cys Thr Ser
85 90 95
Gly His Cys Val His Ser Glu Leu Lys Cys Asp Gly Ser Ala Asp Cys
100 105 110
Leu Asp Ala Ser Asp Glu Ala Asp Cys Pro Thr Arg Phe Pro Asp Gly
115 120 125
Ala Tyr Cys Gln Ala Thr Met Phe Glu Cys Lys Asn His Val Cys Ile
130 135 140
Pro Pro Tyr Trp Lys Cys Asp Gly Asp Asp Asp Cys Gly Asp Gly Ser
145 150 155 160
0 Asp Glu Glu Leu His Leu Cys Leu Asp Val Pro Cys Asn Ser Pro Asn
165 170 175
Arg Phe Arg Cys Asp Asn Asn Arg Cys Ile Tyr Ser His Glu Val Cys
180 185 190
CA 0220~648 1997-0~-20
W O96/15801 PCTAUS95115203
Asn Gly Val Asp Asp Cys Gly Asp Gly Thr Asp Glu Thr Glu Glu His
195 200 205
Cys Arg Lys Pro Thr Pro Lys Pro Cys Thr Glu Tyr GlU Tyr Lys Cys
210 215 220
Gly Asn Gly His Cys Ile Pro His Asp Asn Val Cys Asp Asp Ala Asp
225 230 235 240
Asp Cys Gly Asp Trp Ser Asp Glu Leu Gly Cys Asn Lys Gly Lys G1U
245 250 255
Arg Thr Cys Ala Glu Asn Ile Cys Glu Gln Asn Cys Thr Gln Leu Asn
260 265 270
Glu Gly Gly Phe Ile Cys Ser Cys Thr Ala Gly Phe Glu Thr Asn Val
275 280 285
Phe Asp Arg Thr Ser Cys Leu Asp Ile Asn Glu Cys Glu Gln Phe Gly
290 295 300
Thr Cys Pro Gln His Cys Arg Asn Thr Lys Gly Ser Tyr Glu Cys Val
305 310 315 320
Cys Ala Asp Gly Phe Thr Ser Met Ser Asp Arg Pro Gly Lys Arg Cys
325 330 335
Ala Ala Glu Gly Ser Ser Pro Leu Leu Leu Leu Pro Asp Asn Val Arg
340 345 350
Ile Arg Lys Tyr Asn Leu Ser Ser Glu Arg Phe Ser Glu Tyr Leu Gln
355 360 365
3 5 Asp Glu Glu Tyr Ile Gln Ala Val Asp Tyr Asp Trp Asp Pro Lys Asp
370 375 380
Ile Gly Leu Ser Val Val Tyr Tyr Thr Val Arg Gly Glu Gly Ser Arg
385 390 395 400
Phe Gly Ala Ile Lys Arg Ala Tyr Ile Pro Asn Phe Glu Ser Gly Arg
405 410 415
Asn Asn Leu Val Gln Glu Val Asp Leu Lys Leu Lys Tyr Val Met Gln
420 425 430
Pro Asp Gly Ile Ala Val Asp Trp Val Gly Arg His Ile Tyr Trp Ser
435 440 445
Asp Val Lys Asn Lys Arg Ile Glu Val Ala Lys Leu Asp Gly Arg Tyr
450 455 460
Arg Lys Trp Leu Ile Ser Thr Asp Leu Asp Gln Pro Ala Ala Ile Ala
465 470 475 480
Val Asn Pro Lys Leu Gly Leu Met Phe Trp Thr Asp Trp Gly Lys Glu
485 490 495
Pro Lys Ile Glu Ser Ala Trp Met Asn Gly Glu Asp Arg Asn Ile Leu
500 505 510
Val Phe Glu Asp Leu Gly Trp Pro Thr Gly Leu Ser Ile Asp Tyr Leu
515 520 525
CA 0220~648 l997-0~-20
WO 96/15801 . PCTIUS95/15203
Asn Asn Asp Arg Ile Tyr Trp Ser Asp Phe~Lys Glu Asp Val Ile Glu
530 535 540
Thr Ile Lys Tyr Asp Gly Thr Asp Arg Arg Val Ile Ala Lys Glu Ala
545 550 555 560
Met Asn Pro Tyr Ser Leu Asp Ile Phe Glu Asp Gln Leu Tyr Trp Ile
565 570 575
0 Ser Lys Glu Lys Gly Glu Val Trp Lys Gln Asn Lys Phe Gly Gln Gly
580 585 590
Lys Lys Glu Lys Thr Leu Val Val Asn Pro Tr~ Leu Thr Gln Val Arg
595 600 605
Ile Phe His Gln Leu Arg Tyr Asn Lys Ser Val Pro Asn Leu Cys Lys
610 615 620
Gln Ile Cys Ser His Leu Cys Leu Leu Arg Pro Gly Gly Tyr Ser Cys
625 630 635 640
Ala Cys Pro Gln Gly Ser Ser Phe Ile Glu Gly Ser Thr Thr Glu Cys
645 650 655
Asp Ala Ala Ile Glu Leu Pro Ile Asn Leu Pro Pro Pro Cys Arg Cys
660 665 670
Met His Gly Gly Asn Cys Tyr Phe Asp Glu Thr Asp Leu Pro Lys Cys
675 680 685
Lys Cys Pro Ser Gly Tyr Thr Gly Lys Tyr Cys Glu Met Ala Phe Ser
690 695 700
Lys Gly Ile Ser Pro Gly Thr Thr Ala Val Ala Val Leu Leu Thr Ile
705 710 715 720
Leu Leu Ile Val Val Ile Gly Ala Leu Ala Ile Ala Gly Phe Phe His
725 730 735
4 0 Tyr Arg Arg Thr Gly Ser Leu Leu Pro Ala Leu Pro Lys Leu Pro Ser
740 745 750
Leu Ser Ser Leu Val Lys Pro Ser Glu Asn Gly Asn Gly Val Thr Phe
755 760 765
Arg Ser Gly Ala Asp Leu Asn Met Asp Ile Gly Val Ser Gly Phe Gly
770 775 780
Pro Glu Thr Ala Ile Asp Arg Ser Met Ala Met Ser Glu Asp Phe Val
785 790 795 800
Met Glu Met Gly Lys Gln Pro Ile Ile Phe Glu Asn Pro Met Tyr Ser
805 810 815
5 Ala Arg Asp Ser Ala Val Lys Val Val Gln Pro Ile Gln Val Thr Val
820 825 830
Ser Glu Asn Val Asp Asn Lys Asn Iyr Gly Ser Pro Ile Asn Pro Ser
835 840 845
Glu Ile Val Pro Glu Thr Asn Pro Thr Ser Pro Ala Ala Asp Gly Thr
850 855 860
Gln Val Thr Lys Trp Asn Leu Phe Lys Arg Lys Ser Lys Gln Thr Thr
CA 0220~648 l997-05-20
WO 96/15801 PCT/US95/l5203
865 870 875 880
Asn Phe Glu Asn Pro Ile Tyr Ala Gln Met Glu Asn Glu Gln Lys Glu
885 890 895
Ser Val Ala Ala Thr Pro Pro Pro Ser Pro Ser Leu Pro Ala Lys Pro
900 905 910
Lys Pro Pro Ser Arg Arg Asp Pro Thr Pro Thr Tyr Ser Ala Thr Glu
915 920 925
Asp Thr Phe Lys Asp Thr Ala Asn Leu Val Lys Glu Asp Ser Glu Val
930 935 940
5 *
945
(2) INFORMATION FOR SEQ ID NO:13:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 207 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: C-terminal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:
Arg Arg Thr Gly Ser Leu Leu Pro Ala Leu Pro Lys Leu Pro Ser Leu
5 10 15
Ser Ser Leu Val Lys Pro Ser Glu Asn Gly Asn Gly Val Thr Phe Arg
20 25 30
Ser Gly Ala Asp Leu Asn Met Asp Ile Gly Val Ser Gly Phe Gly Pro
35 40 45
Glu Thr Ala Ile Asp Arg Ser Met Ala Met Ser Glu Asp Phe Val Met
Glu Met Gly Lys Gln Pro Ile Ile Phe Glu Asn Pro Met Tyr Ser Ala
65 70 75 80
Arg Asp Ser Ala Val Lys Val Val Gln Pro Ile Gln Val Thr Val Ser
85 90 95
Glu Asn Val Asp Asn Lys Asn Tyr Gly Ser Pro Ile Asn Pro Ser Glu
100 105 110
Ile Val Pro Glu Thr Asn Pro Thr Ser Pro Ala Ala Asp Gly Thr Gln
115 120 125
Val Thr Lys Trp Asn Leu Phe Lys Arg Lys Ser Lys Gln Thr Thr Asn
130 135 140
CA 02205648 l997-05-20
W O96115801 PCT~US9S/lS203
Phe Glu Asn Pro Ile Tyr Ala Gln Met Glu Asn Glu Gln Lys Glu Ser
145 150 155 160
Val Ala Ala Thr Pro Pro Pro Ser Pro Ser Leu Pro Ala Lys Pro Lys
165 170 175
Pro Pro Ser Arg Arg Asp Pro Thr Pro Thr Tyr Ser Ala Thr Glu Asp
180 185 190
Thr Phe Lys Asp Thr Ala Asn Leu Val Lys Glu Asp Ser Glu Val
195 200 205
(2) INFORMATION FOR SEQ ID NO:14:
(i) SEQUENCE CHARACTE~ISTICS:
(A) LENGTH: 7 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:
Pro Ser Leu Pro Ala Lys Pro
1 5
(2) INFORMATION FOR SEQ ID NO:15:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:
Ser Leu Leu Pro Ala Leu Pro
1 5
(2) INFORMATION FOR SEQ ID NO:16:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
CA 0220~648 1997-0~-20
W O96115801 PCTrUS95115203
(ii) MOLECULE TYPE: peptide ~7
' (iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:
Pro Ala Leu Pro Lys Leu Pro
l 5
(2) INFORMATION FOR SEQ ID NO:17:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 6412 base pairs
(B) TYPE: nucleic acid
(C) STRA-N~N~:ss: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:
GAAll~l~lC AATGAGCTGG CCTTCCTTAT AAAAGGATTT ACA~ ~lG CTTAAGAGGT 60
ATTATTTATA GTTTGAAATA lll~l~Gl~A TATTTGCGGG TGGGATCATA TGTGCTTCAT 120
TGTGCATTTT ATAAAGAACA ACAAATTCAC GGGAAGATGT GC~llll~AT ~ll~llGCTT l80
TGCAAATTTT GCTGAGAAGA ~lC~l~TGATA TTTCCTGTTG TTTAGAAGGA ATCGGCACAT 240
TTATTAGAAA TTGGTGATTG ~~ ~A TGGAAAAGTG ACTCAGAATA TAGTTAAAAG 300
GTTAATGGGC AGAACTTCCA TGGCGCTTCT TAGGGAGCAT TTAATGTAGA AGCTGTTGCA 360
AGTGCTATTG TGGAGGGGTC AATGTGAACG GTGGCTGCAT CCA~L~~ llA CTT~-ll~l~G 420
GATTATCTTT CTTCAGGTCC GGGl~l~CC GAGTGCCAGT GTCCACATGA GGGCAACTGG 480
TATTTGGCCA ACAACAGGAA GCACTGCATT GTGGACAATG GTGAACGATG TGGTGCATCT 540
TCCTTCACCT GCTCCAATGG GCGCTGCATC TCGGAAGAGT GGAAGTGTGA TAATGACAAC 600
GACTGTGGGG ATGGCAGTGA TGAGATGGAA A~r~ G CACTTCACAC CTGCTCACCG 660
ACAGCCTTCA CCTGTGCCAA TGGGCGATGT GTCCAATACT CTTACCGCTG TGATTACTAC 720
AATGACTGTG GTGATGGCAG TGATGAGGCA GGGTGCCTGT TCAGGGACTG CAATGCCACC 780
ACGGAGTTTA TGTGCAATAA CAGAAGGTGC ATACCTCGTG AGTTTATCTG CAATGGTGTA 840
GACAACTGCC ATGATAATAA CACTTCAGAT GAGAAAAATT GCCCTGATCG CACTTGCCAG 900
TCTGGATACA CAAAATGTCA TAATTCAAAT ATTTGTATTC CTCGCGTTTA T~ ~AC 960
CA 0220~648 l997-0~-20
WO 96/15801 PCTAUS95/15203
5-~
GGAGACAATG ACTGTGGAGA TAACAGTGAT GAAAACCCTA CTTATTGCAC CACTCACACA 1020
TGCAGCAGTG AGTTCCAATG CACATCTGGG NGCTGTATTC CTCAACATTG GTATTGTGAT 1080
CAAGAAACAG A1~1~1111~A TGCCTCTCGA TG,AACCTGCC TCCTTGTGGT CACTCTGAGC 1140
GAACATGCCT AGCTGATGAG TTCAAGTGTG A'1~L;'1'L~LAG GTGCATCCCA AGCGAATGGA 1200
TCTGTGACGG TGATAATGAC TGTGGGGATA TGAGTGACGA GGATAAAAGG CACCAGTGTC 1260
AGAATCAAAA CTGCTCGGAT TCCGAGTTTC ~ AAA TGACAGACCT CCGGACAGGA 1320
GTGCATTCCC CAGTCTTGGG TCTGTGATGG CGATGTGGAT TGTACTGACG GCTACATGAG 1380
AATCAGAATT GCACCAGGAG AACTTGCTCT GAAAATGAAT TCACCTGTGG TTACGGAATG 1440
TGTATCCCAA AGATATTGCG AGGTGTGACC GGCACAATGA ~"1G1L.~1~AC TATAGCGACG 1500
AGAGGGCTGC TTATACCTAG ACTTGCCAAC AGAATCAGTT TCCTGTCAGA ACGGGCGCTG 1560
CATTAGTAAA AC~11C~1~1 GTGATGCAGG ATGAATCGAC TGTGGAGACG GATCTGATGA 1620
GCTGATGCAC CTGTGCCACA CCCCACGTGT CCACCTCACG AGTGTCAAAT ATGACAATGG 1680
GCGCTGCATC GAGATGATGA AACTCTGCAA CCACCTAGAT GAL''1'L'1"1"1'LG ACAACAGCGA 1740
TGAGAAAGGC TGTGGCATTA ATGAATGCCA TGACCCTTCA ATCAGTGGCT GCGATCACAA 1800
CTGTATAGAC ACCTTAACCA L~T11LTATTG TTCLl~l~T CC1G~11~ACA AGCTCATGTC 1860
TGACAAGCGG A~1~ L- ATATTGATGA ATGCACAGAG ATGCCTTTTG TCTGTAGCCA 19 20
GAAGTGTGAG AATGTAATAG GCTCCTACAT CTGTAAGTGT GCCCCAGGCT ACCTCCGAGA 19 80
ACCAGATGGA AAGACCTGCC GGCAAAACAG TAACATCGAA CCCTATCTCA TT1TTAGCAA 2040
CCGTTACTAT TTGAGAAATT TAACTATAGA TGGCTATTTT TACTCCCTCA TCTTGGAAGG 2100
ACTGGACAAT GTTGTGGCAT TAGATTTTGA CCGAGTAGAG AAGAGATTGT ATTGGATTGA 2160
TACACAGAGG CAAGTCATTG AGAGAATGTT TCTGAATAAG ACAAACAAGG AGACAATCAT 22 20
AAACCACAGA CTACCAGCTG CAGAAAGTCT GGCTGTAGAC 1~G~111CCA GAAAGCTCTA 2 280
CTGGTTGGAT GCCCGCCTGG ATGGCCTCTT 1~1~1~1~AC CTCAATGGTG GACACCGCCG 2340
CATGCTGGCC CAGCACTGTG TGGATGCCAA CAACACCTTC TGCTTTGATA ATCCCAGAGG 2 400
ACTTGCCCTT CACCCTCAAT ATGGGTACCT CTACTGGGCA GACTGGGGTC ACCGCGCATA 2460
CATTGGGAGA GTAGGCATGG ATGGAACCAA CAALT~1~1L~ ATACTCCACC AAGTTAGAGT . 2520
TGGCCTAATG GCATCACCAT TGATTACACC AATGATCTAC TCTACTGGGC AGATGCCACC 2580
CTGGGTTACA TAGAGTACTC TGATTTGGAG GGCCACCATC GACACACGGT GTATGATGGG 2640
GCACTGCCTC ACCCTTTCGC TATTACCATT TTTGAAGACA CTATTTATTG GACAGATTGG 2700
AATACAAGGA CAGTGGAAAA GGGAAACAAA TATGATGGAT CAAATAGACA GACACTGGTG 2760
AACACAACAC ACAGACCATT TGACATCCAT GTGTACCATC CATATAGGCA GCCCGTACCA 2820
TCCATATAGG CAGCCCATTG TGAGCAATCC CTGTGGTACC AACAATGGTG GL'1'L'1''1'L"1'CA 2880
CA 0220~648 1997-0~-20
W O9611S801 PCTrUS95/15203
TCTCTGCCTC ATCAAGCCAG GAGGAAAAGG GTTCACTTGC GAGTGTCCAG ATGACTTCCG 2940
CACCCTTCAA CTGAGTGGCA GCACCTACTG CATGCCCATG TGCTCCAGCA CCCAGTTCCT 3000
GTGCGCTAAC AATGAAAAGT GCATTCCTAT CTGGTGGAAA TGTGATGGAC AGAAAGACTG 3060
CTCAGATGGC TCTGATGAAC TGGCCCTTTG CCCGCAGCGC TTCTGCCGAC TGGGACAGTT 3120
0 CCAGTGCAGT GACGGCAACT GCACCAGCCC GCAGACTTTA TGCAATGCTC ACCAAAATTG 3180
CCCTCGATGG TCTGATGAAG ACC~'l'~"l"l'~l' TTGTGAGAAT CACCACTGTG ACTCCAATGA . 3240
ATGGCAGTGC GCCAACAAAC GTTGCATCCC AGAATCCTGG CAGTGTGACA CATTTAACGA 3300
CTGTGAGGAT AACTCAGATG AAGACAGTTC CCACTGTGCC AGCAGGACCT GCCGGCCGGG 3360
CCA~lllCGG TGTGCTAATG GCCGCTGCAT CCCGCAGGCC TGGAAGTGTG ATGTGGATAA 3420
20 TGATTGTGGA GACCACTCGG ATGAGCCCAT TGAAGAATGC ATGAGCTCTG CCCATCTCTG 3480
TGACAACTTC ACAGAATTCA GCTGCAAAAC AAATTACCGC TGCATCCCAA AGTGGGCCGT 3540
GTGCAATGGT GTAGATGACT GCAGGGACAA CAGTGATGAG CAAGG~l~lG AGGAGAGGAC 3600
ATGCCATCCT GTGGGGGATT TCCGCTGTAA AACTCACCAC TGCATCCCTC ll~ll~GCA 3660
GTGTGATGGG CAAAATGACT GTGGAGATAA CTCAGATGAG GAAAACTGTG CTCCCCGGGA 3720
30 GTGCACAGAG AGCGAGTTTC GATGTGTCAA TCAGCAGTGC ATTCCCTCGC GATGGATCTG 3780
TGACCATTAC AACGACTGTG GGGACAACTC AGATGAACGG GACTGTGAGA TGAGGACCTG 3840
CCATCCTGAA T~TTTTCAGT GTACAAGTGG ACA'll~l~lA CACAGTGAAC TGAAATGCGA 3900
TGGATCCGCT GA~l~'l"l"l~G ATGCGTCTGA TGAAGCTGAT TGTCCCACAC GCTTTCCTGA 3960
TGGTGCATAC TGCCAGGCTA CTATGTTCGA ATGCAAAAAC CA'l~'l"l"l~'l'A TCCCGCCATA 4020
40 TTGGAAATGT GATGGCGATG ATGACTGTGG CGATGGTTCA GATGAAGAAC TTCACCTGTG 4080
CTTGGATGTT CCCTGTAATT CACCAAACCG TTTCCGGTGT GACAACAATC GCTGCATTTA 4140
TAGTCATGAG GTGTGCAATG GTGTGGATGA CTGTGGAGAT GGAACTGATG AGACAGAGGA 4200
GCACTGTAGA AAACCGACCC CTAAACCTTG TACAGAATAT GAATATAAGT GTGGCAATGG 4260
GCATTGCATT CCACATGACA Al'~'l'~'l~l'~A TGATGCCGAT GACTGTGGTG ACTGGTCCGA 4320
50 TGAACTGGGT TGCAATAAAG GAAAAGAAAG AACATGTGCT GAAAATATAT GCGAGCAAAA 4380
, TTGTACCCAA TTAAATGAGG AGGATTTATC TGCTCCTGTA CAG~l~ll CGAAACCAAT 4440
~l"l"l"l"l"l~AC AGAACCTCCT GTCTAGATAT CAATGAATGT GAACAATTTG GGACTTGTCC 4500
- CCAGCACTGC AGAAATACCA AAGGAAGTTA TGA~'l~'l'~'l'C 'l'~'lG~l'~ATG GCTTCACGTC 4560
TATGAGTGAC CGCCCTGGAA AACGATGTGC AGCTGAGGGT AGCTCTCCTT TGTTGCTACT 4620
GCCTGACAAT GTCCGAATTC GAAAATATAA TCTCTCATCT GAGAGGTTCT CAGAGTATCT 4680
TCAAGATGAG GAATATATCC AAGCTGTTGA TTATGATTGG GATCCCAAGG ACATAGGCCT 4740
CA~l~ll~l~ TATTACACTG TGCGAGGGGA GGGCTCTAGG lll~'l'~CTA TCAAACGTGC 480C
CA 0220~648 1997-0~-20
WO 96/15801 PCT/US95/15203
~y
CTACATCCCC AACTTTGAAT CCGGCCGCAA TAAl~ll~lG CAGGAAGTTG ACCTGAAACT 4860
GAAATACGTA ATGCAGCCAG ATGGAATAGC AGTGGACTGG GTTGGAAGGC ATATTTACTG 4920
GTCAGATGTC AAGAATAAAC GCATTGAGGT GGCTAAACTT GATGGAAGGT ACAGAAAGTG 4980
GCTGATTTCC ACTGACCTGG ACCAACCAGC TGCTATTGCT- GTGAATCCCA AACTAGGGCT 5040
TA~ GG ACTGACTGGG GAAAGGAACC TAAAATCGAG TCTGCCTGGA TGAATGGAGA 5100
GGACCGCAAC ATC~T~'l"l"l' TCGAGGACCT TGGTTGGCCA ACTGGCCTTT CTATCGATTA 5160
TTTGAACGAC CGAATCTACT GGAGTGACTT CAAGGAGGAC GTTATTGAAA CCATAAAATA 5220
TGATGGGACT GATAGGAGAG TCATTGCAAA Gr~AAr~r~ATG AACCCTTACA GCCTGGACAT 5280
CTTTGAAGAC CAGTTATACT GGATATCTAA GGAAAAGGGA GAAGTATGGA AACAAAATAA 5340
ATTTGGGCAA GGAAAGAAAG AGAAAACGCT GGTAGTGAAC CCTTGGCTCA CTCAAGTTCG 5400
AATCTTTCAT CAACTCAGAT ACAATAAGTC AGTGCCCAAC CTTTGCAAAC AGATCTGCAG 5460
CCACCTCTGC CTTCTGAGAC CTGGAGGATA CAGCTGTGCC TGTCCCCAAG GCTCCAGCTT 5520
TATAGAGGGG AGCACCACTG AGTGTGATGC AGCCATCGAA CTGCCTATCA ACCTGCCCCC 5580
CCCATGCAGG TGCATGCACG GAGGAAATTG CTATTTTGAT GAGACTGACC TCCCCAAATG 5640
CAA~l~lC~l AGCGGCTACA CCGGAAAATA TTGTGAAATG GC~llll~AA AAGGCATCTC 5700
TCCAGGAACA ACCGCAGTAG CTGTGCTGTT GACAATCCTC TTGATCGTCG TAATTGGAGC 5760
TCTGGCAATT GCAGGATTCT TCCACTATAG AAGGACCGGC TCCCTTTTGC CTGCTCTGCC 5820
CAAGCTGCCA AGCTTAAGCA ~ L~cAA GCCCTCTGAA AATGGGAATG GGGTGACCTT 5880
CAGATCAGGG GCAGATCTTA ACATGGATAT TGGAGTGTCT G~ l"l~GAC CTGAGACTGC 5940
TATTGACAGG TCAATGGCAA TGAGTGAAGA Clll~rCATG GAAATGGGGA AGCAGCCCAT 6000
AATATTTGAA AACCCAATGT ACTCAGCCAG AGACAGTGCT GTCAAAGTGG TTCAGCCAAT 6060
CCAGGTGACT GTATCTGAAA ATGTGGATAA TAAGAATTAT GGAAGTCCCA TAAACCCTTC 6120
TGAGATAGTT CCAGAGACAA ACCCAACTTC ACCAGCTGCT GATGGAACTC AGGTGACAAA 6180
ATGGAATCTC TTCAAACGAA AATCTAAACA AACTACCAAC TTTGAAAATC CAATCTATGC 6240
ACAGATGGAG AACGAGCAAA AGGAAAGTGT TGCTGCGACA CCACCTCCAT CACCTTCGCT 6300
CCCTGCTAAG CCTAAGCCTC CTTCGAGAAG AGACCCAACT CCAACCTATT CTGCAACAGA 6360
AGACACTTTT AAAGACACCG CAAATCTTGT TAAAGAAGAC TCTGAAGTAT AG 6412
(2) INFORMATION FOR SEQ ID NO:18:
(i) SEOUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
CA 0220~648 l997-0~-20
WO 96115801 PCTIUS95/15203
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
" .
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:
Ala Thr Pro Pro Pro.Ser Pro Ser Leu Pro Ala Lys Pro Lys Pro Pro
1 5 . 10 15
Ser Arg Arg
(2) INFORMATION FOR SEQ ID NO:19:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 12 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQU~NCE DESCRIPTION: SEQ ID NO:19:
Phe Glu Asn Pro Ile Tyr Ala Gln Met Glu Asn Glu
1 5 10
~2) INFORMATION FOR SEQ ID NO:20:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 9 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:
Arg Xaa Leu Pro Pro Arg Pro Xaa Xaa
(2) INFORMATION FOR SEQ ID NO:21:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 9 amino acids
CA 02205648 1997-05-20
Wo 96/15801 PCT/US95/15203
(B) TYPE: amino acid
(C) STRAN~N~:SS:
(D) TOPOLOGY: llnear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
0
(ix) FEATURE:
(A) NAME/KEY: Modified-site
(B) LOCATION: 9
(D) OTHER INFORMATION: /label= hydrophobic
(xi) ~Q~N~: DESCRIPTION: SEQ ID NO:21:
Arg Xaa Leu Pro Pro Leu Pro Arg Xaa
1 5
(2) INFORMATION FOR SEQ ID NO:22:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 11 amino acids
(B) TYPE: amino acid
(C) STRAh~:~h~:SS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:
Pro Thr Met Pro Pro Pro Leu Pro Pro Val Pro
l 5 10
(2) INFORMATION FOR SEQ ID NO:23:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 11 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
. (ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:
Pro Ala Tyr Pro Pro Pro Pro Val Pro Val Pro
CA 0220~648 1997-0~-20
W O 96/15801 PCTrUS95/15203
l 5 170
(2) INFORMATION FOR SEQ ID NO:24:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:
Glu Val Pro Val Pro Pro Pro Val Pro Pro Arg
l 5 l0
(2) INFORMATION FOR SEQ ID NO:25:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:
His Leu Asp Ser Pro Pro Ala Ile Pro Pro Arg
l 5 l0
(2) INFORMATION FOR SEQ ID NO:26:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY.: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:
CA 0220~648 1997-0~-20
W O96/15801 PCT/US951152Q3
His Ser Ile Ala Gly Pro Pro Val Pro Pro Arg
l 5 l0
(2) INFORMATION FOR SEQ ID NO:27:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) sTRA~n~n~s
(D) TOPOLOGY: linear
(ii) MO~ECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:
Ala Pro Ala Val Pro Pro Ala Arg Pro Gly Ser
l 5 l0
(2) INFORMATION FOR SEQ ID NO:28:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRAN~:~N~:SS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:
Gly Ala Pro Pro Val Pro Ser Arg Pro Gly Ala
l 5 l0
(2) INFORMATION FOR SEQ ID NO:29:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
CA 0220~648 1997-0~-20
W O96/1~801 PCTrUS95/15203
~7
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:
Pro Pro Arg Pro Leu Pro Val Ala Pro Gly Ser
l 5 l0
(2) INFORMATION FOR SEQ ID NO:30:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:
Pro Ala Pro Ala Leu Pro Pro Lys Pro Pro Lys
l ' 5 l0
(2) INFORMATION FOR SEQ ID NO:3l:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C; STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:3l:
Ala Pro Lys Pro Met Pro Pro Arg Pro Pro Leu
l 5 l0
(2) INFORMATION FOR SEQ ID NO:32:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRl~GMENlr TYPE: internal
CA 0220~648 1997-0~-20
W O96115801 . PCT/US95/15203
6~
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: v
Pro Pro Thr Pro Pro Pro Leu Pro Pro Pro Leu
l 5 l0
~2) INFORMATION FOR SEQ ID NO:33:
.(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
. (C) STRANV~:~N~SS:
15. (D) TOPOLOGY: li~ear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:
Pro Ala Leu Pro Pro Pro Pro Arg Pro Val Pro
l 5 l0
(2) INFORMATION FOR SEQ ID NO:34:
(i) SEQUENCE CHARACTERISTICS:
(A! LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:
Arg Pro Arg Pro Leu Pro Pro Leu Pro Pro Thr
l 5 l0
(2) INFORMATION FOR SEQ ID NO:35:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
. CA 02205648 1997-05-20
W O 96/15801 PCTAUS95/15203
G/
(v) FRAGMENT TYPE: internal
(xi) ~:yu~:N~ DESCRIPTION: SEQ ID NO:35:
Gly Val Arg Pro Leu Pro Pro Leu Pro Asp Pro
l 5 l0
(2) INFORMATION FOR SEQ ID NO:36:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STR~NV~v~SS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:
30 Pro Pro Arg Pro Leu Pro Pro Arg Pro Pro Ala
. l 5 l0
(2) INFORMATION FOR SEQ ID NO:37:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7 amino acids
(B) TYPE: amino acid
(C) STRANv~V~:SS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(ix) FEATURE:
(A) NAME/~EY: Modified-site
(B) LOCATION: 3
(D) OTHER INFORMATION: /label= hydrophobic
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:5
Xaa Pro Xaa Pro Pro Xaa Pro
l 5
(2) INFORMATION FOR SEQ ID NO:38:0
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 22 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
CA 02205648 1997-05-20
W O9611S801 PCTrUS9S/15203
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:
Glu Ser Asp Gly Gly Tyr Met Asp Met Ser Lys Asp Glu Ser Val Asp
l 5 l0 15
Tyr Val Pro Met Leu Asp
(2) INFORMATION FOR SEQ ID NO:39:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 amino acids
(B) TYPE: ~mino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:
Glu Glu Glu Glu Glu Tyr Met Pro Met Glu Asp Leu Tyr Leu Asp Ile
1 5 l0 15
Leu Pro
(2) INFORMATION FOR SEQ ID NO:40:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 11 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide L
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:
Gln Gly Val Asp Thr Tyr Val Glu ~et Arg Pro
CA 02205648 1997-05-20
W O96/15801 . PCT~US95/15203
63
1 5 10
(2) INFORMATION FOR SEQ ID NO:41:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 11 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
.(iii) HYPOTHETICAL: NO
15 . (v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:
Asp Ser Thr Asn Glu Tyr Met Asp Met Lys Pro
(2) INFORMATION FOR SEQ ID NO:42:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 24 amino acids
(B) TYPE: amino acid
(C~ STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:
Gly Pro Gly Gly Asp Tyr Ala Ala Met Gly Ala Cys Pro Ala Ser Glu
1 5 10 15
Gln Gly Tyr Glu Glu Met Arg Ala
(2) INFORMATION FOR SEQ ID NO:43:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 27 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
- (D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
CA 02205648 1997-05-20
W O96/15801 PCTrUS9S115203
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:
5 Thr Pro Asp Glu Asp Tyr Glu Tyr Met Asn Arg Gln Arg Asp Gly Gly
l 5 l0 15
Gly Pro Gly Gly Asp Tyr Ala Ala Met Gly Ala
t2) INFORMATION FOR SEQ ID NO:44:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
~C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:
30 Cys Thr Ile Asp Val Tyr Met Val Met Val Lys
l 5 l0
(2) INFORMATION FOR SEQ ID NO:45:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: ~mino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
50 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:
Ser Pro Ser Ser Gly Tyr Met Pro Met Asn Gln
l 5 l0
(2) INFORMATION FOR SEQ ID NO:46:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
. (B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
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(iii) HYPOTHETICAL: NO 66
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:
Asp Glu Asp Glu Glu Tyr Glu Tyr Met Asn Arg
l 5 l0
(2) INFORMATION FOR SEQ ID NO:47:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRA~n~N~.~S:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
~iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:
Leu Glu Glu Leu Gly Tyr Glu Tyr Met Asp Val
l 5 l0
(2) INFORMATION FOR SEQ ID NO:48:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:
Glu Glu Leu Ser Asn Tyr Ile Cys Met Gly Gly
l 5 l0
(2) INFORMATION FOR SEQ ID NO:49:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
CA 0220~648 1997-0~-20
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~6
(ii) MOLECULE TYPE: peptide
. (iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:
Val Ser Ile Glu Glu Tyr Thr Glu Met Met Pro
1 5 10
15 . (2) INFORMATION FOR SEQ ID NO:50:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 11 amino acids
(B) TYPE: amino acid
2 0 (C) STRAN~h:~N~:SS:
(D) TOPO~OGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:
His Thr Asp Asp Gly Tyr Met Pro Met Ser Pro
1 5 10
(2) INFORMATION FOR SEQ ID NO:51:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 11 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:
Lys Gly Asn Gly Asp Tyr Met Pro Met Ser Pro
1 5 10
(2) INFORMATION FOR SEQ ID NO:52:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 11 amino acids
(B) TYPE: amino acid
( C ) STRANDEDNES S:
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(D) TOPOLOGY: linear 67
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
.(xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:
Val Asp Pro Asn Gly Tyr Met Met Met Ser Pro
l 5 l0
(2) INFORMATION FOR SEQ ID NO:53:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:
Pro Cys Thr Gly Asp Tyr Met Asn Met Ser Pro
l 5 l0
(2) INFORMATION FOR SEQ ID NO:54:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID No:54:
Thr Gly Ser Glu Glu Tyr Met Asn Met Asp Leu
(2) INFORMATION FOR SEQ ID NO:55:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
CA 02205648 1997-05-20
W O96/15801 . PCTrUS9Sl15203
(B) TYPE: amino acid
(C) STRA~ ~S:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:
Asn Ser Arg Gly Asp Tyr Met Thr Met Gln Ile
l 5 l0
(2) INFORMATION FOR SEQ ID NO:56:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: ~mino acid
(C) STRAh~:~N~SS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:
Val Ala Pro Val Ser Tyr Ala Asp Met Arg Thr
l 5 l0
(2) INFORMATION FOR SEQ ID NO:57:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal L
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:
60 Glu Arg Glu Asn Glu Tyr Met Pro Met Ala Pro Gln Ile His Leu Tyr
l 5 l0 15
Ser Gln Ile Arg Glu
CA 02205648 1997-05-20
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6q
(2) INFORMATION FOR SEQ ID NO:58:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANV~VN~:SS:
(D~ TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:
Leu Ser Asn Pro Thr Tyr Ser Val Met Arg Ser
l 5 l0
(2) INFORMATION FOR SEQ ID NO:59:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRA~ SS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:
Cys Pro Glu Lys Val Tyr Glu Leu Met Arg Ala
l 5 l0
(2) INFORMATION FOR SEQ ID NO:60:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:60:
CA 02205648 1997-05-20
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7~
Asn Thr Thr Val Asp Tyr Val Tyr Met Ser His Gly Asp Asn Gly Asp
l 5 l0 15
Tyr Val Tyr Met Asn
(2) INFORMATION FOR SEQ ID NO:61:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
. (D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:61:
Asn Cys Asn Asp Asp Tyr Val Thr Met His Tyr Thr Thr Asp Gly Asp
l 5 l0 15
Tyr Ile Tyr Met Asn
(2) INFORMATION FOR SEQ ID NO:62:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 27 amino acids
(B) TYPE: amino acid
(C) STRAN~N~:SS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:62:0
Tyr Val Asn Asp Ile Tyr Leu Tyr Met Arg His Lçu Glu Arg Glu Phe
l 5 l0 15
Lys Val Arg Thr Asp Tyr Met Ala Met Gln Glu
(2) INFORMATION FOR SEQ ID NO:63:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
CA 02205648 1997-05-20
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q~
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:63:
Asn Gln Glu Glu Ala Tyr Val Thr Met Ser Ser
l 5 l0
(2) INFORMATION FOR SEQ ID NO:64:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRA~ VN~:SS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:64:
Phe Ile Ala Ser Lys Tyr Glu Asp Met Tyr Pro
l 5 l0
(2) INFORMATION FOR SEQ ID NO:65:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: &mino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
.
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:65:
Leu Gly Ser Gln Ser Tyr Glu Asp Met Arg Gly
l 5 l0
(2) INFORMATION FOR SEQ ID NO:66:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino ~cids
(B) TYPE: amino acid
(C) STRANDEDNESS:
CA 02205648 1997-05-20
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7;~
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:66:
Glu Asp Ala Asp Ser Tyr Glu Asn Met Asp Lys
l 5 l0
(2) INFORMATION FOR SEQ ID NO:67:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQIJENCE DESCRIPTION: SEQ ID NO:67:
Glu Leu Gln Asp Asp Tyr Glu Asp Met Met Glu
l 5 l0
(2) INFORMATION FOR SEQ ID NO:68:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:68:
Ala Ala Cys Val Val Tyr Glu Asp Met Ser His
l 5 l0
(2) INFORMATION FOR SEQ ID NO:69:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
CA 02205648 1997-05-20
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73
(B) TYPE: amino acid
(C) STRANDEDNESS:
tD) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:69:
Ala Pro Pro Glu Glu Tyr Val Pro Met Val Lys
l 5 l0
(2) INFORMATION FOR SEQ ID NO:70:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:70:
Ile Asp Ser Cys Thr Tyr Glu Ala Met Tyr Asn
l 5 l0
(2) INFORMATION FOR SEQ ID NO:7l:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:71:
Val Ala Val Ala Glu Tyr Glu Ile Met Glu Gln
l 5 l~
(2) INFORMATION FOR SEQ ID NO:72:
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7 Y
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii~ HYPOTHETICAL: NO
. . (v) FRAGMENT TYPE: internal
(xi~ SEQUENCE DESCRIPTION: SEQ ID NO:72:
Met Ser Val Glu Ser Tyr Glu Glu Met Lys Met
l 5 l0
(2) INFOR~ATION FOR SEQ ID NO:73:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: ~mino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:73:
His Gln Thr Arg Glu Tyr Glu Ser Met Ile Glu
l 5 l0
(2) INFORMATION FOR SEQ ID NO:74:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRAN~N~:SS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:74:
Thr Leu Gln Asn Glu Tyr Glu Leu Met Arg Glu
l 5 l0
CA 02205648 1997-05-20
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(2) INFORMATION FOR SEQ ID NO:75:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 11 amino acids
(B) TYPE: amino acid
(C) STRANV~VN~SS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE:- peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:75:
Gly Gly Glu Glu Ile Tyr Val Val Met Leu Gly
1 5 10
(2) INFORMATION FOR SEQ ID NO:76:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 11 amino acids
(B) TYPE: amino acid
(C) sTRANn~n~s:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAh: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:76:
Leu Glu Gly Glu His Tyr Ile Asn Met Ala Val
1 5 10
(2) INFORMATION FOR SEQ ID NO:77:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 11 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MO~ECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:77:
Glu Ile Thr Glu Gln Tyr Ile Tyr Met Val Met
CA 02205648 1997-05-20
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~6
l 5 l0
(2) INFORMATION FOR SEQ ID NO:78:
(i) SEQUENCE CHARACTERISTICS:
(A) ~ENGTH: ll amino acids
(B) TYPE: amino acid
(C) STRANV~:~N~:SS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE:.peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
20 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78:
Thr Glu Gln Tyr Ile Tyr Met Val Met Glu Cys
l 5 l0
(2) INFORMATION FOR SEQ ID NO:79:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5 amino acids
(B) TYPE: amino acid
(C) sTRA~n~n~s
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:79:
Leu Pro Ala Lys Pro
l 5
(2) INFORMATION FOR SEQ ID NO:80:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:80:
CA 0220~648 l997-0~-20
W O96/15801 PCT~US95/15203
Leu Pro Ala Leu Pro
1 5
(2) INFORMATION FOR SEQ ID NO:81:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 5 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(il) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO ~
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:81:
Leu Pro Lys Leu Pro
1 5
(2) INFORMATION FOR SEQ ID NO:82:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 11 amino acids
(B) TYPE: amino acid
(C) STRAN~N~:SS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(iii) HYPOTHETICAL: NO
(v) FRAGMENT TYPE: internal
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:82:
Glu Asn Pro Ile Tyr Ala Gln Met Glu Asn Glu
1 5 10
(2) INFORMATION FOR SEQ ID NO:83:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14086 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(vi) ORIGINAL SOURCE:
(A) ORGANISM: Homo sapiens
CA 0220~648 l997-0~-20
WO 96/15801 - PCT/US95/15203
( ix ) FEATURE:
~ A ) NA~E / KEY: CDS
(B) LOCATION: 107. .14074
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:83:
TTGCAGACCT AAAGGAGCGT TCGCTAGCAG AGGCGCTGCC GGTGCGGTGT GCTACGCGCG 60
CCCACCTCCC GGGGAAGGAA CGGCGAGGCC GGGGACCGTC GCGGAG ATG GAT CGC 115
Met Asp Arg
GGG CCG GCA GCA GTG GCG TGC ACG CTG CTC CTG GCT CTC GTC GCC TGC 163
Gly Pro Ala Ala Val Ala Cys Thr Leu Leu Leu Ala Leu Val Ala Cys
950 955 960
CTA GCG CCG GCC AGT GGC CAA GAA TGT GAC AGT GCG CAT TTT CGC TGT 211
2 0 Leu Ala Pro Ala Ser Gly Gln Glu Cys Asp Ser Ala His Phe Arg Cys
965 970 975 980
GGA AGT GGG CAT TGC ATC CCT GCA GAC TGG AGG TGT GAT GGG ACC AAA 259
Gly Ser Gly His Cys Ile Pro Ala Asp Trp Arg Cys Asp Gly Thr Lys
985 990 995
GAC TGT TCA GAT GAC GCG GAT GAA ATT GGC TGC GCT GTT GTG ACC TGC 307
Asp Cys Ser Asp Asp Ala Asp Glu Ile Gly Cys Ala Val Val Thr Cys
1000 1005 1010
CAG CAG GGC TAT TTC AAG TGC CAG AGT GAG GGA CAA TGC ATC CCC AGC 355
Gln Gln Gly Tyr Phe Lys Cys Gln Ser Glu Gly Gln Cys Ile Pro Ser
1015 1020 1025
3 5 TCC TGG GTG TGT GAC CAA GAT CAA GAC TGT GAT GAT GGC TCA GAT GAA 403
Ser Trp Val Cys Asp Gln Asp Gln Asp Cys Asp Asp Gly Ser Asp Glu
1030 1035 1040
CGT CAA GAT TGC TCA CAA AGT ACA TGC TCA AGT CAT CAG ATA ACA TGC 451
Arg Gln Asp Cys Ser Gln Ser Thr Cys Ser Ser His Gln Ile Thr Cys
1045 1050 1055 1060
TCC AAT GGT CAG TGT ATC CCA AGT GAA TAC AGG TGC GAC CAC GTC AGA 4 g 9
Ser Asn Gly Gln Cys Ile Pro Ser Glu Tyr Arg Cys Asp His Val Arg
1065 1070 1075
GAC TGC CCC GAT GGA GCT GAT GAG AAT GAC TGC CAG TAC CCA ACA TGT 547
Asp Cys Pro Asp Gly Ala Asp Glu Asn Asp Cys Gln Tyr Pro Thr Cys
1080 1085 1090
GAG CAG CTT ACT TGT GAC AAT GGG GCC TGC TAT AAC ACC AGT CAG AAG 595
Glu Gln Leu Thr Cys Asp Asn Gly Ala Cys Tyr Asn Thr Ser Gln Lys
1095 1100 1105
TGT GAT TGG AAA GTT GAT TGC AGG GAC TCC TCA GAT GAA ATC AAC TGC 643
Cys Asp Trp Lys Val Asp Cys Arg Asp Ser Ser Asp Glu Ile Asn Cys
1110 1115 1120
ACT GAG ATA TGC TTG CAC AAT GAG TTT TCA TGT GGC AAT GGA GAG TGT 691
Thr Glu Ile Cys Leu His Asn Glu Phe Ser Cys Gly Asn Gly Glu Cys
1125 1130 1135 1140
ATC CCT CGT GCT TAT GTC TGT GAC CAT GAC AAT GAT TGC CAA GAC GGC 739
Ile Pro Arg Ala Tyr Val Cys Asp His Asp Asn Asp Cys Gln Asp Gly
CA 0220~648 l997-0~-20
WO 96115801 . PCTrUS95/15203
7q
1145 llSo 1155
AGT GAT GAA CAT GCT TGC AAC TAT CCG ACC TGC GGT GGT TAC CAG TTC 787
Ser Asp Glu His Ala Cys Asn Tyr Pro Thr Cys Gly Gly Tyr Gln Phe
1160 1165 1170
ACT TGC CCC AGT GGC CGA TGC ATT TAT CAA AAC TGG GTT TGT GAT GGA 8 35
Thr Cys Pro Ser Gly Arg Cys Ile Tyr Gln Asn Trp Val Cys Asp Gly
1175 1180 1185
GAA GAT GAC TGT AAA GAT AAT GGA GAT GAA GAT GGA TGT GAA AGC GGT 883
Glu Asp Asp Cys Lys Asp Asn Gly Asp Glu Asp Gly Cys Glu Ser Gly
ll9o 1195 1200
CCT CAT GAT GTT CAT AAA TGT TCC CCA AGA GAA TGG TCT TGC CCA GAG 931
Pro His Asp Val His Lys Cys Ser Pro Arg Glu Trp Ser Cys Pro Glu
1205 1210 1215 1220
TCG GGA CGA TGC ATC TCC ATT TAT AAA GTT TGT GAT GGG ATT TTA GAT 9 7 9
Ser Gly Arg Cys Ile Ser Ile Tyr Lys Val Cys Asp Gly Ile Leu Asp
1225 1230 1235
TGC CCA GGA AGA GAA GAT GAA AAC AAC ACT AGT ACC GGA AAA TAC TGT 1027
Cys Pro Gly Arg Glu Asp Glu Asn Asn Thr Ser Thr Gly Lys Tyr Cys
1240 1245 1250
AGT ATG ACT CTG TGC TCT GCC TTG AAC TGC CAG TAC CAG TGC CAT GAG 1075
Ser Met Thr Leu Cys Ser Ala Leu Asn Cys Gln Tyr Gln Cys His Glu
1255 1260 1265
ACG CCG TAT GGA GGA GCG TGT TTT TGT CCC CCA GGT TAT ATC ATC AAC 1123
Thr Pro Tyr Gly Gly Ala Cys Phe Cys Pro Pro Gly Tyr Ile Ile Asn
1270 1275 1280
CAC AAT GAC AGC CGT ACC TGT GTT GAG TTT GAT GAT TGC CAG ATA TGG 1171
His Asn Asp Ser Arg Thr Cys Val Glu Phe Asp Asp Cys Gln Ile Trp
1285 1290 1295 1300
GGA ATT TGT GAC CAG AAG TGT GAA AGC CGA CCT GGC CGT CAC CTG TGC 1219
Gly Ile Cys Asp Gln Lys Cys Glu Ser Arg Pro Gly Arg His Leu Cys
1305 1310 1315
CAC TGT GAA GAA GGG TAT ATC TTG GAG CGT GGA CAG TAT TGC AAA GCT 12 6 7
His Cys Glu Glu Gly Tyr Ile Leu Glu Arg Gly Gln Tyr Cys Lys Ala
1320 1325 1330
AAT GAT TCC TTT GGC GAG GCC TCC ATT ATC TTC TCC AAT GGT CGG GAT 1315
Asn Asp Ser Phe Gly Glu Ala Ser Ile Ile Phe Ser Asn Gly Arg Asp
1335 1340 1345
TTG TTA ATT GGT GAT ATT CAT GGA AGG AGC TTC CGG ATC CTA GTG GAG 13 63
Leu Leu Ile Gly Asp Ile His Gly Arg Ser Phe Arg Ile Leu Val Glu
1350 I355 1360
TCT CAG AAT CGT GGA GTG GCC GTG GGT GTG GCT TTC CAC TAT CAC CTG 1411
- Ser Gln Asn Arg Gly Val Ala Val Gly Val Ala Phe His Tyr His Leu
365 1370 1375 1380
CAA AGA GTT TTT TGG ACA GAC ACC GTG CAA AAT AAG GTT TTT TCA GTT 14 59
Gln Arg Val Phe Trp Thr Asp Thr Val Gln Asn Lys Val Phe Ser Val
1385 1390 1395
GAC ATT AAT GGT TTA AAT ATC CAA GAG GTT CTC AAT GTT TCT GTT GAA 1507
Asp Ile Asn Gly Leu Asn Ile Gln Glu Val Leu Asn Val Ser Val Glu
CA 0220~648 l997-0~-20
WO 96/lS801 PCT/US95/1~203
1400 1405 1410
ACC CCA GAG AAC CTG GCT GTG GAC TGG GTT AAT AAT AAA ATC TAT CTA 1555
Thr Pro Glu Asn Leu Ala Val Asp Trp Val Asn Asn Lys Ile Tyr Leu
1415 1420 1425
GTG GAA ACC AAG GTC AAC CGC ATA GAT ATG GTA AAT TTG GAT GGA AGC 1603
Val G1U Thr Lys Val Asn Arg Ile Asp Met Val Asn Leu Asp Gly Ser Y
1430 1435 1440
TAT CGG GTT ACC CTT ATA ACT GAA AAC TTG GGG CAT CCT AGA GGA ATT 1651
Tyr Arg Val Thr Leu Ile Thr Glu Asn Leu C-ly His Pro Arg Gly Ile
. 1445 1450 1455 1460
GCC GTG GAC CCA ACT GTT GGT TAT TTA TTT TTC TCA GAT TGG GAG AGC 1699
Ala Val Asp Pro Thr Val Gly Tyr Leu Phe Phe Ser Asp Trp Glu Ser
1465 1470 1475
CTT TCT GGG GAA CCT AAG CTG GAA AGG GCA TTC ATG GAT GGC AGC AAC 1747
2 0 Leu Ser Gly Glu Pro Lys Leu Glu Arg Ala Phe Met Asp Gly Ser Asn
1480 1485 1490
CGT AAA GAC TTG GTG AAA ACA AAG CTG GGA TGG CCT GCT GGG GTA ACT 1795
Arg Lys Asp Leu Val Lys Thr Lys Leu Gly Trp Pro Ala Gly Val Thr
1495 1500 1505
CTG GAT ATG ATA TCG AAG CGT GTT TAC TGG GTT GAC TCT CGG TTT GAT 1843
Leu Asp Met Ile Ser Lys Arg Val Tyr Trp Val Asp Ser Arg Phe Asp
1510 1515 1520
TAC ATT GAA ACT GTA ACT TAT GAT GGA ATT CAA AGG AAG ACT GTA GTT 1891
Tyr Ile Glu Thr Val Thr Tyr Asp Gly Ile Gln Arg Lys Thr Val Val
1525 1530 1535 1540
3 5 CAT GGA GGC TCC CTC ATT CCT CAT CCC TTT GGA GTA AGC TTA TTT GAA 1939
His Gly Gly Ser Leu Ile Pro His Pro Phe Gly Val Ser Leu Phe Glu
1545 1550 1555
GGT CAG GTG TTC TTT ACA GAT TGG ACA AAG ATG GCC GTG CTG AAG GCA 1987
Gly Gln Val Phe Phe Thr Asp Trp Thr Lys Met Ala Val Leu Lys Ala
1560 1565 1570
AAC AAG TTC ACA GAG ACC AAC CCA CAA GTG TAC TAC CAG GCT TCC CTG 2035
Asn Lys Phe Thr Glu Thr Asn Pro Gln Val Tyr Tyr Gln Ala Ser Leu
1575 1580 1585
AGG CCC TAT GGA GTG ACT GTT TAC CAT TCC CTC AGA CAG CCC TAT GCT 2083
Arg Pro Tyr Gly Val Thr Val Tyr His Ser Leu Arg Gln Pro Tyr Ala
1590 1595 1600
ACC AAT CCG TGT AAA GAT AAC AAT GGG GGC TGT GAG CAG GTC TGT GTT 2131
Thr Asn Pro Cys Lys Asp Asn Asn Gly Gly Cys Glu Gln Val Cys Val
1605 1610 1615 1620
5 5 CTC AGC CAC AGA ACA GAT AAT GAT GGT TTG GGT TTC CGT TGC AAG TGC 2179
Leu Ser His Arg Thr Asp Asn Asp Gly Leu Gly Phe Arg Cys Lys Cys
1625 1630 1635
ACA TTC GGC TTC CAA CTG GAT ACA GAT GAG CGC CAC TGC ATT GCT GTT 2227
Thr Phe Gly Phe Gln Leu Asp Thr Asp Glu Arg His Cys Ile Ala Val
1640 1645 1650
CAG AAT TTC CTC ATT TTT TCA TCC CAA GTT GCT ATT CGT GGG ATC CCG 2275
Gln Asn Phe Leu Ile Phe Ser Ser Gln Val Ala Ile Arg Gly Ile Pro
CA 0220~648 l997-0~-20
W O 96/15801 PCTIUS95/lS203
~1
1655 1660 1665
TTC ACC TTG TCT ACC CAG GAA GAT GTC ATG GTT CCA GTT TCG GGG AAT 2323
Phe Thr Leu Ser Thr Gln Glu Asp Val Met Val Pro Val Ser Gly Asn
1670 1675 1680
CCT TCT TTC TTT GTC GGG ATT GAT TTT GAC GCC CAG GAC AGC ACT ATC 2371
Pro Ser Phe Phe Val Gly Ile Asp Phe Asp Ala Gln Asp Ser Thr Ile
1685 1690 1695 1700
. . TTT TTT TCA GAT ATG TCA AAA CAC ATG ATT TTT AAG CAA AAG ATT GAT 2419
Phe Phe Ser Asp Met Ser Lys His Met Ile Phe Lys Gln Lys Ile Asp
1705 1710 1715
15 . GGC ACA GGA AGA GAA ATT CTC GCA GCT AAC AGG GTG GAA AAT GTT GAA 2467
Gly Thr Gly Arg Glu Ile Leu Ala Ala Asn Arg Val Glu Asn Val Glu
1720 1725 1730
AGT TTG GCT TTT GAT TGG ATT TCA AAG AAT CTC TAT TGG ACA GAC TCT 2515
20 Ser Leu Ala Phe Asp Trp Ile Ser Lys Asn Leu Tyr Trp Thr Asp Ser
1735 1740 1745
CAT TAC AAG AGT ATC AGT GTC ATG AGG CTA GCT GAT AAA ACG AGA CGC 2563
His Tyr Lys Ser Ile Ser Val Met Arg Leu Ala Asp Lys Thr Arg Arg
1750 1755 1760
ACA GTA GTT CAG TAT TTA AAT AAC CCA CGG TCG GTG GTA GTT CAT CCT 2611
Thr Val Val Gln Tyr Leu Asn Asn Pro Arg Ser Val Val Val His Pro
1765 1770 1775 1780
TTT GCC GGG TAT CTA TTC TTC ACT GAT TGG TTC CGT CCT GCT AAA ATT 2659
Phe Ala Gly Tyr Leu Phe Phe Thr Asp Trp Phe Arg Pro Ala Lys Ile
1785 1790 1795
35 ATG AGA GCA TGG AGT GAC GGA TCT CAC CTC TTG CCT GTA ATA AAC ACT 2707
Met Arg Ala Trp Ser Asp Gly Ser His Leu Leu Pro Val Ile Asn Thr
1800 1805 1810
ACT CTT GGA TGG CCC AAT GGC TTG GCC ATC GAT TGG GCT GCT TCA CGA 2755
40 Thr Leu Gly Trp Pro Asn Gly Leu Ala Ile Asp Trp Ala Ala Ser Arg
1815 1820 1825
TTG TAC TGG GTA GAT GCC TAT TTT GAT AAA ATT GAG CAC AGC ACC TTT 2803
Leu Tyr Trp Val Asp Ala Tyr Phe Asp Lys Ile Glu His Ser Thr Phe
1830 1835 1840
GAT GGT TTA GAC AGA AGA AGA CTG GGC CAT ATA GAG CAG ATG ACA CAT 2851
Asp Gly Leu Asp Arg Arg Arg Leu Gly His Ile Glu Gln Met Thr His
1845 1850 1855 1860
CCG TTT GGA CTT GCC ATC TTT GGA GAG CAT TTA TTT TTT ACT GAC TGG 2899
Pro Phe Gly Leu Ala Ile Phe Gly Glu His Leu Phe Phe Thr Asp Trp
1865 1870 1875
55 AGA CTG GGT GCC ATT ATT CGA GTC AGG AAA GCA GAT GGT GGA GAA ATG 2947
- Arg Leu Gly Ala Ile Ile Arg Val Arg Lys Ala Asp Gly Gly Glu Met
1880 1885 1890
ACA GTT ATC CGA AGT GGC ATT GCT TAC ATA CTG CAT TTG AAA TCG TAT 2995
60 Thr Val Ile Arg Ser Gly Ile Ala Tyr Ile Leu His Leu Lys Ser Tyr
1895 1900 1905
GAT GTC AAC ATC CAG ACT GGT TCT AAC GCC TGT AAT CAA CCC ACG CAT 3043
Asp Val Asn Ile Gln Thr Gly Ser Asn Ala Cys Asn Gln Pro Thr His
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
1910 1915 1920
CCT AAC GGT GAC TGC AGC CAC TTC TGC TTC CCG GTG CCA AAT TTC CAG 3091
Pro Asn Gly Asp Cys Ser His Phe Cys Phe Pro Val Pro Asn Phe Gln
1925 1930 1935 1940
CGA GTG TGT GGG TGC CCT TAT GGA ATG AGG CTG GCT TCC AAT CAC TTG 3139
Arg Val Cys Gly Cys Pro Tyr Gly Met Arg Leu Ala Ser Asn Hls Leu
1945 1950 1955
ACA TGC GAG GGG GAC CCA ACC AAT GAA CCA CCC ACG GAG CAG TGT GGC 3187
Thr Cys Glu Gly Asp Pro Thr .Asn Glu Pro Pro Thr Glu Gln Cys Gly
1960 1965 1970
TTA TTT TCC TTC CCC TGT AAA AAT GGC AGA TGT GTG CCC AAT TAC TAT 3235
Leu Phe Ser Phe Pro Cys Lys Asn Gly Arg Cys Val Pro Asn Tyr Tyr
1975 lg80 1985
CTC TGT GAT GGA GTC GAT GAT TGT CAT GAT AAC AGT GAT GAG CAA CTA 3283
2 0 Leu Cys Asp Gly Val Asp Asp Cys His Asp Asn Ser Asp Glu Gln Leu
1990 1995 2000
TGT GGC ACA CTT AAT AAT ACC TGT TCA TCT TCG GCG TTC ACC TGT GGC 3331
Cys Gly Thr Leu Asn Asn Thr Cys Ser Ser Ser Ala Phe Thr Cys Gly
2005 2010 2015 2020
CAT GGG GAG TGC ATT CCT GCA CAC TGG CGC TGT GAC AAA CGC AAC GAC 3379
His Gly Glu Cys Ile Pro Ala His Trp Arg Cys Asp Lys Arg Asn Asp
2025 2030 2035
TGT GTG GAT GGC AGT GAT GAG CAC AAC TGC CCC ACC CAC GCA CCT GCT 3427
Cys Val Asp Gly Ser Asp Glu His Asn Cys Pro Thr His Ala Pro Ala
2040 2045 2050
TCC TGC CTT GAC ACC CAA TAC ACC TGT GAT AAT CAC CAG TGT ATC TCA 3475
Ser Cys Leu Asp Thr Gln Tyr Thr Cys Asp Asn His Gln Cys Ile Ser
2055 2060 2065
AAG AAC TGG GTC TGT GAC ACA GAC AAT GAT TGT GGG GAT GGA TCT GAT 3523
4 0 Lys Asn Trp Val Cys Asp Thr Asp Asn Asp Cys Gly Asp Gly Ser Asp
2070 2075 2080
GAA AAG AAC TGC AAT TCG ACA GAG ACA TGC CAA CCT AGT CAG TTT AAT 3571
Glu Lys Asn Cys Asn Ser Thr Glu Thr Cys Gln Pro Ser Gln Phe Asn
2085 2090 2095 2100
TGC CCC AAT CAT CGA TGT ATT GAC CTA TCG TTT GTC TGT GAT GGT GAC 3619
Cys Pro Asn His Arg Cys Ile Asp Leu Ser Phe Val Cys Asp Gly Asp
2105 2110 2115
AAG GAT TGT GTT GAT GGA TCT GAT GAG GTT GGT TGT GTA TTA AAC TGT 3667
Lys Asp Cys Val Asp Gly Ser Asp Glu Val Gly Cys Val Leu Asn Cys
2120 2125 2130
5 5 ACT GCT TCT CAA TTC AAG TGT GCC AGT GGG GAT AAA TGT ATT GGC GTC 3715
Thr Ala Ser Gln Phe Lys Cys Ala Ser Gly Asp Lys Cys Ile Gly Val
2135 2140 2145
ACA AAT CGT TGT GAT GGT GTT TTT GAT TGC AGT GAC AAC TCG GAT GAA 3763
Thr Asn Arg Cys Asp Gly Val Phe Asp Cys Ser Asp Asn Ser Asp Glu
2150 2155 2160
GCG GGC TGT CCA ACC AGG CCT CCT GGT ATG TGC CAC TCA GAT GAA TTT 3811
Ala Gly Cys Pro Thr Arg Pro Pro Gly Met Cys His Ser Asp Glu Phe
CA 0220~648 l997-0~-20
WO 96/1580 l PCT/US95115203
~3
2165 2170 2175 2180
CAG TGC CAA GAA GAT GGT ATC TGC ATC CCG AAC TTC TGG GAA TGT GAT 3859
Gln Cys Gln Glu Asp Gly Ile Cys Ile Pro Asn Phe Trp Glu Cys Asp
2185 2190 2195
GGG CAT CCA GAC TGC CTC TAT GGA TCT GAT GAG CAC AAT GCC TGT GTC 3907
Gly His Pro Asp Cys Leu Tyr Gly Ser Asp G1U His Asn Ala Cys Val
2200 2205 2210
CCC AAG .ACT TGC CCT TCA .TCA TAT TTC CAC TGT GAC AAC GGA AAC TGC 3955
Pro Lys Thr Cys Pro Ser Ser Tyr Phe His Cys Asp Asn Gly Asn Cys
2215 2220 2225
1 5 ATC CAC AGG GCA TGG CTC TGT GAT CGG GAC AAT GAC TGC GGG GAT ATG 4003
Ile His Arg Ala Trp Leu Cys Asp Arg Asp Asn Asp Cys Gly Asp Met
2230 2235 2240
AGT GAT GAG AAG GAC TGC CCT ACT CAG CCC TTT CGC TGT CCT AGT TGG 4051
2 0 Ser Asp Glu Lys Asp Cys Pro Thr Gln Pro Phe Arg Cys Pro Ser Trp
2245 2250 2255 2260
CAA TGG CAG TGT CTT GGC CAT AAC ATC TGT GTG AAT CTG AGT GTA GTG 4099
Gln Trp Gln Cys Leu Gly His Asn Ile Cys Val Asn Leu Ser Val Val
2265 2270 2275
TGT GAT GGC ATC TTT GAC TGC CCC AAT GGG ACA GAT GAG TCC CCA CTT 4147
Cys Asp Gly Ile Phe Asp Cys Pro Asn Gly Thr Asp Glu Ser Pro Leu
2280 2285 2290
TGC AAT GGG AAC AGC TGC TCA GAT TTC AAT GGT GGT TGT ACT CAC GAG 4195
Cys Asn Gly Asn Ser Cys Ser Asp Phe Asn Gly Gly Cys Thr His Glu
2295 2300 2305
3 5 TGT GTT CAA GAG CCC TTT GGG GCT AAA TGC CTA TGT CCA TTG GGA TTC 4243
Cys Val Gln Glu Pro Phe Gly Ala Lys Cys Leu Cys Pro Leu Gly Phe
2310 2315 .2320
TTA CTT GCC AAT GAT TCT AAG ACC TGT GAA GAC ATA GAT GAA TGT GAT 4291
Leu Leu Ala Asn Asp Ser Lys Thr Cys Glu Asp Ile Asp Glu Cys Asp
2325 2330 2335 2340
ATT CTA GGC TCT TGT AGC CAG CAC TGT TAC AAT ATG AGA GGT TCT TTC 4339
Ile Leu Gly Ser Cys Ser Gln His Cys Tyr Asn Met Arg Gly Ser Phe
2345 2350 2355
CGG TGC TCG TGT GAT ACA GGC TAC ATG TTA GAA AGT GAT GGG AGG ACT 4387
Arg Cys Ser Cys Asp Thr Gly Tyr Met Leu Glu Ser Asp Gly Arg Thr
2360 2365 2370
TGC AAA GTT ACA GCA TCT GAG AGT CTG CTG TTA CTT GTG GCA AGT CAG 4435
Cys Lys Val Thr Ala Ser Glu Ser Leu Leu Leu Leu Val Ala Ser Gln
2375 2380 2385
AAC AAA ATT ATT GCC GAC AGT GTC ACC TCC CAG GTC CAC AAT ATC TAT 4483
Asn Lys Ile Ile Ala Asp Ser Val Thr Ser Gln Val His Asn Ile Tyr
2390 2395 2400
TCA TTG GTC GAG AAT GGT TCT TAC ATT GTA GCT GTT GAT TTT GAT TCA 4531
Ser Leu Val Glu Asn Gly Ser Tyr Ile Val Ala Val Asp Phe Asp Ser
2405 2410 2415 2420
ATT AGT GGT CGT ATC TTT TGG TCT GAT GCA ACT CAG GGT AAA ACC TGG 4579
Ile Ser Gly Arg Ile Phe Trp Ser Asp Ala Thr Gln Gly Lys Thr Trp
CA 0220~648 1997-0~-20
W O96/15801 . PCTfUS95/152Q3
~Y
2425 2430 2435
AGT GCG TTT CAA AAT GGA ACG GAC AGA AGA GTG GTA TTT GAC AGT AGC 4627
Ser Ala Phe Gln Asn Gly Thr Asp Arg Arg Val Val Phe Asp Ser Ser
2440 2445 2450
ATC ATC TTG ACT GAA ACT ATT GCA ATA GAT TGG GTA GGT CGT AAT CTT 4675
Ile Ile Leu Thr Glu Thr Ile Ala Ile Asp Trp Val Gly Arg Asn Leu
2455 2460 2465
- TAC TGG ACA GAC TAT GCT CTG GAA ACA ATT GAA GTC TCC AAA ATT GAT 4723
Tyr Trp Thr Asp Tyr Ala Leu Glu Thr Ile Glu Val Ser Lys Ile Asp
.2470 2475 2480
GGG AGC CAC AGG ACT GTG CTG ATT AGT AAA AAC CTA ACA AAT CCA AGA 4771
Gly Ser His Arg Thr Val Leu Ile Ser Lys Asn Leu Thr Asn Pro Arg
2485 2490 2495 2500
GGA CTA GCA TTA GAT CCC AGA ATG AAT GAG CAT CTA CTG TTC TGG TCT 4819
Gly Leu Ala Leu Asp Pro Arg Met Asn Glu His Leu Leu Phe Trp Ser
2505 2510 2515
GAC TGG GGC CAC CAC CCT CGC ATC GAG CGA GCC AGC ATG GAC GGC AGC 4867
Asp Trp Gly His His Pro Arg Ile Glu Arg Ala Ser Met Asp Gly Ser
2520 2525 2530
ATG CGC ACT GTC ATT GTC CAG GAC AAG ATC TTC TGG CCC TGC GGC TTA 4915
Met Arg Thr Val Ile Val Gln Asp Lys Ile Phe Trp Pro Cys Gly Leu
2535 2540 2545
ACT ATT GAC TAC CCC AAC AGA CTG CTC TAC TTC ATG GAC TCC TAT CTT 4963
Thr Ile Asp Tyr Pro Asn Arg Leu Leu Tyr Phe Met Asp Ser Tyr Leu
2550 2555 2560
3 5 GAT TAC ATG GAC TTT TGC GAT TAT AAT GGA CAC CAT CGG AGA CAG GTG 5011
Asp Tyr Met Asp Phe Cys Asp Tyr Asn Gly His His Arg Arg Gln Val
2565 2570 2575 2580
ATA GCC AGT GAT TTG ATT ATA CGG CAC CCC TAT GCC CTA ACT CTC TTT 5059
Ile Ala Ser Asp Leu Ile Ile Arg His Pro Tyr Ala Leu Thr Leu Phe
2585 2590 2595
GAA GAC TCT GTG TAC TGG ACT GAC CGT GCT ACT CGT CGG GTT ATG CGA 5107
Glu Asp Ser Val Tyr Trp Thr Asp Arg Ala Thr Arg Arg Val Met Arg
2600 2605 2610
GCC AAC AAG TGG CAT GGA GGG AAC CAG TCA GTT GTA ATG TAT AAT ATT 5155
Ala Asn Lys Trp His Gly Gly Asn Gln Ser Val Val Met Tyr Asn Ile
2615 2620 2625
CAA TGG CCC CTT GGG ATT GTT GCG GTT CAT CCT TCG AAA CAA CCA AAT 5203
Gln Trp Pro Leu Gly Ile Val Ala Val His Pro Ser Lys Gln Pro Asn
2630 2635 2640
TCC GTG AAT CCA TGT GCC TTT TCC CGC TGC AGC CAT CTC TGC CTG CTT 5251
Ser Val Asn Pro Cys Ala Phe Ser Arg Cys Ser His Leu Cys Leu Leu
2645 2650 2655 2660
TCC TCA CAG GGG CCT CAT TTT TAC TCC TGT GTT TGT CCT TCA GGA TGG 5299
Ser Ser Gln Gly Pro His Phe Tyr Ser Cys Val Cys Pro Ser Gly Trp
2665 2670 2675
AGT CTG TCT CCT GAT CTC CTG AAT TGC TTG AGA GAT GAT CAA CCT TTC 5347
Ser Leu Ser Pro Asp Leu Leu Asn Cys Leu Arg Asp Asp Gln Pro Phe
CA 0220~648 l997-0~-20
W O96/15801 PCT/US95/15203
2680 2685 2690
TTA ATA ACT GTA AGG CAA CAT ATA ATT TTT GGA ATC TCC CTT AAT CCT 5395
Leu Ile Thr Val Arg Gln His Ile Ile Phe Gly Ile Ser Leu Asn Pro
2695 2700 2705
GAG GTG AAG AGC AAT GAT GCT ATG GTC CCC ATA GCA GGG ATA CAG AAT 5443
Glu Val Lys Ser Asn Asp Ala Met Val Pro Ile Ala Gly Ile Gln Asn
. 2710 2715 2720
GGT TTA GAT GTT GAA TTT GAT GAT GCT GAG CAA TAC ATC TAT TGG GTT 5491
Gly Leu Asp Val Glu Phe Asp Asp Ala Glu Gln Tyr Ile Tyr Trp Val . .
2725 2730 2735 2740
15 GAA AAT CCA GGT GAA ATT CAC AGA GTG AAG ACA GAT GGC ACC AAC AGG 5539
Glu Asn Pro Gly Glu Ile His Arg Val Lys Thr Asp Gly Thr Asn Arg
2745 2750 2755
ACA GTA TTT GCT TCT ATA TCT ATG GTG GGG CCT TCT ATG AAC CTG GCC 5587
20 Thr Val Phe Ala Ser Ile Ser Met Val Gly Pro Ser Met Asn Leu Ala
2760 2765 2770
TTA GAT TGG ATT TCA AGA AAC CTT TAT TCT ACC AAT CCT AGA ACT CAG 5635
Leu Asp Trp Ile Ser Arg Asn Leu Tyr Ser Thr Asn Pro Arg Thr Gln
2775 2780 2785
TCA ATC GAG GTT TTG ACA CTC CAC GGA GAT ATC AGA TAC AGA AAA ACA 5683
Ser Ile Glu Val Leu Thr Leu His Gly Asp Ile Arg Tyr Arg Lys Thr
2790 2795 2800
TTG ATT GCC AAT GAT GGG ACA GCT CTT GGA GTT GGC TTT CCA ATT GGC 5731
Leu Ile Ala Asn Asp Gly Thr Ala Leu Gly Val Gly Phe Pro Ile Gly
2805 2810 2815 2820
35 ATA ACT GTT GAT CCT GCT CGT GGG AAG CTG TAC TGG TCA GAC CAA GGA 5779
Ile Thr Val Asp Pro Ala Arg Gly Lys Leu Tyr Trp Ser Asp Gln Gly
2825 2830 2835
ACT GAC AGT GGG GTT CCT GCC AAG ATC GCC AGT GCT AAC ATG GAT GGC 5827
40 Thr Asp Ser Gly Val Pro Ala Lys Ile Ala Ser Ala Asn Met Asp Gly
2840 2845 2850
ACA TCT GTG AAA ACT CTC TTT ACT GGG AAC CTC GAA CAC CTG GAG TGT 5875
Thr Ser Val Lys Thr Leu Phe Thr Gly Asn Leu Glu His Leu Glu Cys
2855 2860 2865
GTC ACT CTT GAC ATC GAA GAG CAG AAA CTC TAC TGG GCA GTC ACT GGA 5923
Val Thr Leu Asp Ile Glu Glu Gln Lys Leu Tyr Trp Ala Val Thr Gly
2870 2875 2880
AGA GGA GTG ATT GAA AGA GGA AAC GTG GAT GGA ACA GAT CGG ATG ATC 5971
Arg Gly Val Ile Glu Arg Gly Asn Val Asp Gly Thr Asp Arg Met Ile
2885 2890 2895 2900
55 CTG GTA CAC CAG CTT TCC CAC CCC TGG GGA ATT GCA GTC CAT GAT TCT 6019
Leu Val His Gln Leu Ser His Pro Trp Gly Ile Ala Val His Asp Ser
2905 2910 2915
TTC CTT TAT TAT ACT GAT GAA CAG TAT GAG GTC ATT GAA AGA GTT GAT 6067
60 Phe Leu Tyr Tyr Thr Asp Glu Gln Tyr Glu Val Ile Glu Arg Val Asp
2920 2925 2930
AAG GCC ACT GGG GCC AAC AAA ATA GTC TTG AGA GAT AAT GTT CCA AAT 6115
Lys Ala Thr Gly Ala Asn Lys Ile Val Leu Arg Asp Asn Val Pro Asn
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US9S/15203
~Ç;
2935 2940 2945
CTG AGG GGT CTT CAA GTT TAT CAC AGA CGC AAT GCC GCC GAA TCC TCA 6163
Leu Arg Gly Leu Gln Val Tyr His Arg Arg Asn Ala Ala Glu Ser Ser
2950 2955 2960
AAT GGC TGT AGC AAC AAC ATG AAT GCC TGT CAG CAG ATT TGC CTG CCT 6211
Asn Gly Cys Ser Asn Asn Met Asn Ala Cys Gln Gln Ile Cys Leu Pro
2965 297D 2975 2980
GTA CCA GGA GGA TTG TTT TCC TGC GCC TGT GCC ACT GGA TTT AAA CTC 6259
Val Pro Gly Gly Leu Phe Ser Cys Ala Cys Ala Thr Gly Phe Lys Leu
2985 2990 29g5
AAT CCT GAT AAT CGG TCC TGC TCT CCA TAT AAC TCT TTC ATT GTT GTT 6307
Asn Pro Asp Asn Arg Ser Cys Ser Pro Tyr Asn Ser Phe Ile Val Val
3000 3005 3010
TCA ATG CTG TCT GCA ATC AGA GGC TTT AGC TTG GAA TTG TCA GAT CAT 6355
Ser Met Leu Ser Ala Ile Arg Gly Phe Ser Leu Glu Leu Ser Asp His
3015 3020 3025
TCA GAA ACC ATG GTG CCG GTG GCA GGC CAA GGA CGA AAC GCA CTG CAT 6403
Ser Glu Thr Met Val Pro Val Ala Gly Gln Gly Arg Asn Ala Leu His
3030 3035 3040
GTG GAT GTG GAT GTG TCC TCT GGC TTT ATT TAT TGG TGT GAT TTT AGC 6451
Val Asp Val Asp Val Ser Ser Gly Phe Ile Tyr Trp Cys Asp Phe Ser
3045 3050 3055 3060
AGC TCA GTG GCA TCT GAT AAT GCG ATC CGT AGA ATT AAA CCA GAT GGA 6499
Ser Ser Val Ala Ser Asp Asn Ala Ile Arg Arg Ile Lys Pro Asp Gly
3065 3070 3075
3 5 TCT TCT CTG ATG AAC ATT GTG ACA CAT GGA ATA GGA GAA AAT GGA GTC 6547
Ser Ser Leu Met Asn Ile Val Thr His Gly Ile Gly Glu Asn Gly Val
3080 3085 3090
CGG GGT ATT GCA GTG GAT TGG GTA GCA GGA AAT CTT TAT TTC ACC AAT 6595
Arg Gly Ile Ala Val Asp Trp Val Ala Gly Asn Leu Tyr Phe Thr Asn
3095 3100 3105
GCC TTT GTT TCT GAA ACA CTG ATA GAA GTT CTG CGG ATC AAT ACT ACT 6643.
Ala Phe Val Ser Glu Thr Leu Ile Glu Val Leu Arg Ile Asn Thr Thr
3110 3115 3120
TAC CGC CGT GTT CTT CTT AAA GTC ACA GTG GAC ATG CCT AGG CAT ATT 6691
Tyr Arg Arg Val Leu Leu Lys Val Thr Val Asp Met Pro Arg His Ile
3125 3130 3135 3140
GTT GTA GAT CCC AAG AAC AGA TAC CTC TTC TGG GCT GAC TAT GGG CAG 6739
Val Val Asp Pro Lys Asn Arg Tyr Leu Phe Trp Ala Asp Tyr Gly Gln
3145 3150 3155 r
AGA CCA AAG ATT GAG CGT TCT TTC CTT GAC TGT ACC AAT CGA ACA GTG 6787
Arg Pro Lys Ile Glu Arg Ser Phe Leu Asp Cys Thr Asn Arg Thr Val
3160 3165 3170
CTT GTG TCA GAG GGC ATT GTC ACA CCA CGG GGC TTG GCA GTG GAC CGA 6835
Leu Val Ser Glu Gly Ile Val Thr Pro Arg Gly Leu Ala Val Asp Arg
3175 3180 3185
AGT GAT GGC TAC GTT TAT TGG GTT GAT GAT TCT TTA GAT ATA ATT GCA 6883
Ser Asp Gly Tyr Val Tyr Trp Val Asp Asp Ser Leu Asp Ile Ile Ala
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
.
~7
3190 3195 3200
AGG ATT CGT ATC AAT GGA GAG AAC TCT GAA GTG ATT CGT TAT GGC AGT 6931
Arg Ile Arg Ile Asn Gly Glu Asn Ser Glu Val Ile Arg Tyr Gly Ser
3205 ~ 3210 3215 3220
- CGT TAC CCA ACT CCT TAT GGC ATC ACT GTT TTT GAA AAT TCT ATC ATA 6979
Arg Tyr Pro Thr Pro Tyr Gly Ile Thr Val Phe Glu Asn Ser Ile Ile
~~ 3225 3230 3235
TGG GTA GAT AGG AAT TTG AAA AAG ATC TTC CAA GCC AGC AAG GAA CCA 7027
Trp Val Asp Arg Asn Leu Lys Lys Ile Phe Gln Ala Ser Lys Glu Pro
3240 3245 3250
GAG AAC ACA GAG CCA CCC ACA GTG ATA AGA GAC AAT ATC AAC TGG CTA 7075
Glu Asn Thr Glu Pro Pro Thr Val Ile Arg Asp Asn Ile Asn Trp Leu
3255 3260 3265
AGA GAT GTG ACC ATC TTT GAC AAG CAA GTC CAG CCC CGG TCA CCA GCA 7123
Arg Asp Val Thr Ile Phe Asp Lys Gln Val Gln Pro Arg Ser Pro Ala
3270 3275 3280
GAG GTC AAC AAC AAC CCT TGC TTG GAA AAC AAT GGT GGG TGC TCT CAT 7171
Glu Val Asn Asn Asn Pro Cys Leu Glu Asn Asn Gly Gly Cys Ser His
3285 3290 3295 3300
CTC TGC TTT GCT CTG CCT GGA TTG CAC ACC CCA AAA TGT GAC TGT GCC 7219
Leu Cys Phe Ala Leu Pro Gly Leu His Thr Pro IJYS Cys Asp Cys Ala
3305 3310 3315
TTT GGG ACC CTG CAA AGT GAT GGC AAG AAT TGT GCC ATT TCA ACA GAA 7267
Phe Gly Thr Leu Gln Ser Asp Gly Lys Asn Cys Ala Ile Ser Thr Glu
3320 3325 3330
3 5 AAT TTC CTC ATC TTT GCC TTG TCT AAT TCC TTG AGA AGC TTA CAC TTG 7315
Asn Phe Leu Ile Phe Ala Leu Ser Asn Ser Leu Arg Ser Leu His Leu
3335 3340 334S
GAC CCT GAA AAC CAT AGC CCA CCT TTC CAA ACA ATA AAT GTG GAA AGA 7363
Asp Pro Glu Asn His Ser Pro Pro Phe Gln Thr Ile Asn Val Glu Ary
33S0 33SS 3360
ACT GTC ATG TCT CTA GAC TAT GAC AGT GTA AGT GAT AGA ATC TAC TTC 7411
Thr Val Met Ser Leu Asp Tyr Asp Ser Val Ser Asp Arg Ile Tyr Phe
3365 3370 3375 3380
ACA CAA AAT TTA GCC TCT GGA GTT GGA CAG ATT TCC TAT GCC ACC CTG 7459
Thr Gln Asn Leu Ala Ser Gly Val Gly Gln Ile Ser Tyr Ala Thr Leu
3385 3390 3395
TCT TCA GGG ATC CAT ACT CCA ACT GTC ATT GCT TCA GGT ATA GGG ACT 7507
y Ser Ser Gly Ile His Thr Pro Thr Val Ile Ala Ser Gly Ile Gly Thr
3400 3405 3410
GCT GAT GGC ATT GCC TTT GAC TGG ATT ACT AGA AGA ATT TAT TAC AGT 7555
Ala Asp Gly Ile Ala Phe- Asp Trp Ile Thr Arg Arg Ile Tyr Tyr Ser
3415 3420 3425
GAC TAC CTC AAC CAG ATG ATT AAT TCC ATG GCT GAA GAT GGG TCT AAC 7603
Asp Tyr Leu Asn Gln Met Ile Asn Ser Met Ala Glu Asp Gly Ser Asn
3430 3435 3440
CGC ACT GTG ATA GCC CGC GTT CCA AAA CCA AGA GCA ATT GTG TTA GAT 7651
Arg Thr Val Ile Ala Arg Val Pro Lys Pro Arg Ala Ile Val Leu Asp
CA 0220~648 l997-0~-20
WO 96/lS801 PCT/US95/15203
3445 3450 3455 3460
CCC TGC CAA GGG TAC CTG TAC TGG GCT GAC TGG GAT ACA CAT GCC AAA 7699
Pro Cys Gln Gly Tyr Leu Tyr Trp Ala Asp Trp Asp Thr His Ala Lys
3465 3470 3475
ATC GAG AGA GCC ACA TTG GGA GGA AAC TTC CGG GTA CCC ATT GTG AAC 7747
Ile G1U Arg Ala Thr Leu Gly Gly Asn Phe Arg Val Pro Ile Val Asn
3480 3485 3490
AGC AGT CTG GTC ATG CCC AGT GGG CTG ACT CTG GAC TAT GAA GAG GAC 7795
Se~ Ser Leu Val Met Pro Ser Gly Leu Thr Leu Asp Tyr Glu Glu Asp
3495 3500 3505
15 CTT CTC TAC TGG GTG GAT GCT AGT CTG CAG AGG ATT GAA CGC AGC ACT 7843
Leu Leu Tyr Trp Val Asp Ala Ser Leu Gln Arg Ile Glu Arg Ser Thr
3510 3515 3520
CTG ACG GGC GTG GAT CGT GAA GTC ATT GTC AAT GCA GCC GTT CAT GCT 7891
20 Leu Thr Gly Val Asp Arg Glu Val Ile Val Asn Ala Ala Val His Ala
3525 3530 3535 3540
TTT GGC TTG ACT CTC TAT GGC CAG TAT ATT TAC TGG ACT GAC TTG TAC 7939
Phe Gly Leu Thr Leu Tyr Gly Gln Tyr Ile Tyr Trp Thr Asp Leu Tyr
3545 3550 3555
ACA CAA AGA ATT TAC CGA GCT AAC AAA TAT GAC GGG TCA GGT CAG ATT 7987
Thr Gln Arg Ile Tyr Arg Ala Asn Lys Tyr Asp Gly Ser Gly Gln Ile
3560 3565 3570
GCA ATG ACC ACA AAT TTG CTC TCC CAG CCC AGG GGA ATC AAC ACT GTT 8035
Ala Met Thr Thr Asn Leu Leu Ser Gln Pro Arg Gly Ile Asn Thr Val
3575 3580 3585
35 GTG AAG AAC CAG AAA CAA CAG TGT AAC AAT CCT TGT GAA CAG TTT AAT 8083
Val Lys Asn Gln Lys Gln Gln Cys Asn Asn Pro Cys Glu Gln Phe Asn
3590 3595 3600
GGG GGC TGC AGC CAT ATC TGT GCA CCA GGT CCA AAT GGT GCC GAG TGC 8131
40 Gly Gly Cys Ser His Ile Cys Ala Pro Gly Pro Asn Gly Ala Glu Cys
3605 3610 3615 3620
CAG TGT CCA CAT GAG GGC AAC TGG TAT TTG GCC AAC AAC AGG AAG CAC 8179
Gln Cys Pro His Glu Gly Asn Trp Tyr Leu Ala Asn Asn Arg Lys His
3625 3630 3635
TGC ATT GTG GAC AAT GGT GAA CGA TGT GGT GCA TCT TCC TTC ACC TGC 8227
Cys I le Val Asp Asn Gly Glu Arg Cys Gly Ala Ser Ser Phe Thr Cys
3640 3645 3650
TCC AAT GGG CGC TGC ATC TCG GAA GAG TGG AAG TGT GAT AAT GAC .AAC 8275
Ser Asn Gly Arg Cys Ile Ser Glu Glu Trp Lys Cys Asp Asn Asp Asn
3655 3660 3665
55 GAC TGT GGG GAT GGC AGT GAT GAG ATG GAA AGT GTC TGT GCA CTT CAC 8323
Asp Cys Gly Asp Gly Ser Asp Glu Met Glu Ser Val Cys Ala Leu His
3670 3675 3680
ACC TGC TCA CCG ACA GCC TTC ACC TGT GCC AAT GGG CGA TGT GTC CAA 8371
60 Thr Cys Ser Pro Thr Ala Phe Thr Cys Ala Asn Gly Arg Cys Val Gln
3685 3690 3695 3700
TAC TCT TAC CGC TGT GAT TAC TAC AAT GAC TGT GGT GAT GGC AGT GAT 8419
Tyr Ser Tyr Arg Cys Asp Tyr Tyr Asn Asp Cys Gly Asp Gly Ser Asp
CA 0220~648 1997-0~-20
WO 96/15801 . PCT/US95/15203
3705 3710 3715
GAG GCA GGG TGC CTG TTC AGG GAC TGC AAT GCC ACC ACG GAG TTT ATG 8467
Glu Ala Gly Cys Leu Phe Arg Asp Cys Asn Ala Thr Thr Glu Phe Met
3720 3725 3730
TGC AAT AAC AGA AGG TGC ATA CCT CGT GAG TTT ATC TGC AAT GGT GTA 8515
Cys Asn Asn Arg Arg Cys Ile Pro Arg Glu Phe Ile Cys Asn Gly Val
3735 3740 3745
GAC AAC TGC CAT GAT AAT AAC ACT TCA GAT GAG AAA AAT TGC CCT GAT 8563
Asp Asn Cys His Asp Asn Asn.Thr Ser Asp Glu Lys Asn Cys Pro Asp
3750 3755 3760
CGC ACT TGC CAG TCT GGA TAC ACA AAA TGT CAT AAT TCA AAT ATT TGT 8611
Arg Thr Cys Gln Ser Gly Tyr Thr Lys Cys His Asn Ser Asn Ile Cys
3765 3770 3775 3780
ATT CCT CGC GTT TAT TTG TGT GAC GGA GAC AAT GAC TGT GGA GAT AAC 8659
Ile Pro Arg Val Tyr Leu Cys Asp Gly Asp Asn Asp Cys Gly Asp Asn
3785 3790 3795
AGT GAT GAA AAC CCT ACT TAT TGC ACC ACT CAC ACA TGC AGC AGC AGT 8707
Ser Asp Glu Asn Pro Thr T}~r Cys Thr Thr His Thr Cys Ser Ser Ser
3800 3805 3810
GAG TTC CAA TGC GCA TCT GGG CGC TGT ATT CCT CAA CAT TGG TAT TGT 8755
Glu Phe Gln Cys Ala Ser Gly Arg Cys Ile Pro Gln His Trp Tyr Cys
3815 3820 3825
GAT CAA GAA ACA GAT TGT TTT GAT GCC TCT GAT GAA CCT GCC TCT TGT 8803
Asp Gln Glu Thr Asp Cys Phe Asp Ala Ser Asp Glu Pro Ala Ser Cys
3830 3835 3840
3 5 GGT CAC TCT GAG CGA ACA TGC CTA GCT GAT GAG TTC AAG TGT GAT GGT 8851
Gly His Ser Glu Arg Thr Cys Leu Ala Asp Glu Phe Lys Cys Asp Gly
3845 3850 3855 . 3860
GGG AGG TGC ATC CCA AGC GAA TGG ATC TGT GAC GGT GAT AAT GAC TGT 8899
Gly Arg Cys Ile Pro Ser Glu Trp Ile Cys Asp Gly Asp Asn Asp Cys
3865 3870 3875
GGG GAT ATG AGT GAC GAG GAT AAA AGG CAC CAG TGT CAG AAT CAA AAC 8947
Gly Asp Met Ser Asp Glu Asp Lys Arg His Gln Cys Gln Asn Gln Asn
3880 3885 3890
TGC TCG GAT TCC GAG TTT CTC TGT GTA AAT GAC AGA CCT CCG GAC AGG 8995
Cys Ser Asp Ser Glu Phe Leu Cys Val Asn Asp Arg Pro Pro Asp Arg
3895 3900 3905
AGG TGC ATT CCC CAG TCT TGG GTC TGT GAT GGC GAT GTG GAT TGT ACT 9043
r Arg Cys Ile Pro Gln Ser Trp Val Cys Asp Gly Asp Val Asp Cys Thr
3910 3915 3920
5 5 GAC GGC TAC GAT GAG AAT CAG AAT TGC ACC AGG AGA ACT TGC TCT GAA 9091
- Asp Gly Tyr Asp Glu Asn Gln Asn Cys Thr Arg Arg Thr Cys Ser Glu
3925 3930 3935 3940
AAT GAA TTC ACC TGT GGT TAC GGA CTG TGT ATC CCA AAG ATA TTC AGG 9139
Asn Glu Phe Thr Cys Gly Tyr Gly Leu Cys Ile Pro Lys Ile Phe Arg
3945 3950 3955
TGT GAC CGG CAC AAT GAC TGT GGT GAC TAT AGC GAC GAG AGG GGC TGC 9187
Cys Asp Arg His Asn Asp Cys Gly Asp Tyr Ser Asp Glu Arg Gly Cys
CA 0220~648 1997-0~-20
WO 96/15801 PCTIUS95/15203
~o
3960 3965 3970
TTA TAC CAG ACT TGC CAA CAG AAT CAG TTT ACC TGT CAG AAC GGG CGC 9235
Leu Tyr Gln Thr Cys Gln Gln Asn Gln Phe Thr Cys Gln Asn Gly Arg
3975 3980 3985
TGC ATT AGT AAA ACC TTC GTC TGT GAT GAG GAT AAT GAC TGT GGA GAC .9283
Cys Ile Ser Lys Thr Phe Val Cys Asp Glu Asp Asn Asp Cys Gly Asp
3990 3995 4000
GGA TCT GAT GAG CTG ATG CAC CTG TGC CAC ACC CCA GAA CCC ACG TGT 9331
Gly Ser Asp Glu . Leu Met His Leu Cys His Thr Pro Glu Pro Thr Cys
. 4005 4010 4015 4020
CCA CCT CAC GAG TTC AAG TGT GAC AAT GGG CGC TGC ATC GAG ATG ATG g379
Pro Pro His Glu Phe Lys Cys Asp Asn Gly Arg Cys Ile Glu Met Met
4025 4030 4035
AAA CTC TGC AAC CAC CTA GAT GAC TGT TTG GAC AAC AGC GAT GAG AAA 9427
Lys Leu Cys Asn His Leu Asp Asp Cys Leu Asp Asn Ser Asp Glu Lys
4040 4045 4050
GGC TGT GGC ATT AAT GAA TGC CAT GAC CCT TCA ATC AGT GGC TGC GAT 9475
Gly Cys Gly Ile Asn Glu Cys His Asp Pro Ser Ile Ser Gly Cys Asp
4055 4060 4065
CAC AAC TGC ACA GAC ACC TTA ACC AGT TTC TAT TGT TCC TGT CGT CCT 9523
His Asn Cys Thr Asp Thr Leu Thr Ser Phe Tyr Cys Ser Cys Arg Pro
4070 4075 4080
GGT TAC AAG CTC ATG TCT GAC AAG CGG ACT TGT GTT GAT ATT GAT GAA 9571
Gly Tyr Lys Leu Met Ser Asp Lys Arg Thr Cys Val Asp Ile Asp Glu
4085 4090 4095 4100
3 5 TGC ACA GAG ATG CCT TTT GTC TGT AGC CAG AAG TGT GAG AAT GTA ATA 9619
Cys Thr Glu Met Pro Phe Val Cys Ser Gln Lys Cys Glu Asn Val Ile
4105 4110 . 4115
GGC TCC TAC ATC TGT AAG TGT GCC CCA GGC TAC CTC CGA GAA CCA GAT 9667
4 0 Gly Ser Tyr Ile Cys Lys Cys Ala Pro Gly Tyr Leu Arg Glu Pro Asp
4120 4125 4130
GGA AAG ACC TGC CGG CAA AAC AGT AAC ATC GAA CCC TAT CTC ATT TTT 9715
Gly Lys Thr Cys Arg Gln Asn Ser Asn Ile Glu Pro Tyr Leu Ile Phe
4135 4140 4145
AGC AAC CGT TAC TAT TTG AGA AAT TTA ACT ATA GAT GGC TAT TTT TAC 9763
Ser Asn Arg Tyr Tyr Leu Arg Asn Leu Thr Ile Asp Gly Tyr Phe Tyr
4150 4155 4160
TCC CTC ATC TTG GAA GGA CTG GAC AAT GTT GTG GCA TTA GAT TTT GAC 9811
Ser Leu Ile Leu Glu Gly Leu Asp Asn Val Val Ala Leu Asp Phe Asp
4165 4170 4175 4180
5 5 CGA GTA GAG AAG AGA TTG TAT TGG ATT GAT ACA CAG AGG CAA GTC ATT 9859
Arg Val Glu Lys Arg Le~ Tyr Trp Ile Asp Thr Gln Arg Gln Val Ile
4185 4190 4195
GAG AGA ATG TTT CTG AAT AAG ACA AAC AAG GAG ACA ATC ATA AAC CAC 9907
Glu Arg Met Phe Leu Asn Lys Thr Asn Lys Glu Thr Ile Ile Asn His
4200 4205 4210
AGA CTA CCA GCT GCA GAA AGT CTG GCT GTA GAC TGG GTT TCC AGA AAG 9955
Arg Leu Pro Ala Ala Glu Ser Leu Ala Val Asp Trp Val Ser Arg Lys
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
~/
4215 4220 4225
CTC TAC TGG TTG GAT GCC CGC CTG GAT GGC CTC TTT GTC TCT GAC CTC 10003
Leu Tyr Trp Leu Asp Ala Arg Leu Asp Gly Leu Phe Val Ser Asp Leu
4230 4235 4240
AAT GGT GGA CAC CGC CGC ATG CTG GCC CAG CAC TGT GTG GAT GCC AAC 10051
Asn Gly Gly His Arg Arg Met Leu Ala Gln His Cys Val Asp Ala Asn
4245 4250 4255 4260
AAC ACC TTC TGC TTT GAT AAT CCC AGA GGA CTT GCC CTT CAC CCT CAA 10099
Asn Thr Phe Cys Phe Asp Asn Pro Arg Gly Leu Ala Leu His Pro Gln
4265 4270 4275
TAT GGG TAC CTC TAC TGG GCA GAC TGG GGT CAC CGC GCA TAC ATT GGG 10147
Tyr Gly Tyr Leu Tyr Trp Ala Asp Trp Gly His Arg Ala Tyr Ile Gly
4280 4285 4290
AGA GTA GGC ATG GAT GGA ACC AAC AAG TCT GTG ATA ATC TCC ACC AAG 10195
Arg Val Gly Met Asp Gly Thr Asn Lys Ser Val Ile Ile Ser Thr Lys
4295 4300 4305
TTA GAG TGG CCT AAT GGC ATC ACC ATT GAT TAC ACC AAT GAT CTA CTC 10243
Leu Glu Trp Pro Asn Gly Ile Thr Ile Asp Tyr Thr Asn Asp Leu Leu
4310 4315 4320
TAC TGG GCA GAT GCC CAC CTG GGT TAC ATA GAG TAC TCT GAT TTG GAG 10291
Tyr Trp Ala Asp Ala His Leu Gly Tyr Ile Glu Tyr Ser Asp Leu Glu
4325 4330 4335 4340
GGC CAC CAT CGA CAC ACG GTG TAT GAT GGG GCA CTG CCT CAC CCT TTC 10339
Gly His His Arg His Thr Val Tyr Asp Gly Ala Leu Pro His Pro Phe
4345 4350 . 4355
GCT ATT ACC ATT TTT GAA GAC ACT ATT TAT TGG ACA GAT TGG AAT ACA 10387
Ala Ile Thr Ile Phe Glu Asp Thr Ile Tyr Trp Thr Asp Trp Asn Thr
4360 4365 4370
AGG ACA GTG GAA AAG GGA AAC AAA TAT GAT GGA TCA AAT AGA CAG ACA 10435
Arg Thr Val Glu Lys Gly Asn Lys Tyr Asp Gly Ser Asn Arg Gln Thr
4375 4380 4385
CTG GTG AAC ACA ACA CAC AGA CCA TTT GAC ATC CAT GTG TAC CAT CCA 10483
Leu Val Asn Thr Thr His Arg Pro Phe Asp Ile His Val Tyr His Pro
4390 4395 4400
TAT AGG CAG CCC ATT GTG AGC AAT CCC TGT GGT ACC AAC AAT GGT GGC 10531
Tyr Arg Gln Pro Ile Val Ser Asn Pro Cys Gly Thr Asn Asn Gly Gly
4405 4410 4415 4420
TGT TCT CAT CTC TGC CTC ATC AAG CCA GGA GGA AAA GGG TTC ACT TGC 10579
Cys Ser His Leu Cys Leu Ile Lys Pro Gly Gly Lys Gly Phe Thr Cys
4425 4430 4435
55 GAG TGT CCA GAT GAC TTC CGC ACC CTT CAA CTG AGT GGC AGC ACC TAC 10627
Glu Cys Pro Asp Asp Phe Arg Thr Leu Gln Leu Ser Gly Ser Thr Tyr
4440 4445 4450
TGC ATG CCC ATG TGC TCC AGC ACC CAG TTC CTG TGC GCT AAC AAT GAA 10675
Cys Met Pro Met Cys Ser Ser Thr Gln Phe Leu Cys Ala Asn Asn Glu
4455 4460 4465
AAG TGC ATT CCT ATC TGG TGG AAA TGT GAT GGA CAG AAA GAC TGC TCA 10723
Lys Cys Ile Pro Ile Trp Trp Lys Cys Asp Gly Gln Lys Asp Cys Ser
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US9S/l5203
9~L
4470 4475 4480
GAT GGC TCT GAT GAA CTG GCC CTT TGC CCG CAG CGC TTC TGC CGA CTG 10 771
Asp Gly Ser Asp Glu Leu Ala Leu Cys Pro Gln Arg Phe Cys Arg Leu
4485 4490 4495 4500
GGA CAG TTC CAG TGC AGT GAC GGC AAC TGC ACC AGC CCG CAG ACT TTA 10 819
Gly Gln Phe Gln Cys Ser Asp Gly Asn Cys Thr Ser Pro Gln Thr Leu
4505 4510 4515
TGC AAT GCT CAC CAA AAT TGC CCT GAT GGG TCT GAT GAA GAC CGT CTT 10867
Cys Asn Ala His Gln Asn Cys Pro Asp Gly Ser Asp Glu Asp Arg Leu
4520 4525 4530
CTT TGT GAG AAT CAC CAC TGT GAC TCC AAT GAA TGG CAG TGC GCC AAC 10 915
Leu Cys Glu Asn His His Cys Asp Ser Asn Glu Trp Gln Cys Ala Asn
4535 4540 4545
AAA CGT TGC ATC CCA GAA TCC TGG CAG TGT GAC ACA TTT AAC GAC TGT 10963
Lys Arg Cys Ile Pro Glu Ser Trp Gln Cys Asp Thr Phe Asn Asp Cys
4550 4555 4560
GAG GAT AAC TCA GAT GAA GAC AGT TCC CAC TGT GCC AGC AGG ACC TGC 11011
Glu Asp Asn Ser Asp Glu Asp Ser Ser His Cys Ala Ser Arg Thr Cys
4565 4570 4575 4580
CGG CCG GGC CAG TTT CGG TGT GCT AAT GGC CGC TGC ATC CCG CAG GCC 110 59
Arg Pro Gly Gln Phe Arg Cys Ala Asn Gly Arg Cys Ile Pro Gln Ala
4585 4590 4595
TGG AAG TGT GAT GTG GAT AAT GAT TGT GGA GAC CAC TCG GAT GAG CCC 1110 7
Trp Lys Cys Asp Val Asp Asn Asp Cys Gly Asp His Ser Asp Glu Pro
4600 4605 4610
ATT GAA GAA TGC ATG AGC TCT GCC CAT CTC TGT GAC AAC TTC ACA GAA 11155
Ile Glu Glu Cys Met Ser Ser Ala His Leu Cys Asp Asn Phe Thr Glu
4615 4620 4625
TTC AGC TGC AAA ACA AAT TAC CGC TGC ATC CCA AAG TGG GCC GTG TGC 11203
Phe Ser Cys Lys Thr Asn Tyr Arg Cys Ile Pro Lys Trp Ala Val Cys
4630 4635 4640
AAT GGT GTA GAT GAC TGC AGG GAC AAC AGT GAT GAG CAA GGC TGT GAG 11251
Asn Gly Val Asp Asp Cys Arg Asp Asn Ser Asp Glu Gln Gly Cys Glu
4645 4650 4655 4660
GAG AGG ACA TGC CAT CCT GTG GGG GAT TTC CGC TGT AAA AAT CAC CAC 11299
Glu Arg Thr Cys His Pro Val Gly Asp Phe Arg Cys Lys Asn His His
4665 4670 4675
TGC ATC CCT CTT CGT TGG CAG TGT GAT GGG CAA AAT GAC TGT GGA GAT 11347
Cys Ile Pro Leu Ars Trp Gln Cys Asp Gly Gln Asn Asp Cys Gly Asp
4680 4685 4690
AAC TCA GAT GAG GAA AAC TGT GCT CCC CGG GAG TGC ACA GAG AGC GAG 11395
Asn Ser Asp Glu Glu Asn Cys Ala Pro Arg Glu Cys Thr Glu Ser Glu
4695 4700 4705
TTT CGA TGT GTC AAT CAG CAG TGC ATT CCC TCG CGA TGG ATC TGT GAC 11443
Phe Arg Cys Val Asn Gln Gln Cys Ile Pro Ser Arg Trp Ile Cys Asp
4710 4715 4720
CAT TAC AAC GAC TGT GGG GAC AAC TCA GAT GAA CGG GAC TGT GAG ATG 114 91
His Tyr Asn Asp Cys Gly Asp Asn Ser Asp Glu Arg Asp Cys Glu Met
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
4725 4730 4735 4740
AGG ACC TGC CAT CCT GAA TAT TTT CAG TGT ACA AGT GGA CAT TGT GTA 11539
Arg Thr Cys His Pro Glu Tyr Phe Gln Cys Thr Ser Gly His Cys Val
4745 4750 4755
CAC AGT GAA CTG AAA TGC GAT GGA TCC GCT GAC TGT TTG GAT GCG TCT 11587
His Ser Glu Leu Lys Cys Asp Gly Ser Ala Asp Cys Leu Asp Ala Ser
4760 4765 4770
GAT GAA GCT GAT TGT CCC ACA CGC TTT CCT GAT GGT GCA TAC TGC CAG 11635
Asp Glu Ala Asp Cys Pro Thr Arg Phe Pro Asp Gly Ala Tyr Cys Gln
4775 4780 4785
GCT ACT ATG TTC GAA TGC AAA AAC CAT GTT TGT ATC CCG CCA TAT TGG 11683
Ala Thr Met Phe Glu Cys Lys Asn His Val Cys Ile Pro Pro Tyr Trp
4790 4795 4800
AAA TGT GAT GGC GAT GAT GAC TGT GGC GAT GGT TCA GAT GAA GAA CTT 11731
2 0 Lys Cys Asp Gly Asp Asp Asp Cys Gly Asp Gly Ser Asp Glu Glu Leu
4805 4810 4815 4820
CAC CTG TGC TTG GAT GTT CCC TGT AAT TCA CCA AAC CGT TTC CGG TGT 11779
His Leu Cys Leu Asp Val Pro Cys Asn Ser Pro Asn Arg Phe Arg Cys
4825 4830 4835
GAC AAC AAT CGC TGC ATT TAT AGT CAT GAG GTG TGC AAT GGT GTG GAT 11827
Asp Asn Asn Arg Cys Ile Tyr Ser His Glu Val Cys Asn Gly Val Asp
4840 4845 4850
GAC TGT GGA GAT GGA ACT GAT GAG ACA GAG GAG CAC TGT AGA AAA CCG 11875
Asp Cys Gly Asp Gly Thr Asp Glu Thr Glu Glu His Cys Arg Lys Pro
4855 4860 4865
ACC CCT AAA CCT TGT ACA GAA TAT GAA TAT AAG TGT GGC AAT GGG CAT 11923
Thr Pro Lys Pro Cys Thr Glu Tyr Glu Tyr Lys Cys Gly Asn Gly His
4870 4875 4880
TGC ATT CCA CAT GAC AAT GTG TGT GAT GAT GCC GAT GAC TGT GGT GAC 11971
Cys Ile Pro His Asp Asn Val Cys Asp Asp Ala Asp Asp Cys Gly Asp
4885 4890 4895 4900
TGG TCC GAT GAA CTG GGT TGC AAT AAA GGA AAA GAA AGA ACA TGT GCT 12019
Trp Ser Asp Glu Leu Gly Cys Asn Lys Gly Lys Glu Arg Thr Cys Ala
4905 4910 4915
GAA AAT ATA TGC GAG CAA AAT TGT ACC CAA TTA AAT GAA GGA GGA TTT 1206.7
Glu Asn Ile Cys Glu Gln Asn Cys Thr Gln Leu Asn Glu Gly Gly Phe
4920 4925 4930
ATC TGC TCC TGT ACA GCT GGG TTC GAA ACC AAT GTT TTT GAC AGA ACC 12115
Ile Cys Ser Cys Thr Ala Gly Phe Glu Thr Asn Val Phe Asp Arg Thr
4935 4940 4945
TCC TGT CTA GAT ATC AAT GAA TGT GAA CAA TTT GGG ACT TGT CCC CAG 12163
Ser Cys Leu Asp Ile Asn Glu Cys Glu Gln Phe Gly Thr Cys Pro Gln
4950 4955 4960
CAC TGC AGA AAT ACC AAA GGA AGT TAT GAG TGT GTC TGT GCT GAT GGC 12211
His Cys Arg Asn Thr Lys Gly Ser Tyr Glu Cys Val Cys Ala Asp Gly
4965 4970 4975 4980
TTC ACG TCT ATG AGT GAC CGC CCT GGA AAA CGA TGT GCA GCT GAG GGT 12259
Phe Thr Ser Met Ser Asp Arg Pro Gly Lys Arg Cys Ala Ala Glu Gly
CA 0220~648 l997-0~-20
W O96115801 PCT~US9S/lS203
9Y
4985 ~990 4995
AGC TCT CCT TTG TTG CTA CTG CCT GAC AAT GTC CGA ATT CGA AAA TAT 12307
Ser Ser Pro Leu Leu Leu Leu Pro Asp Asn Val Arg Ile Arg Lys Tyr
5000 5005 5010 .
AAT CTC TCA TCT GAG AGG TTC TCA GAG TAT CTT CAA GAT GAG GAA TAT 12355
Asn Leu Ser Ser Glu Arg Phe Ser Glu Tyr Leu Gln Asp Glu Glu Tyr
5015 5020 5025
ATC CAA GCT GTT GAT TAT GAT TGG GAT CCC AAG GAC ATA GGC CTC AGT 12403
Ile Gln Ala Val Asp Tyr Asp Trp Asp Pro Lys Asp Ile Gly Leu Ser
5030 5035 5040
GTT GTG TAT TAC ACT GTG CGA GGG GAG GGC TCT AGG TTT GGT GCT ATC 12451
Val Val Tyr Tyr Thr Val Arg Gly Glu Gly Ser Arg Phe Gly Ala Ile
5045 5050 5055 5060
AAA CGT GCC TAC ATC CCC AAC TTT GAA TCC GGC CGC AAT AAT CTT GTG 12499
Lys Arg Ala Tyr Ile Pro Asn Phe Glu Ser Gly Arg Asn Asn Leu Val
5065 5070 5075
CAG GAA GTT GAC CTG AAA CTG AAA TAC GTA ATG CAG CCA GAT GGA ATA 12547
Gln Glu Val Asp Leu Lys Leu Lys Tyr Val Met Gln Pro Asp Gly Ile
5080 5085 5090
GCA GTG GAC TGG GTT GGA AGG CAT ATT TAC TGG TCA GAT GTC AAG AAT 12595
Ala Val Asp Trp Val Gly Arg His Ile Tyr Trp Ser Asp Val Lys Asn
5095 5100 5105
AAA CGC ATT GAG GTG GCT AAA CTT GAT GGA AGG TAC AGA AAG TGG CTG 12643
Lys Arg Ile Glu Val Ala Lys Leu Asp Gly Arg Tyr Arg Lys Trp Leu
5110 5115 5120
ATT TCC ACT GAC CTG GAC CAA CCA GCT GCT ATT GCT GTG AAT CCC AAA 12691
Ile Ser Thr Asp Leu Asp Gln Pro Ala Ala Ile Ala Val Asn Pro Lys
5125 5130 5135 5140
CTA GGG CTT ATG TTC TGG ACT GAC TGG GGA AAG GAA CCT AAA ATC GAG 12739
Leu Gly Leu Met Phe Trp Thr Asp Trp Gly Lys Glu Pro Lys Ile Glu
5145 5150 5155
TCT GCC TGG ATG AAT GGA GAG GAC CGC AAC ATC CTG GTT TTC GAG GAC 12787
Ser Ala Trp Met Asn Gly Glu Asp Arg Asn Ile Leu Val Phe Glu Asp
5160 5165 5170
CTT GGT TGG CCA ACT GGC CTT TCT ATC GAT TAT TTG AAC AAT GAC CGA 12835
Leu Gly Trp Pro Thr Gly Leu Ser Ile Asp Tyr Leu Asn Asn Asp Arg
5175 5180 5185
ATC TAC TGG AGT GAC TTC AAG GAG GAC GTT ATT GAA ACC ATA AAA TAT 12883
Ile Tyr Trp Ser Asp Phe Lys Glu Asp Val Ile Glu Thr Ile Lys Tyr
5190 5195 5200
GAT GGG ACT GAT AGG AGA GTC ATT GCA AAG GAA GCA ATG AAC CCT TAC 12931
Asp Gly Thr Asp Arg Arg Val Ile Ala Lys Glu Ala Met Asn Pro Tyr
5205 5210 5215 5220
AGC CTG GAC ATC TTT GAA GAC CAG TTA TAC TGG ATA TCT AAG GAA AAG 12979
Ser Leu Asp Ile Phe Glu Asp Gln Leu Tyr Trp Ile Ser Lys Glu Lys
5225 5230 5235
GGA GAA GTA TGG AAA CAA AAT AAA TTT GGG CAA GGA AAG AAA GAG AAA 13027
Gly Glu Val Trp Lys Gln Asn Lys Phe Gly Gln Gly Lys Lys Glu Lys
CA 0220~648 l997-0~-20
WO 96/15801 PCT/USgS/15ZO~
5240 5245 5250
ACG CTG GTA GTG AAC CCT TGG CTC ACT CAA GTT CGA ATC TTT CAT CAA 13075
. Thr Leu Val Val Asn Pro Trp Leu Thr Gln Val Arg Ile Phe His Gln
5255 5260 5265
CTC AGA TAC AAT AAG TCA GTG CCC AAC CTT TGC AAA CAG ATC TGC AGC 13123
Leu Arg Tyr Asn Lys Ser Val Pro Asn Leu Cys Lys Gln Ile Cys Ser
5270 5275 5280
CAC CTC TGC CTT CTG AGA CCT GGA GGA TAC AGC TGT GCC TGT CCC CAA 13171
His Leu Cys Leu Leu Arg Pro Gly Gly Tyr Ser Cys Ala Cys Pro Gln
5285 5290 5295 5300
GGC TCC AGC TTT ATA GAG GGG AGC ACC ACT GAG TGT GAT GCA GCC ATC 13219
Gly Ser Ser Phe Ile Glu Gly Ser Thr Thr Glu Cys Asp Ala Ala Ile
5305 5310 5315
GAA CTG CCT ATC AAC CTG CCC CCC CCA TGC AGG TGC ATG CAC GGA GGA 13267
2 0 Glu Leu Pro Ile Asn Leu Pro Pro Pro Cys Arg Cys Met His Gly Gly
5320 5325 5330
AAT TGC TAT TTT GAT GAG ACT GAC CTC CCC AAA TGC AAG TGT CCT AGC 13315
Asn Cys Tyr Phe Asp Glu Thr Asp Leu Pro Lys Cys Lys Cys Pro Ser
5335 5340 5345
GGC TAC ACC GGA AAA TAT TGT GAA ATG GCG TTT TCA AAA GGC ATC TCT 13363
Gly Tyr Thr Gly Lys Tyr Cys Glu Met Ala Phe Ser Lys Gly Ile Ser
5350 5355 5360
CCA GGA ACA ACC GCA GTA GCT GTG CTG TTG ACA ATC CTC TTG ATC GTC 13411
Pro Gly Thr Thr Ala Val Ala Val Leu Leu Thr Ile Leu Leu Ile Val
5365 5370 5375 5380
GTA ATT GGA GCT CTG GCA ATT GCA GGA TTC TTC CAC TAT AGA AGG ACC 13459
Val Ile Gly Ala Leu Ala Ile Ala Gly Phe Phe His Tyr Arg Arg Thr
5385 5390 5395
GGC TCC CTT TTG CCT GCT CTG CCC AAG CTG CCA AGC TTA AGC AGT CTC 13507
Gly Ser Leu Leu Pro Ala Leu Pro Lys Leu Pro Ser Leu Ser Ser Leu
5400 5405 5410
GTC AAG CCC TCT GAA AAT GGG AAT GGG GTG ACC TTC AGA TCA GGG GCA 13555
Val Lys Pro Ser Glu Asn Gly Asn Gly Val Thr Phe Arg Ser Gly Ala
5415 5420 5425
GAT CTT AAC ATG GAT ATT GGA GTG TCT GGT TTT GGA CCT GAG ACT GCT 13603
Asp Leu Asn Met Asp Ile Gly Val Ser Gly Phe Gly Pro Glu Thr Ala
5430 5435 5440
ATT GAC AGG TCA ATG GCA ATG AGT GAA GAC TTT GTC ATG GAA ATG GGG 13651
Ile Asp Arg Ser Met Ala Met Ser Glu Asp Phe Val Met Glu Met Gly
5445 5450 5455 5460
5 5 AAG CAG CCC ATA ATA TTT GAA AAC CCA ATG TAC TCA GCC AGA GAC AGT 13699
Lys Gln Pro Ile Ile Phe Glu Asn Pro Met Tyr Ser Ala Arg Asp Ser
5465 5470 5475
GCT GTC AAA GTG GTT CAG CCA ATC CAG GTG ACT GTA TCT GAA AAT GTG 13747
Ala Val Lys Val Val Gln Pro Ile Gln Val Thr Val Ser Glu Asn Val
5480 5485 5490
GAT AAT AAG AAT TAT GGA AGT CCC ATA AAC CCT TCT GAG ATA GTT CCA 13795
Asp Asn Lys Asn Tyr Gly Ser Pro Ile Asn Pro Ser Glu Ile Val Pro
CA 0220~648 l997-0~-20
WO 96/15801 PCTIUS95/15203
~6
5495 5500 5505
GAG ACA AAC CCA ACT TCA CCA GCT GCT GAT GGA ACT CAG GTG ACA AAA 13843
Glu Thr Asn Pro Thr Ser Pro Ala Ala Asp Gly Thr Gln Val Thr Lys
5510 5515 5520 v
TGG AAT CTC TTC AAA CGA AAA TCT AAA CAA ACT ACC AAC TTT GAA AAT 13 891
Trp Asn Leu Phe Lys Arg Lys Ser Lys Gln Thr Thr Asn Phe Glu Asn
5525 5530 55~5 5540
CCA ATC TAT GCA CAG ATG GAG AAC GAG CAA AAG GAA AGT GTT GCT GCG 13939
Pro Ile Tyr Ala Gln Met Glu Asn Glu Gln Lys Glu Ser Val Ala Ala
5545 5550 5555
ACA CCA CCT CCA TCA CCT TCG CTC CCT GCT AAG CCT AAG CCT CCT TCG 13987
Thr Pro Pro Pro Ser Pro Ser Leu Pro Ala Lys Pro Lys Pro Pro Ser
5560 5565 5570
AGA AGA GAC CCA ACT CCA ACC TAT TCT GCA ACA GAA GAC ACT TTT AAA 14035
2 0 Arg Arg Asp Pro Thr Pro Thr Tyr Ser Ala Thr Glu Asp Thr Phe Lys
5575 5580 5585
GAC ACC GCA AAT CTT GTT AAA GAA GAC TCT GAA GTA TAG GATCAAGAAG 14084
Asp Thr Ala Asn Leu Val Lys Glu Asp Ser Glu Val *
5590 5595 5600
AA 14086
(2) INFORMATION FOR SEQ ID No:84:
( i ) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 4656 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:84:
4~
Met Asp Arg Gly Pro Ala Ala Val Ala Cys Thr Leu Leu Leu Ala Leu
5 10 15
Val Ala Cys Leu Ala Pro Ala Ser Gly Gln Glu Cys Asp Ser Ala His
20 25 30
Phe Arg Cys Gly Ser Gly His Cys Ile Pro Ala Asp Trp Arg Cys Asp
35 40 45
Gly Thr Lys Asp Cys Ser Asp Asp Ala Asp Glu Ile Gly Cys Ala Val
50 55 60
Val Thr Cys Gln Gln Gly Tyr Phe Lys Cys Gln Ser Glu Gly Gln Cys
65 70 75 80
Ile Pro Ser Ser Trp Val Cys Asp Gln Asp Gln Asp Cys Asp Asp Gly
85 90 95
Ser Asp Glu Arg Gln Asp Cys Ser Gln Ser Thr Cys Ser Ser His Gln
100 105 110
Ile Thr Cys Ser Asn Gly Gln Cys Ile Pro Ser Glu Tyr Arg Cys Asp
115 120 125
CA 0220~648 l997-0~-20
WO 96/1580 l PCT/US95/15203
His Val Arg Asp Cys Pro Asp Gly Ala Asp Glu Asn Asp Cys Gln Tyr
130 135 140
Pro Thr Cys Glu Gln Leu Thr Cys Asp Asn Gly Ala Cys Tyr Asn Thr
145 150 155 160
Ser Gln Lys Cys Asp Trp Lys Val Asp Cys Arg Asp Ser Ser Asp Glu
165 170 175
0 Ile Asn Cys Thr Glu Ile Cys Leu His Asn Glu Phe Ser Cys Gly Asn
180 185 190
Gly Glu Cys Ile Pro Arg Ala Tyr Val Cys Asp His Asp Asn Asp Cys
195 200 205
Gln Asp Gly Ser Asp Glu His Ala Cys Asn Tyr Pro Thr Cys Gly Gly
210 215 220
Tyr Gln Phe Thr Cys Pro Ser Gly Arg Cys Ile Tyr Gln Asn Trp Val
225 230 235 240
Cys Asp Gly Glu Asp Asp Cys Lys Asp Asn Gly Asp Glu Asp Gly Cys
245 250 255
Glu Ser Gly Pro His Asp Val His Lys Cys Ser Pro Arg Glu Trp Ser
260 265 270
Cys Pro Glu Ser Gly Arg Cys Ile Ser Ile Tyr Lys Val Cys Asp Gly
275 280 285
Ile Leu Asp Cys Pro Gly Arg Glu Asp Glu Asn Asn Thr Ser Thr Gly
290 295 300
Lys Tyr Cys Ser Met Thr Leu Cys Ser Ala Leu Asn Cys Gln Tyr Gln
305 310 315 320
Cys His Glu Thr Pro Tyr Gly Gly Ala Cys Phe Cys Pro Pro Gly Tyr
325 330 335
Ile Ile Asn His Asn Asp Ser Arg Thr Cys Val Glu Phe Asp Asp Cys
340 345 350
Gln Ile Trp Gly Ile Cys Asp Gln Lys Cys Glu Ser Arg Pro Gly Arg
355 360 365
His Leu Cys His Cys Glu Glu Gly Tyr Ile Leu Glu Arg Gly Gln Tyr
370 375 380
Cys Lys Ala Asn Asp Ser Phe Gly Glu Ala Ser Ile Ile Phe Ser Asn
385 390 395 400
Gly Arg Asp Leu Leu Ile Gly Asp Ile His Gly Arg Ser Phe Arg Ile
405 410 415
5 Leu Val Glu Ser Gln Asn Arg Gly Val Ala Val Gly Val Ala Phe His
420 425 430
Tyr His Leu Gln Arg Val Phe Trp Thr Asp Thr Val Gln Asn Lys Val
435 440 445
Phe Ser Val Asp Ile Asn Gly Leu Asn Ile Gln Glu Val Leu Asn Val
450 455 460
Ser Val Glu Thr Pro Glu Asn Leu Ala Val Asp Trp Val Asn Asn Lys
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15ZO3
q~/
465 470 475 480
Ile Tyr Leu Val Glu Thr Lys Val Asn Arg Ile Asp Met Val Asn Leu
485 490 g95
Asp Gly Ser Tyr Arg Val Thr Leu Ile Thr Glu Asn Leu Gly His Pro
500 505 510
Arg Gly Ile Ala Val Asp Pro Thr Val Gly Tyr Leu Phe Phe Ser Asp
515 520 525
Trp Glu Ser Leu Ser Gly Glu Pro Lys Leu Glu Arg Ala Phe Met Asp
530 535 540
Gly Ser Asn Arg Lys Asp Leu Val Lys Thr Lys Leu Gly Trp Pro Ala
545 550 555 560
Gly Val Thr Leu Asp Met Ile Ser Lys Arg Val Tyr Trp Val Asp Ser
565 570 575
Arg Phe Asp Tyr Ile Glu Thr Val Thr Tyr Asp Gly Ile Gln Arg Lys
580 585 590
Thr Val Val His Gly Gly Ser Leu Ile Pro His Pro Phe Gly Val Ser
595 600 605
Leu Phe Glu Gly Gln Val Phe Phe Thr Asp Trp Thr Lys Met Ala Val
610 615 620
3 0 Leu Lys Ala Asn Lys Phe Thr Glu Thr Asn Pro Gln Val Tyr Tyr Gln
625 630 635 640
Ala Ser Leu Arg Pro Tyr Gly Val Thr Val Tyr His Ser Leu Arg Gln
645 650 655
Pro Tyr Ala Thr Asn Pro Cys Lys Asp Asn Asn Gly Gly Cys Glu Gln
660 665 670
Val Cys Val Leu Ser His Arg Thr Asp Asn Asp Gly Leu Gly Phe Arg
675 680 685
Cys Lys Cys Thr Phe Gly Phe Gln Leu Asp Thr Asp Glu Arg His Cys
690 695 700
Ile Ala Val Gln Asn Phe Leu Ile Phe Ser Ser Gln Val Ala Ile Arg
705 710 715 720
Gly Ile Pro Phe Thr Leu Ser Thr Gln Glu Asp Val Met Val Pro Val
725 730 735
5.0
Ser Gly Asn Pro Ser Phe Phe Val Gly Ile Asp Phe Asp Ala Gln .Asp
740 745 750
Ser Thr Ile Phe Phe Ser Asp Met Ser Lys His Met Ile Phe Lys Gln
755 760 765
Lys Ile Asp Gly Thr Gly Arg Glu Ile Leu Ala Ala Asn Arg Val Glu
770 775 780
60 Asn Val Glu Ser Leu Ala Phe Asp Trp Ile Ser Lys Asn Leu Tyr Trp
785 790 795 800
Thr Asp Ser His Tyr Lys Ser Ile Ser Val Met Arg Leu Ala Asp Lys
805 810 815
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
Thr Arg Arg Thr Val Val Gln Tyr Leu Asn Asn Pro Arg Ser Val Val
820 825 830
Val His Pro Phe Ala Gly Tyr Leu Phe Phe Thr Asp Trp Phe Arg Pro
835 840 845
Ala Lys Ile Met Arg Ala Trp Ser Asp Gly Ser His Leu Leu Pro Val
850 855 860
Ile Asn Thr Thr Leu Gly Trp Pro Asn Gly Leu Ala Ile Asp Trp Ala
865 870 875 880
Ala Ser Arg Leu Tyr Trp Val Asp Ala Tyr Phe Asp Lys Ile Glu His
885 890 895
Ser Thr Phe Asp Gly Leu Asp Arg Arg Arg Leu Gly His Ile G1U Gln
900 905 910
Met Thr His Pro Phe Gly Leu Ala Ile Phe Gly Glu His Leu Phe Phe
915 920 925
Thr Asp Trp Arg Leu Gly Ala Ile Ile Arg Val Arg Lys Ala Asp Gly
930 935 940
Gly Glu Met Thr Val Ile Arg Ser Gly Ile Ala Tyr Ile Leu His Leu
945 950 955 960
Lys Ser Tyr Asp Val Asn Ile Gln Thr Gly Ser Asn Ala Cys Asn Gln
965 970 975
Pro Thr His Pro Asn Gly Asp Cys Ser His Phe Cys Phe Pro Val Pro
980 985 990
3 5 Asn Phe Gln Arg Val Cys Gly Cys Pro Tyr Gly Met Arg Leu Ala Ser
995 1000 1005
Asn His Leu Thr Cys Glu Gly Asp Pro Thr Asn Glu Pro Pro Thr Glu
1010 1015 1020
Gln Cys Gly Leu Phe Ser Phe Pro Cys Lys Asn Gly Arg Cys Val Pro
1025 1030 1035 1040
Asn Tyr Tyr Leu Cys Asp Gly Val Asp Asp Cys His Asp Asn Ser Asp
1045 1050 1055
Glu Gln Leu Cys Gly Thr Leu Asn Asn Thr Cys Ser Ser Ser Ala Phe
1060 1065 1070
50 Thr Cys Gly His Gly Glu Cys Ile Pro Ala His Trp Arg Cys Asp Lys
1075 1080 1085
Arg Asn Asp Cys Val Asp Gly Ser Asp Glu His Asn Cys Pro Thr His
1090 1095 1100
Ala Pro Ala Ser Cys Leu Asp Thr Gln Tyr Thr Cys Asp Asn His Gln
1105 1110 1115 1120
Cys Ile Ser Lys Asn Trp Val Cys Asp Thr Asp Asn Asp Cys Gly Asp
1125 1130 1135
Gly Ser Asp Glu Lys Asn Cys Asn Ser Thr Glu Thr Cys Gln Pro Ser
1140 1145 1150
CA 0220~648 1997-0~-20
W O96/15801 PCTrUS95/15203
~oo
Gln Phe Asn Cys Pro Asn His Arg Cys Ile Asp Leu Ser Phe Val Cys
1155 1160 1165
Asp Gly Asp Lys Asp Cys Val Asp Gly Ser Asp Glu Val Gly Cys Val
1170 1175 1180
Leu Asn Cys Thr Ala Ser Gln Phe Lys Cys Ala Ser Gly Asp Lys Cys
1185 1190 1195 1200
0 Ile Gly Val Thr Asn Arg Cys Asp Gly Val Phe Asp Cys Ser Asp Asn
1205 1210 1215
Ser Asp Glu Ala Gly Cys Pro Thr Arg Pro Pro Gly Met Cys His Ser
1220 1225 1230
Asp Glu Phe Gln Cys Gln Glu Asp Gly Ile Cys Ile Pro Asn Phe Trp
1235 1240 1245
Glu Cys Asp Gly His Pro Asp Cys Leu Tyr. Gly Ser Asp Glu His Asn
1250 1255 1260
Ala Cys Val Pro Lys Thr Cys Pro Ser Ser Tyr Phe His Cys Asp Asn
1265 1270 1275 1280
25 Gly Asn Cys Ile His Arg Ala Trp Leu Cys Asp Arg Asp Asn Asp Cys
1285 1290 1295
Gly Asp Met Ser Asp Glu Lys Asp Cys Pro Thr Gln Pro Phe Arg Cys
1300 1305 1310
Pro Ser Trp Gln Trp Gln Cys Leu Gly His Asn Ile Cys Val Asn Leu
1315 1320 1325
Ser Val Val Cys Asp Gly Ile Phe Asp Cys Pro Asn Gly Thr Asp Glu
1330 1335 1340
Ser Pro Leu Cys Asn Gly Asn Ser Cys Ser Asp. Phe Asn Gly Gly Cys
1345 1350 1355 1360
40 Thr His Glu Cys Val Gln Glu Pro Phe Gly Ala Lys Cys Leu Cys Pro
1365 1370 1375
Leu Gly Phe Leu Leu Ala Asn Asp Ser Lys Thr Cys Glu Asp Ile Asp
1380 1385 1390
Glu Cys Asp Ile Leu Gly Ser Cys Ser Gln His Cys Tyr Asn Met Arg
1395 1400 1405
Gly Ser Phe Arg Cys Ser Cys Asp Thr Gly Tyr Met Leu Glu Ser Asp
1410 1415 1420
Gly Arg Thr Cys Lys Val Thr Ala Ser Glu Ser Leu Leu Leu Leu Val
1425 1430 1435 1440
55 Ala Ser Gln Asn Lys Ile Ile Ala Asp Ser Val Thr Ser Gln Val His
1445 1450 1455
Asn Ile Tyr Ser Leu Val Glu Asn Gly Ser Tyr Ile Val Ala Val Asp
1460 1465 1470
Phe Asp Ser Ile Ser Gly Arg Ile Phe Trp Ser Asp Ala Thr Gln Gly
1475 1480 1485
Lys Thr Trp Ser Ala Phe Gln Asn Gly Thr Asp Arg Arg Val Val Phe
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
~al
1490 1495 1500
Asp Ser Ser Ile Ile Leu Thr Glu Thr Ile Ala Ile Asp Trp Val Gly
1505 1510 1515 1520
Arg Asn Leu Tyr Trp Thr Asp Tyr Ala. Leu Glu Thr Ile Glu Val Ser
1525 1530 1535
Lys Ile Asp Gly Ser His Arg Thr Val Leu Ile Ser Lys Asn Leu Thr
1540 1545 1550
Asn Pro Arg Gly Leu Ala Leu Asp Pro Arg Met Asn Glu His Leu Leu
1555 1560 1565
Phe Trp Ser Asp Trp Gly His His Pro Arg Ile Glu Arg Ala Ser Met
1570 1575 1580
Asp Gly Ser Met Arg Thr Val Ile Val Gln Asp Lys Ile Phe Trp Pro
1585 1590 1595 1600
Cys Gly Leu Thr Ile Asp Tyr Pro Asn Arg heu Leu Tyr Phe Met Asp
1605 1610 1615
Ser Tyr Leu Asp Tyr Met Asp Phe Cys Asp Tyr Asn Gly His His Arg
1620 1625 1630
Arg Gln Val Ile Ala Ser Asp Leu Ile Ile Arg His Pro Tyr Ala Leu
1635 1640 1645
3 0 Thr Leu Phe Glu Asp Ser Val Tyr Trp Thr Asp Arg Ala Thr Arg Arg
1650 1655 1660
Val Met Arg Ala Asn Lys Trp His Gly Gly Asn Gln Ser Val Val Met
1665 1670 1675 1680
Tyr Asn Ile Gln Trp Pro Leu Gly Ile Val Ala Val His Pro Ser Lys
1685 1690 1695
Gln Pro Asn Ser Val Asn Pro Cys Ala Phe Ser Arg Cys Ser His Leu
1700 1705 1710
Cys Leu Leu Ser Ser Gln Gly Pro His Phe Tyr Ser Cys Val Cys Pro
1715 1720 1725
Ser Gly Trp Ser Leu Ser Pro Asp Leu Leu Asn Cys Leu Arg Asp Asp
1730 1735 1740
Gln Pro Phe Leu Ile Thr Val Arg Gln His Ile Ile Phe Gly Ile Ser
1745 17S0 1755 1760
Leu Asn Pro Glu Val Lys Ser Asn Asp Ala Met Val Pro Ile Ala Gly
1765 1770 1775
Ile Gln Asn Gly Leu Asp Val Glu Phe Asp Asp Ala Glu Gln Tyr Ile
55 1780 1785 1790
Tyr Trp Val Glu Asn Pro Gly Glu Ile His Arg Val Lys Thr Asp Gly
1795 1800 1805
60 Thr Asn Arg Thr Val Phe Ala Ser Ile Ser Met Val Gly Pro Ser Met
1810 1815 1820
Asn Leu Ala Leu Asp Trp Ile Ser Arg Asn I eu Tyr Ser Thr Asn Pro
1825 1830 1835 1840
CA 0220~648 l997-0~-20
WO 96115801 PCTIUS95/15203
l o ~)
Arg Thr Gln Ser Ile Glu Val Leu Thr Leu His Gly Asp Ile Arg Tyr
1845 1850 1855
Arg Lys Thr Leu Ile Ala Asn Asp Gly Thr Ala Leu Gly Val Gly Phe
1860 1865 1870
Pro Ile Gly Ile Thr Val Asp Pro Ala Arg Gly Lys Leu Tyr Trp Ser
1875 1880 1885
Asp Gln Gly Thr Asp Ser Gly Val Pro Ala Lys Ile Ala Ser Ala Asn
1890 1895 1900 .
Met Asp Gly Thr Ser Val Lys Thr Leu Phe Thr Gly Asn Leu Glu His
1905 1910 1915 1920
Leu Glu Cys Val Thr Leu Asp Ile Glu Glu Gln Lys Leu Tyr Trp Ala
1925 1930 1935
0 Val Thr Gly Arg Gly Val I le Glu Arg Gly Asn Val Asp Gly Thr Asp
1940 1945 1950
Arg Met Ile Leu Val His Gln Leu Ser His Pro Trp Gly Ile Ala Val
1955 1960 1965
His Asp Ser Phe Leu Tyr Tyr Thr Asp Glu Gln Tyr Glu Val Ile Glu
1970 1975 1980
Arg Val Asp Lys Ala Thr Gly Ala Asn Lys Ile Val Leu Arg Asp Asn
1985. 1990 1995 2000
Val Pro Asn Leu Arg Gly Leu Gln Val Tyr His Arg Arg Asn Ala Ala
2005 2010 2015
3 5 Glu Ser Ser Asn Gly Cys Ser Asn Asn Met Asn Ala Cys Gln Gln Ile
2020 2025 2030
Cys Leu Pro Val Pro Gly Gly Leu Phe Ser Cys Ala Cys Ala Thr Gly
2035 2040 2045
Phe Lys Leu Asn Pro Asp Asn Arg Ser Cys Ser Pro Tyr Asn Ser Phe
2050 2055 2060
Ile Val Val Ser Met Leu Ser Ala Ile Arg Gly Phe Ser Leu Glu Leu
2065 2070 2075 2080
Ser Asp His Ser Glu Thr Met Val Pro Val Ala Gly Gln Gly Arg Asn
2085 2090 2095
Ala Leu His Val Asp Val Asp Val Ser Ser Gly Phe Ile Tyr Trp Cys
2100 2105 2110
Asp Phe Ser Ser Ser Val Ala Ser Asp Asn Ala Ile Arg Arg Ile Lys
2115 2120 2125
Pro Asp Gly Ser Ser Leu Met Asn Ile Val Thr His Gly Ile Gly Glu
2130 2135 2140
Asn Gly Val Arg Gly Ile Ala Val Asp Trp Val Ala Gly Asn Leu Tyr
2145 2150 2155 2160
Phe Thr Asn Ala Phe Val Ser Glu Thr Leu Ile Glu Val Leu Arg Ile
2165 2170 2175
CA 0220~648 l997-0~-20
WO 96/1~801 PCT/US95115203
/O3
Asn Thr Thr Tyr Arg Arg Val Leu Leu Lys Val Thr Val Asp Met Pro
2180 2185 2190
Arg His Ile Val Val Asp Pro Lys Asn Arg Tyr Leu Phe Trp Ala Asp
2195 2200 2205
Tyr Gly Gln Arg Pro Lys I le Glu Arg Ser Phe Leu Asp Cys Thr Asn
2210 2215 2220
0 Arg Thr Val Leu Val Ser Glu Gly Ile Val Thr Pro Arg Gly Leu Ala
2225 2230 2235 2240
Val Asp Arg Ser Asp Gly Tyr Val Tyr Trp Val Asp Asp Ser Leu Asp
2245 2250 2255
Ile Ile Ala Arg Ile Arg Ile Asn Gly Glu Asn Ser Glu Val Ile Arg
2260 2265 2270
Tyr Gly Ser Arg Tyr Pro Thr Pro Tyr Gly Ile Thr Val Phe Glu Asn
2275 2280 2285
Ser Ile Ile Trp Val Asp Arg Asn Leu Lys Lys Ile Phe Gln Ala Ser
2290 2295 2300
Lys Glu Pro Glu Asn Thr Glu Pro Pro Thr Val Ile Arg Asp Asn Ile
2305 2310 2315 2320
Asn Trp Leu Arg Asp Val Thr Ile Phe Asp Lys Gln Val Gln Pro Arg
2325 2330 2335
Ser Pro Ala Glu Val Asn Asn Asn Pro Cys Leu Glu Asn Asn Gly Gly
2340 2345 2350
Cys Ser His Leu Cys Phe Ala Leu Pro Gly Leu His Thr Pro Lys Cys
3 5 2355 2360 2365
Asp Cys Ala Phe Gly Thr Leu Gln Ser Asp Gly Lys Asn Cys Ala I le
2370 2375 2380
Ser Thr Glu Asn Phe Leu Ile Phe Ala Leu Ser Asn Ser Leu Arg Ser
2385 2390 2395 2400
Leu His Leu Asp Pro Glu Asn His Ser Pro Pro Phe Gln Thr Ile Asn
2405 2410 2415
Val Glu Arg Thr Val Met Ser Leu Asp Tyr Asp Ser Val Ser Asp Arg
2420 2425 2430
Ile Tyr Phe Thr Gln Asn Leu Ala Ser Gly Val Gly Gln Ile Ser Tyr
2435 2440 2445
Ala Thr Leu Ser Ser Gly Ile His Thr Pro Thr Val Ile Ala Ser Gly
2450 2455 2460
55 Ile Gly Thr Ala Asp Gly Ile Ala Phe Asp Trp Ile Thr Arg Arg Ile
2465 2470 2475 2480
Tyr Tyr Ser Asp Tyr Leu Asn Gln Met Ile Asn Ser Met Ala Glu Asp
2485 2490 2495
Gly Ser Asn Arg Thr Val Ile Ala Arg Val Pro Lys Pro Arg Ala Ile
2500 2505 2510
Val Leu Asp Pro Cys Gln Gly Tyr Leu Tyr Trp Ala Asp Trp Asp Thr
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
1~
2515 2520 2525
His Ala Lys Ile Glu Arg Ala Thr Leu Gly Gly Asn Phe Arg Val Pro
2530 2535 2540
Ile Val Asn Ser Ser Leu Val Met Pro.Ser Gly Leu Thr Leu Asp Tyr
2545 2550 2555 2560
Glu Glu Asp Leu Leu Tyr Trp Val Asp Ala Ser Leu Gln Arg Ile Glu
0 2565 2570 2575
Arg Ser Thr Leu Thr Gly Val Asp Arg Glu Val Ile Val Asn Ala Ala
2580 2585 25gO
Val His Ala Phe Gly Leu Thr Leu Tyr Gly Gln Tyr Ile Tyr Trp Thr
2595 2600 2605
Asp Leu Tyr Thr Gln Arg Ile Tyr Arg Ala Asn l.ys Tyr Asp Gly Ser
2610 2615 2620
Gly Gln Ile Ala Met Thr Thr Asn Leu Leu Ser Gln Pro Arg Gly Ile
2625 2630 2635 2640
Asn Thr Val Val Lys Asn Gln Lys Gln Gln Cys Asn Asn Pro Cys Glu
2645 2650 2655
Gln Phe Asn Gly Gly Cys Ser His Ile Cys Ala Pro Gly Pro Asn Gly
2660 2665 2670
3 0 Ala Glu Cys Gln Cys Pro His Glu Gly Asn Trp Tyr Leu Ala Asn Asn
2675 2680 2685
Arg Lys His Cys Ile Val Asp Asn Gly Glu Arg Cys Gly Ala Ser Ser
2690 2695 2700
Phe Thr Cys Ser Asn Gly Arg Cys I le Ser Glu Glu Trp Lys Cys Asp
2705 2710 2715 2720
Asn Asp Asn Asp Cys Gly Asp Gly Ser Asp Glu Met Glu Ser Val Cys
2725 2730 2735
Ala Leu His Thr Cys Ser Pro Thr Ala Phe Thr Cys Ala Asn Gly Arg
2740 2745 2750
Cys Val Gln Tyr Ser Tyr Arg Cys Asp Tyr Tyr Asn Asp Cys Gly Asp
2755 2760 2765
Gly Ser Asp Glu Ala Gly Cys Leu Phe Arg Asp Cys Asn Ala Thr Thr
2770 2775 2780
Glu Phe Met Cys Asn Asn Arg Arg Cys Ile Pro Arg Glu Phe Ile Cys
2785 2790 2795 2800
Asn Gly Val Asp Asn Cys His Asp Asn Asn Thr Ser Asp Glu Lys Asn
2805 2810 2815
Cys Pro Asp Arg Thr Cys Gln Ser Gly Tyr Thr Lys Cys His Asn Ser
2820 2825 2830
60 Asn Ile Cys Ile Pro Arg Val Tyr Leu Cys Asp Gly Asp Asn Asp Cys
2835 2840 _ 2845
Gly Asp Asn Ser Asp Glu Asn Pro Thr Tyr Cys Thr Thr His Thr Cys
2850 2855 2860
_
CA 0220~648 l997-0~-20
WO 96/1~801 PCTlUSg5/15203
~D~
Ser Ser Ser Glu Phe Gln Cys Ala Ser Gly Arg Cys Ile Pro Gln His
2865 2870 2875 2880
Trp Tyr Cys Asp Gln Glu Thr Asp Cys Phe Asp Ala Ser Asp Glu Pro
2885 2890 2895
Ala Ser Cys Gly His Ser Glu Arg Thr Cys Leu Ala Asp Glu Phe Lys
2900 2905 2910
- Cys Asp Gly Gly Arg Cys Ile Pro Ser Glu Trp Ile Cys Asp Gly Asp 2915 2920 2925
Asn Asp Cys Gly Asp Met Ser Asp Glu Asp Lys Arg His Gln Cys Gln
2930 29j5 2940
Asn Gln Asn Cys Ser Asp Ser Glu Phe Leu Cys Val Asn Asp Arg Pro
2945 2950 2955 2960
Pro Asp Arg Arg Cys Ile Pro Gln Ser Trp Val Cys Asp Gly Asp Val
2965 2970 2975
Asp Cys Thr Asp Gly Tyr Asp Glu Asn Gln Asn Cys Thr Arg Arg Thr
2980 2985 2990
Cys Ser Glu Asn Glu Phe Thr Cys Gly Tyr Gly Leu Cys Ile Pro Lys
2995 3000 3005
Ile Phe Arg Cys Asp Arg His Asn Asp Cys Gly Asp Tyr Ser Asp Glu
3010 3015 3020
Arg Gly Cys Leu Tyr Gln Thr Cys Gln Gln Asn Gln Phe Thr Cys Gln
3025 3030 3035 3040
3 5 Asn Gly Arg Cys Ile Ser Lys Thr Phe Val Cys Asp Glu Asp Asn Asp
3045 3050 3055
Cys Gly Asp Gly Ser Asp Glu Leu Met His Leu Cys His Thr Pro Glu
3060 3065 3070
Pro Thr Cys Pro Pro His Glu Phe Lys Cys Asp Asn Gly Arg Cys Ile
3075 3080 3085
Glu Met Met Lys Leu Cys Asn His Leu Asp Asp Cys Leu Asp Asn Ser
3090 3095 3100
Asp Glu Lys Gly Cys Gly Ile Asn Glu Cys His Asp Pro Ser Ile Ser
3105 3110 3115 3120
Gly Cys Asp His Asn Cys Thr Asp Thr Leu Thr Ser Phe Tyr Cys Ser
3125 3130 3135
Cys Arg Pro Gly l'yr Lys Leu Met Ser Asp Lys Arg Thr Cys Val Asp
3140 3145 3150
Ile Asp Glu Cys Thr Glu Met Pro Phe Val Cys Ser Gln Lys Cys Glu
3155 3160 3165
Asn Val Ile Gly Ser Tyr Ile Cys Lys Cys Ala Pro Gly Tyr Leu Arg
3170 3175 3180
Glu Pro Asp Gly Lys Thr Cys Arg Gln Asn Ser Asn Ile Glu Pro Tyr
3185 3190 3195 3200
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
J~6
Leu Ile Phe Ser Asn Arg Tyr Tyr Leu Arg Asn Leu Thr Ile Asp Gly
3205 3210 3215
Tyr Phe Tyr Ser Leu Ile Leu Glu Gly Leu Asp Asn Val Val Ala Leu
3220 3225 3230
Asp Phe Asp Arg Val Glu Lys Arg Leu Tyr Trp Ile Asp Thr Gln Arg
3235 3240 3245
0 Gln Val Ile Glu Arg Met Phe Leu Asn Lys Thr Asn Lys Glu Thr Ile
3250 3255 3260
Ile Asn His Arg Leu Pro Ala Ala Glu Ser Leu Ala Val Asp Trp Val
3265~ 3270 3275 3280
Ser Arg Lys Leu Tyr Trp Leu Asp Ala Arg Leu Asp Gly Leu Phe Val
3285 3290 3295
Ser Asp Leu Asn Gly Gly His Arg Arg Met Leu Ala Gln His Cys Val
3300 3305 3310
Asp Ala Asn Asn Thr Phe Cys Phe Asp Asn Pro Arg Gly Leu Ala Leu
3315 3320 3325
His Pro Gln Tyr Gly Tyr Leu Tyr Trp Ala Asp Trp Gly His Arg Ala
3330 3335 3340
Tyr Ile Gly Arg Val Gly Met Asp Gly Thr Asn Lys Ser Val Ile Ile
3345 3350 3355 3360
Ser Thr Lys Leu Glu Trp Pro Asn Gly Ile Thr Ile Asp Tyr Thr Asn
3365 3370 3375
Asp Leu Leu Tyr Trp Ala Asp Ala His Leu Gly Tyr Ile Glu Tyr Ser
3380 3385 3390
Asp Leu Glu Gly His His Arg His Thr Val Tyr Asp Gly Ala Leu Pro
3395 3400 3405
His Pro Phe Ala Ile Thr Ile Phe Glu Asp Thr Ile Tyr Trp Thr Asp
3410 3415 3420
Trp Asn Thr Arg Thr Val Glu Lys Gly Asn Lys Tyr Asp Gly Ser Asn
3425 3430 3435 3440
Arg Gln Thr Leu Val Asn Thr Thr His Arg Pro Phe Asp Ile His Val
3445 3450 3455
Tyr His Pro Tyr Arg Gln Pro Ile Val Ser Asn Pro Cys Gly Thr Asn
3460 3465 3470
Asn Gly Gly Cys Ser His Leu Cys Leu Ile Lys Pro Gly Gly Lys Gly
3475 3480 3485 ;'
55 Phe Thr Cys Glu Cys Pro Asp Asp Phe Arg Thr Leu Gln Leu Ser Gly
3490 3495 3500
Ser Thr Tyr Cys Met Pro ~let Cys Ser Ser Thr Gln Phe Leu Cys Ala
3505 3510 3515 3520
Asn Asn Glu Lys Cys Ile Pro Ile Trp Trp Lys Cys Asp Gly Gln Lys
3525 3530 3535
Asp Cys Ser Asp Gly Ser Asp Glu Leu Ala Leu Cys Pro Gln Arg Phe
CA 0220~648 l997-0~-20
WO 96115801 PCT/US9S/15203
~0~
3540 3545 3550
Cys Arg Leu Gly Gln Phe Gln Cys Ser Asp Gly Asn Cys Thr Ser Pro
3555 3560 3565
Gln Thr Leu Cys Asn Ala His Gln Asn Cys Pro Asp Gly Ser Asp Glu
3570 3575 3580
Asp Arg Leu Leu Cys Glu Asn His His Cys Asp Ser Asn Glu Trp Gln
0 3585 3590 3595 3600
Cys Ala Asn Lys Arg Cys Ile Pro Glu Ser Trp Gln Cys Asp Thr Phe
3605 3610 3615
Asn Asp Cys Glu Asp Asn Ser Asp Glu Asp Ser Ser His Cys Ala Ser
3620 3625 3630
Arg Thr Cys Arg Pro Gly Gln Phe Arg Cys Ala Asn Gly Arg Cys Ile
3635 3640 3645
Pro Gln Ala Trp Lys Cys Asp Val Asp Asn Asp Cys Gly Asp His Ser
3650 3655 3660
Asp Glu Pro Ile Glu Glu Cys Met Ser Ser Ala His Leu Cys Asp Asn
3665 3670 3675 3680
Phe Thr Glu Phe Ser Cys Lys Thr Asn Tyr Arg Cys Ile Pro Lys Trp
3685 3690 3695
3 0 Ala Val Cys Asn Gly Val Asp Asp Cys Arg Asp Asn Ser Asp Glu Gln
3700 3705 3710
Gly Cys Glu Glu Arg Thr Cys His Pro Val Gly Asp Phe Arg Cys Lys
3715 3720 3725
Asn His His Cys Ile Pro Leu Arg Trp Gln Cys Asp Gly Gln Asn Asp
3730 3735 3740
Cys Gly Asp Asn Ser Asp Glu Glu Asn Cys Ala Pro Arg Glu Cys Thr
3745 3750 3755 3760
Glu Ser Glu Phe Arg Cys Val Asn Gln Gln Cys Ile Pro Ser Arg Trp
3765 3770 3775
Ile Cys Asp His Tyr Asn Asp Cys Gly Asp Asn Ser Asp Glu Arg Asp
3780 3785 3790
Cys Glu Met Arg Thr Cys His Pro Glu Tyr Phe Gln Cys Thr Ser Gly
3795 3800 3805
His Cys Val His Ser Glu Leu Lys Cys Asp Gly Ser Ala Asp Cys Leu
3810 3815 3820
Asp Ala Ser Asp Glu Ala Asp Cys Pro Thr Arg Phe Pro Asp Gly Ala
3825 3830 3835 3840
Tyr Cys Gln Ala Thr Met Phe Glu Cys Lys Asn His Val Cys Ile Pro
3845 3850 3855
60 Pro Tyr Trp Lys Cys Asp Gly Asp Asp Asp Cys Gly Asp Gly Ser Asp
3860 3865 3870
Glu Glu Leu His Leu Cys Leu Asp Val Pro Cys Asn Ser Pro Asn Arg
3875 3880 3885
CA 0220~648 1997-0~-20
WO 96/15801 PCT/US95/15203
~0~
Phe Arg Cys Asp Asn Asn Arg Cys Ile Tyr Ser His Glu Val Cys Asn
3890 3895 3900
5 Gly Val Asp Asp Cys Gly Asp Gly Thr Asp Glu Thr Glu Glu His Cys
3905 3910 3915 3920
Arg Lys Pro Thr Pro Lys Pro Cys Thr Glu Tyr Glu Tyr Lys Cys Gly
3925 3930 3935
Asn Gly His Cys Ile Pro His Asp Asn Val Cys Asp Asp Ala Asp Asp
3940 3945 3950
Cys Gly Asp Trp Ser Asp Glu Leu Gly Cys Asn Lys Gly Lys Glu Arg
3955 3960 3965
Thr Cys Ala Glu Asn Ile Cys Glu Gln Asn Cys Thr Gln Leu Asn Glu
3970 3975 3980
Gly Gly Phe Ile Cys Ser Cys Thr Ala Gly Phe Glu Thr Asn Val Phe
3985 3990 3995 4000
Asp Arg Thr Ser Cys Leu Asp Ile Asn Glu Cys Glu Gln Phe Gly Thr
4005 4010 4015
Cys Pro Gln His Cys Arg Asn Thr Lys Gly Ser Tyr Glu Cys Val Cys
4020 4025 4030
Ala Asp Gly Phe Thr Ser Met Ser Asp Arg Pro Gly Lys Arg Cys Ala
4035 4040 4045
Ala Glu Gly Ser Ser Pro Leu Leu Leu Leu Pro Asp Asn Val Arg Ile
4050 4055 4060
3 5 Arg Lys Tyr Asn Leu Ser Ser Glu Arg Phe Ser Glu Tyr Leu Gln Asp
4065 4070 4075 4080
Glu Glu Tyr Ile Gln Ala Val Asp Tyr Asp Trp Asp Pro Lys Asp Ile
4085 4090 4095
Gly Leu Ser Val Val Tyr Tyr Thr Val Arg Gly Glu Gly Ser Arg Phe
4100 4105 4110
Gly Ala Ile Lys Arg Ala Tyr Ile Pro Asn Phe Glu Ser Gly Arg Asn
4115 4120 4125
Asn Leu Val Gln Glu Val Asp Leu Lys Leu Lys Tyr Val Met Gln Pro
4130 4135 4140
Asp Gly Ile Ala Val Asp Trp Val Gly Arg His Ile Tyr Trp Ser Asp
4145 4150 4155 4160
Val Lys Asn Lys Arg Ile Glu Val Ala Lys Leu Asp Gly Arg Tyr Arg
4165 4170 4175
Lys Trp Leu Ile Ser Thr Asp Leu Asp Gln Pro Ala Ala Ile Ala Val
4180 4185 4190
Asn Pro Lys Leu Gly Leu Met Phe Trp Thr Asp Trp Gly Lys Glu Pro
4195 4200 4205
Lys Ile Glu Ser Ala Trp Met Asn Gly Glu Asp Arg Asn Ile Leu Val
4210 4215 4220
CA 0220~648 l997-0~-20
WO 96115801 PCTIUS95/15203
loq
Phe Glu Asp heu Gly Trp Pro Thr Gly Leu Ser Ile Asp Tyr Leu Asn
4225 4230 4235 4240
Asn Asp Arg Ile Tyr Trp Ser Asp Phe Lys Glu Asp Val Ile Glu Thr
4245 4250 4255
Ile Lys Tyr Asp Gly Thr Asp Arg Arg Val Ile Ala Lys Glu Ala Met
4260 4265 4270
0 Asn Pro Tyr Ser Leu Asp Ile Phe Glu Asp Gln Leu Tyr Trp Ile Ser
4275 4280 4285
Lys Glu Lys Gly Glu Val Trp Lys Gln Asn Lys Phe Gly Gln Gly Lys
4290 4295 4300
Lys Glu Lys Thr Leu Val Val Asn Pro Trp Leu Thr Gln Val Arg Ile
4305 4310 4315 4320
Phe His Gln Leu Arg Tyr Asn Lys Ser Val Pro Asn Leu Cys Lys Gln
4325 4330 4335
Ile Cys Ser His Leu Cys Leu Leu Ar~ Pro Gly Gly Tyr Ser Cys Ala
4340 4345 4350
Cys Pro Gln Gly Ser Ser Phe Ile Glu Gly Ser Thr Thr Glu Cys Asp
4355 4360 4365
Ala Ala Ile Glu Leu Pro Ile Asn Leu Pro Pro Pro Cys Arg Cys Met
4370 4375 4380
His Gly Gly Asn Cys Tyr Phe Asp Glu Thr Asp Leu Pro Lys Cys Lys
4385 4390 4395 4400
Cys Pro Ser Gly Tyr Thr Gly Lys Tyr Cys Glu Met Ala Phe Ser Lys
4405 4410 4415
Gly Ile Ser Pro Gly Thr Thr Ala Val Ala Val Leu Leu Thr Ile Leu
4420 4425 4430
Leu Ile Val Val Ile Gly Ala Leu Ala Ile Ala Gly Phe Phe His Tyr
4435 4440 4445
Arg Arg Thr Gly Ser Leu Leu Pro Ala Leu Pro Lys Leu Pro Ser Leu
4450 4455 4460
Ser Ser Leu Val Lys Pro Ser Glu Asn Gly Asn Gly Val Thr Phe Arg
4465 4470 4475 4480
Ser Gly Ala Asp Leu Asn Met Asp Ile Gly Val Ser Gly Phe Gly Pro
4485 4490 4495
Glu Thr Ala Ile Asp Arg Ser Met Ala Met Ser Glu Asp Phe Val Met
4500 4505 4510
55 Glu Met Gly Lys Gln Pro Ile Ile Phe Glu Asn Pro Met Tyr Ser Ala
4515 4520 4525
Arg Asp Ser Ala Val Lys Val Val Gln Pro Ile Gln Val Thr Val Ser
4530 4535 4540
Glu Asn Val Asp Asn Lys Asn Tyr Gly Ser Pro Ile Asn Pro Ser Glu
4545 4550 4555 4560
Ile Val Pro Glu Thr Asn Pro Thr Ser Pro Ala Ala Asp Gly Thr Gln
CA 02205648 l997-05-20
W O 96/15801 PCT~USg5/lS203
4565 4570 4575
Val Thr Lys Trp Asn ~eu Phe Lys Arg Lys Ser Lys Gln Thr Thr Asn
4580 4585 4590
Phe Glu Asn Pro Ile Tyr Ala Gln Met Glu Asn Glu Gln Lys Glu Ser
4595 4600 4605
Val Ala Ala Thr Pro Pro Pro Ser Pro Ser Leu Pro Ala Lys Pro Lys
0 4610 4615 4620
Pro Pro Ser Arg Arg Asp Pro Thr Pro Thr Tyr Ser Ala Thr Glu Asp
~625 4630 4635 4640
Thr Phe Lys Asp Thr Ala Asn Leu Val Lys Glu Asp Ser Glu Val *
4645 4650 4655
(2) INFORMATION FOR SEQ ID NO:85:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14042 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(iii) HYPOTHETICAL: NO
.(iv) ANTI-SENSE: NO
(vi) ORIGINAL SOURCE:
(A) ORGANISM: Homo sapiens
(F) TISSUE TYPE: Placenta
(ix) FEATURE:
(A) NAME/KEY: CDS
(B) LOCATION: 68..14035
. (xi) S~QUENCE DESCRIPTION: SEQ ID NO:85:
CGGTGCGGTG TGCTACGCGC GCCCACCTCC CGGGGAAGGA ACGGCGAGGC CGGGGACCGT 60
45 CGCGGAG ATG GAT CGC GGG CCG GCA GCA GTG GCG TGC ACG CTG CTC CTG 109
Met Asp Arg Gly Pro Ala Ala Val Ala Cys Thr Leu Leu Leu
1 5 10
GCT CTC GTC GCC TGC CTA GCC CCG GCC AGT GGC CAA GAA TGT GAC AGT 157
50 Ala Leu Val Ala Cys Leu Ala Pro Ala Ser Gly Gln Glu Cys Asp Ser
.15 20 25 30
GCG CAT TTT CGC TGT GGA AGT GGG CAT TGC ATC CCT GCA GAC TGG AGG 205
Ala His Phe Arg Cys Gly Ser Gly His Cys Ile Pro Ala Asp Trp Arg
35 40 45
TGT GAT GGG ACC AAA GAC TGT TCA GAT GAC GCG GAT GAA ATT GGC TGC 253
Cys Asp Gly Thr Lys Asp Cys Ser Asp Asp Ala Asp Glu Ile Gly Cys
50 55 60
GCT GTT GTG ACC TGC CAG CAG GGC TAT TTC AAG TGC CAG AGT GAG GGA 301
Ala Val Val Thr Cys Gln Gln Gly Tyr Phe Lys Cys Gln Ser Glu Gly
CA 0220~648 l997-0~-20
WO 96/lS801 PCTIUS95/1!;203
CAA TGC ATC CCC AGC TCC TGG GTG TGT GAC CAA GAT CAA GAC TGT GAT 349
Gln Cys Ile Pro Ser Ser Trp Val Cys Asp Gln Asp Gln Asp Cys Asp
80 ' 85 90
GAT GGC TCA GAT GAA CGT CAA GAT TGC TCA CAA AGT ACA TGC TCA AGT 397
Asp Gly Ser Asp Glu Arg Gln Asp Cys Ser Gln Ser Thr Cys Ser Ser
95 100 105 110
CAT CAG ATA ACA TGC TCC AAT GGT CAG TGT ATC CCA AGT GAA TAC AGG 445
0 His Gln Ile Thr Cys Ser Asn Gly Gln Cys Ile Pro Ser Glu Tyr Arg
115 - 120 125
TGC GAC CAC GTC AGA GAC TGC CCC GAT GGA GCT GAT GAG AAT GAC TGC 493
Cys Asp His Val Arg Asp Cys Pro Asp Gly Ala Asp Glu Asn Asp Cys
130 135 140
CAG TAC CCA ACA TGT GAG CAG CTT ACT TGT GAC AAT GGG GCC TGC TAT 541
Gln Tyr Pro Thr Cys Glu Gln Leu Thr Cys Asp Asn Gly Ala Cys Tyr
145 150 155
AAC ACC AGT CAG AAG TGT GAT TGG AAA GTT GAT TGC AGG GAC TCC TCA 589
Asn Thr Ser Gln Lys Cys Asp Trp Lys Val Asp Cys Arg Asp Ser Ser
160 165 170
2 5 GAT GAA ATC AAC TGC ACT GAG ATA TGC TTG CAC AAT GAG TTT TCA TGT 637
Asp Glu Ile Asn Cys Thr Glu Ile Cys Leu His Asn Glu Phe Ser Cys
175 180 185 190
GGC AAT GGA GAG TGT ATC CCT CGT GCT TAT GTC TGT GAC CAT GAC AAT 685
3 0 Gly Asn Gly Glu Cys Ile Pro Arg Ala Tyr Val Cys Asp His Asp Asn
195 200 205
GAT TGC CAA GAC GGC AGT GAY GAA CAT GCT TGC AAC TAT CCG ACC TGC 733
Asp Cys Gln Asp Gly Ser Asp Glu His Ala Cys Asn Tyr Pro Thr Cys
210 215 220
GGT GGT TAC CAG TTC ACT TGC CCC AGT GGC CGA TGC ATT TAT CAA AAC 781
Gly Gly Tyr Gln Phe Thr Cys Pro Ser Gly Arg Cys Ile Tyr Gln Asn
225 230 235
TGG GTT TGT GAT GGA GAA GAT GAC TGT AAA GAT AAT GGA GAT GAA GAT 829
Trp Val Cys Asp Gly Glu Asp Asp Cys Lys Asp Asn Gly Asp Glu Asp
240 245 250
GGA TGT GAA AGC GGT CCT CAT GAT GTT CAT AAA TGT TCC CCA AGA GAA 877
Gly Cys Glu Ser Gly Pro His Asp Val His Lys Cys Ser Pro Arg Glu
255 260 265 270
TGG TCT TGC CCA GAG TCG GGA CGA TGC ATC TCC ATT TAT AAA GTT TGT 925
Trp Ser Cys Pro Glu Ser Gly Arg Cys Ile Ser Ile Tyr Lys Val Cys
275 280 285
GAT GGG ATT TTA GAT TGC CCA GGA AGA GAA GAT GAA AAC AAC ACT AGT 973
Asp Gly Ile Leu Asp Cys Pro Gly Arg Glu Asp Glu Asn Asn Thr Ser
290 295 300
ACC GGA AAA TAC TGT AGT ATG ACT CTG TGC TCT GCC TTG AAC TGC CAG 1021
Thr Gly Lys Tyr Cys Ser Met Thr Leu Cys Ser Ala Leu Asn Cys Gln
305 310 315
TAC CAG TGC CAT GAG ACG CCG TAT GGA GGA GCG TGT TTT TGT CCC CCA 1069
Tyr Gln Cys His Glu Thr Pro Tyr Gly Gly Ala Cys Phe Cys Pro Pro
320 325 330
CA 0220~648 l997-0~-20
W O96/15801 PCT~US95/15203
GGT TAT ATC ATC AAC CAC AAT GAC AGC CGT ACC TGT GTT GAG TTT GAT 1117
Gly Tyr Ile Ile Asn His Asn Asp Ser Arg Thr Cys Val Glu Phe Asp
335 340 345 350
5 GAT TGC CAG ATA TGG GGA ATT TGT GAC CAG AAG TGT GAA AGC CGA CCT 1165
Asp Cys Gln Ile Trp Gly Ile Cys-Asp Gln Lys Cys Glu Ser Arg Pro
355 360 365
GGC CGT CAC CTG TGC CAC TGT GAA GAA GGG TAT ATC TTG GAG CGT GGA 1213
0 Gly Arg His Leu Cys His Cys Glu Glu Gly Tyr Ile Leu Glu Arg Gly
370 375 380
CAG TAT TGC AAA GCT AAT GAT TCC TTT GGC GAG GCC TCC ATT ATC TTC 1261
Gln Tyr Cys Lys Ala Asn Asp Ser Phe Gly Glu Ala Ser Ile Ile Phe
385 390 395
TCC AAT GGT CGG GAT TTG TTA ATT GGT GAT ATT CAT GGA AGG AGC TTC 1309
Ser Asn Gly Arg Asp ~eu Leu Ile Gly Asp Ile His Gly Arg Ser Phe
400 405 410
CGG ATC CTA GTG GAG TCT CAG AAT CGT GGA GTG GCC GTG GGT GTG GCT 1357
Arg Ile Leu Val Glu Ser Gln Asn Arg Gly Val Ala Val Gly Val Ala
415 420 425 430
25 TTC CAC TAT CAC CTG CAA AGA GTT TTT TGG ACA GAC ACC GTG CAA AAT 1405
Phe His Tyr His Leu Gln Arg Val Phe Trp Thr Asp Thr Val Gln Asn
435 440 445
AAG GTT TTT TCA GTT GAC ATT AAT GGT TTA AAT ATC CAA GAG GTT CTC 1453
30 Lys Val Phe Ser Val Asp Ile Asn Gly Leu Asn Ile Gln Glu Val Leu
450 455 460
AAT GTT TCT GTT GAA ACC CCA GAG AAC CTG GCT GTG GAC TGG GTT AAT 1501
Asn Val Ser Val Glu Thr Pro Glu Asn Leu Ala Val Asp Trp Val Asn
465 470 475
AAT AAA ATC TAT CTA GTG GAA ACC AAG GTC AAC CGC ATA GAT ATG GTA 1549
Asn Lys Ile Tyr Leu Val Glu Thr Lys Val Asn Arg Ile Asp Met Val
480 485 490
AAT TTG GAT GGA AGC TAT CGG GTT ACC CTT ATA ACT GAA AAC TTG GGG 1597
Asn Leu Asp Gly Ser Tyr Arg Val Thr Leu Ile Thr Glu Asn Leu Gly
495 500 505 510
45 CAT CCT AGA GGA ATT GCC GTG GAC CCA ACT GTT GGT TAT TTA TTT TTC 1645
His Pro Arg Gly Ile Ala Val Asp Pro Thr Val Gly Tyr Leu Phe Phe
515 520 525
TCA GAT TGG GAG AGC CTT TCT GGG GAA CCT AAG CTG GAA AGG GCA TTC 1693
50 Ser Asp Trp Glu Ser Leu Ser Gly Glu Pro Lys Leu Glu Arg Ala Phe
530 535 540
ATG GAT GGC AGC AAC CGT AAA GAC TTG GTG AAA ACA AAG CTG GGA TGG 1741
Met Asp Gly Ser Asn Arg Lys Asp Leu Val Lys Thr Lys Leu Gly Trp
545 . 550 555
CCT GCT GGG GTA ACT CTG GAT ATG ATA TCG AAG CGT GTT TAC TGG GTT 1789
Pro Ala Gly Val Thr Leu Asp Met Ile Ser Lys Arg Val Tyr Trp Val
560 565 570
GAC TCT CGG TTT GAT TAC ATT GAA ACT GTA ACT TAT GAT GGA ATT CAA 1837
Asp Ser Arg Phe Asp Tyr Ile Glu Thr Val Thr Tyr Asp Gly Ile Gln
575 58G 585 590
CA 0220~648 1997-0~-20
W O96/lS801 PCTrUS95/15203
AGG AAG ACT GTA GTT CAT GGA GGC TCC CTC ATT CCT CAT CCC TTT GGA 1885
Arg. Lys Thr Val Val His Gly Gly Ser Leu Ile Pro His Pro Phe Gly
595 600 605
5 GTA AGC TTA TTT GAA GGT CAG GTG TTC TTT ACA GAT TGG ACA AAG ATG 1933
Val Ser Leu Phe Glu Gly Gln Val Phe Phe Thr Asp Trp Thr Lys Met
610 615 620
. GCC GTG CTG AAG GCA AAC AAG TTC ACA GAG ACC AAC CCA CAA GTG TAC 1981
0 Ala Val Leu Lys Ala Asn Lys Phe Thr Glu Thr Asn Pro Gln Val Tyr
625 630 635
TAC CAG GCT TCC CTG AGG CCC TAT GGA GTG ACT GTT TAC CAT TCC CTC 2029
Tyr Gln Ala Ser Leu Arg Pro Tyr Gly Val Thr Val Tyr His Ser Leu
640 645 650
AGA CAG CCC TAT GCT ACC AAT CCG TGT AAA GAT AAC AAT GGG GGC TGT 2077
Arg Gln Pro Tyr Ala Thr Asn Pro Cys Lys Asp Asn Asn Gly Gly Cys
655 660 . 665 670
GAG CAG GTC TGT GTY CTC AGC CAC AGA ACA GAT AAT GAT GGT TTG GGT 2125
Glu Gln Val Cys Val Leu Ser His Arg Thr Asp Asn Asp Gly ~eu Gly
675 680 685
25 TTC CGT TGC AAG TGC ACA TTC GGC TTC CAA CTG GAT ACA GAT GAG CGC 2173
Phe Arg Cys Lys Cys Thr Phe Gly Phe Gln Leu Asp Thr Asp Glu Arg
690 695 700
CAC TGC ATT GCT GTT CAG AAT TTC CTC ATT TTT TCA TCC CAA GTT GCT 2221
30 His Cys Ile Ala Val Gln Asn Phe Leu Ile Phe Ser Ser Gln Val Ala
705 710 715
ATT CGT GGG ATC CCG TTC ACC TTG TCT ACC CAG GAA GAT GTC ATG GTT 2269
Ile Arg Gly Ile Pro Phe Thr Leu Ser Thr Gln Glu Asp Val Met Val
720 725 730
CCA GTT TCG GC7G AAT CCT TCT TTC TTT GTC GGG ATT GAT TTT GAC GCC 2317
Pro Val Ser Gly Asn Pro Ser Phe Phe Val Gly Ile Asp Phe Asp Ala
735 740 745 750
CAG GAC AGC ACT ATC TTT TTT TCA GAT ATG TCA AAA CAC ATG ATT TTT 2365
Gln Asp Ser Thr Ile Phe Phe Ser Asp Met Ser Lys His Met Ile Phe
755 760 765
45 AAG CAA AAG ATT GAT GGC ACA GGA AGA GAA ATT CTC GCA GCT AAC AGG 2413
Lys Gln Lys Ile Asp Gly Thr Gly Arg Glu Ile Leu Ala Ala Asn Arg
770 775 780
GTG GAA AAT GTT GAA AGT TTG GCT TTT GAC TGG ATT TCA AAG AAT CTC 2461
50 Val Glu Asn Val Glu Ser Leu Ala Phe Asp Trp Ile Ser Lys Asn Leu
785 790 795
TAT TGG ACA GAC TCT CAT TAC AAG AGT ATC AGT GTC ATG AGG CTA GCT 2509
Tyr Trp Thr Asp Ser His Tyr Lys Ser Ile Ser Val Met Arg Leu Ala
800 805 810
GAT AAA ACG AGA CGC ACG GTA GTT CAG TAT TTA AAT AAC CCA CGG TCG 2557
Asp Lys Thr Arg Arg Thr Val Val Gln Tyr Leu Asn Asn Pro Arg Ser
815 820 825 830
GTG GTA GTT CAT CCT TTT GCC GGG TAT CTA TTC TTC ACT GAT TGG TTC 2605
Val Val Val His Pro Phe Ala Gly Tyr Leu Phe Phe Thr Asp Trp Phe
835 840 845
CA 0220~648 1997-0~-20
W O96/15801 PCTrUS95tl5203
CGT CCT GCT AAA ATT ATG AGA GCA TGG AGT GAC GGA TCT CAC CTC TTG 2653
Arg Pro Ala Lys Ile Met Arg Ala Trp Ser Asp Gly Ser His Leu Leu
850 855 860
CCT GTA ATA AAC ACT ACT CTT GGA TGG CCC AAT GGC TTG GCC ATC GAT 2701
Pro Val Ile Asn Thr Thr Leu Gly Trp.Pro Asn Gly Leu Ala Ile Asp
865 870 875
TGG GCT GCT TCA CGA TTG TAC TGG GTA GAT GCC TAT TTT GAT AAA ATT 2749
0 Trp Ala Ala Ser Arg Leu Tyr Trp Val Asp Ala Tyr Phe Asp Lys Ile
88~ 885 890
GAG CAC AGC ACC TTT GAT GGT TTA GAC AGA AGA AGA CTG GGC CAT ATA 2797
Glu His Ser Thr Phe Asp Gly Leu Asp Arg Arg Arg Leu Gly His Ile
895 900 905 910
GAG CAG ATG ACA CAT CCG TTT GGA CTT GCC ATC TTT GGA GAG CAT TTA 2845
Glu Gln Met Thr His Pro Phe Gly Leu Ala Ile Phe Gly Glu His Leu
915 92.0 925
TTT TTT ACT GAC TGG AGA CTG GGT GCC ATT ATT CGA GTC AGG AAA GCA 2893
Phe Phe Thr Asp Trp Arg Leu Gly Ala Ile Ile Arg Val Arg Lys Ala
930 935 940
2 5 GAT GGT GGA GAA ATG ACA GTT ATC CGA AGT GGC ATT GCT TAC ATA CTG 2941
Asp Gly Gly Glu Met Thr Val Ile Arg Ser Gly Ile Ala Tyr Ile Leu
945 950 955
CAT TTG AAA TCG TAT GAT GTC AAC ATC CAG ACT GGT TCT AAC GCC TGT 2989
His Leu Lys Ser Tyr Asp Val Asn Ile Gln Thr Gly Ser Asn Ala Cys
960 965 970
AAT CAA CCC ACG CAT CCT AAC GGT GAC TGC AGC CAC TTC TGC TTC CCG 3037
Asn Gln Pro Thr His Pro Asn Gly Asp Cys Ser His Phe Cys Phe Pro
975 980 985 990
GTG CCA AAT TTC CAG CGA GTG TGT GGG TGC CCT TAT GGA ATG AGG CTG 3085
Val Pro Asn Phe Gln Arg Val Cys Gly Cys Pro Tyr Gly Met Arg Leu
995 1000 1005
GCT TCC AAT CAC TTG ACA TGC GAG GGG GAC CCA ACA AAT GAA CCA CCC 3133
Ala Ser Asn His Leu Thr Cys Glu Gly Asp Pro Thr Asn Glu Pro Pro
1010 1015 1020
4 5 ACG GAG CAG TGT GGC TTA TTT TCC TTC CCC TGT AAA AAT GGC AGA TGT 3181
Thr Glu Gln Cys Gly Leu Phe Ser Phe Pro Cys Lys Asn Gly Arg Cys
1025 1030 1035
GTG CCC AAT TAC TAT CTC TGT GAT GGA GTC GAT GAT TGT CAT GAT AAC 3229
Val Pro Asn Tyr Tyr Leu Cys Asp Gly Val Asp Asp Cys His Asp Asn
1040 1045 1050
AGT GAT GAG CAA CTA TGT GGC ACA CTT AAT AAT ACC TGT TCA TCT TCG 3277
Ser Asp Glu Gln Leu Cys Gly Thr Leu Asn Asn Thr Cys Ser Ser Ser
1055 1060 1065 1070
GCG TTC ACC TGT GGC CAT GGG GAG TGC ATT CCT GCA CAC TGG CGC TGT 3325
Ala Phe Thr Cys Gly His Gly Glu Cys Ile Pro Ala His Trp Arg Cys
1075 1080 1085
GAC AAA CGC AAC GAC TGT GTG GAT GGC AGT GAT GAG CAC AAC TGC CCC 3373
Asp Lys Arg Asn Asp Cys Val Asp Gly Ser Asp Glu His Asn Cys Pro
1090 1095 1100
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
ACC CAC GCA CCT GCT TCC TGC CTT GAC ACC CAA TAC ACC TGT GAT AAT 3421
Thr His Ala Pro Ala Ser Cys Leu Asp Thr Gln Tyr Thr Cys Asp Asn
1105 1110 1115
CAC CAG TGT ATC TCA AAG AAC TGG GTC TGT GAC ACA GAC AAT GAT TGT 3469
His Gln Cys Ile Ser Lys Asn Trp Val Cys Asp Thr Asp Asn Asp Cys
1120 1125 1130
GGG GAT GGA TCT GAT GAA AAG AAC TGC AAT TCG ACA GAG ACA TGC CAA 3517
0 Gly Asp Gly Ser Asp Glu Lys Asn Cys Asn Ser Thr Glu Thr Cys Gln
1135 1140 1145 1150
CCT AGT CAG TTT AAT TGC CCC AAT CAT CGA TGT ATT GAC CTA TCG TTT 3565
Pro Ser Gln Phe Asn Cys Pro Asn His Arg Cys Ile Asp Leu Ser Phe
1155 1160 1165
GTC TGT GAT GGT GAC AAG GAT TGT GTT GAT GGA TCT GAT GAG GTT GGT 3613
Val Cys Asp Gly Asp Lys Asp Cys Val Asp Gly Ser Asp Glu Val Gly
1170 1175 1180
TGT GTA TTA AAC TGT ACT GCT TCT CAA TTC AAG TGT GCC AGT GGG GAT 3661
Cys Val Leu Asn Cys Thr Ala Ser Gln Phe Lys Cys Ala Ser Gly Asp
1185 1190 1195
2 5 AAA TGT ATT GGC GTC ACA AAT CGT TGT GAT GGT GTT TTT GAT TGC AGT 3709
Lys Cys Ile Gly Val Thr Asn Arg Cys Asp Gly Val Phe Asp Cys Ser
1200 1205 1210
GAC AAC TCG GAT GAA GCG GGC TGT CCA ACC AGG CCT CCT GGT ATG TGC 3757
3 0 Asp Asn Ser Asp Glu Ala Gly Cys Pro Thr Arg Pro Pro Gly Met Cys
1215 1220 1225 1230
CAC TCA GAT GAA TTT CAG TGC CAA GAA GAT GGT ATC TGC ATC CCG AAC 3805
His Ser Asp Glu Phe Gln Cys Gln Glu Asp Gly Ile Cys Ile Pro Asn
1235 1240 1245
TTC TGG GAA TGT GAT GGG CAT CCA GAC TGC CTC TAT GGA TCT GAT GAG 3853
Phe Trp Glu Cys Asp Gly His Pro Asp Cys Leu Tyr Gly Ser Asp Glu
1250 1255 1260
CAC AAT GCC TGT GTC CCC AAG ACT TGC CCH TCA TCA TAT TTC CAC TGT 3901
His Asn Ala Cys Val Pro Lys Thr Cys Pro Ser Ser Tyr Phe His Cys
1265 1270 1275
GAC AAC GGA AAC TGC ATC CAC AGG SCA TGG CTC TGT GAT CGG GAC AAT 3949
Asp Asn Gly Asn Cys Ile His Arg Xaa Trp Leu Cys Asp Arg Asp Asn
1280 1285 1290
GAC TGC GGG GAT ATG AGT GAT GAG AAG GAC TGC CCT ACT CAG CCC TTT 3997
Asp Cys Gly Asp Met Ser Asp Glu Lys Asp Cys Pro Thr Gln Pro Phe
- 1295 1300 1305 1310
CGC TGT CCT AGT TGG CAA TGG CAG TGT CTT GGC CAT AAC ATC TGT GTG 4045
Arg Cys Pro Ser Trp Gln Trp Gln Cys Leu Gly His Asn Ile Cys Val
1315 . 1320 1325
AAT CTG AGT GTA GTG TGT GAT GGC ATC TTT GAC TGC CCC AAT GGG ACA 4093
Asn Leu Ser Val Val Cys Asp Gly Ile Phe Asp Cys Pro Asn Gly Thr
1330 1335 1340
GAT GAG TCC CCA CTT TGC AAT GGG AAC AGC TGC TCA GAT TTC AAT GGT 4141
Asp Glu Ser Pro Leu Cys Asn Gly Asn Ser Cys Ser Asp Phe Asn Gly
1345 1350 1355
CA 0220~648 l997-0~-20
WO 96115801 PCT/US95/15203
GGT TGT ACT CAC GAG TGT GTT CAA GAG CCC TTT GGG GCT AAA TGC CTA 4189
Gly Cys Thr His Glu Cys Val Gln Glu Pro Phe Gly Ala Lys Cys Leu
1360 1365 1370
TGT CCA TTG GGA TTC TTA CTT GCC AAT GAT TCT AAG ACC TGT GAA GAC 4237
Cys Pro Leu Gly Phe Leu Leu Ala Asn Asp Ser Lys Thr Cys Glu Asp
1375 1380 1385 1390
ATA GAT GAA TGT GAT ATT CTA GGC TCT TGT AGC CAG CAC TGT TAC AAT 4285
Ile Asp Glu Cys Asp Ile Leu Gly Ser Cys Ser Gln His Cys Tyr Asn
1395 1400 1405
ATG AGA GGT TCT TTC CGG TGC TCG TGT GAT ACA GGC TAC ATG TTA GAA 4333
Met Arg Gly Ser Phe Arg Cys Ser Cys Asp Thr Gly Tyr Met Leu Glu
1410 1415 1420
AGT GAT GGG AGG ACT TGC AAA GTT ACA GCA TCT GAG AGT CTG CTG TTA 4381
Ser Asp Gly Arg Thr Cys Lys Val Thr Ala Ser Glu Ser Leu Leu Leu
1425 1430 1435
CTT GTG GCA AGT CAG AAC AAA ATT ATT GCC GAC AGT GTC ACC TCC CAG 4429
Leu Val Ala Ser Gln Asn Lys Ile Ile Ala Asp Ser Val Thr Ser Gln
1440 1445 1450
GTC CAC AAT ATC TAT TCA TTG GTC GAG AAT GGT TCT TAC ATT GTA GCT 4477
Val His Asn Ile Tyr Ser Leu Val Glu Asn Gly Ser Tyr Ile Val Ala
1455 1460 1465 1470
GTT GAT TTT GAT TCA ATT AGT GGT CGT ATC TTT TGG TCT GAT GCA ACT 4525
3 0 Val Asp Phe Asp Ser Ile Ser Gly Arg Ile Phe Trp Ser Asp Ala Thr
1475 1480 1485
CAG GGT AAA ACC TGG AGT GCG TTT CAA AAT GGA ACG GAC AGA AGA GTG 4573
Gln Gly Lys Thr Trp Ser Ala Phe Gln Asn Gly Thr Asp Arg Arg Val
1490 1495 1500
GTA TTT GAC AGT AGC ATC ATC TTG ACT GAA ACT ATT GCA ATA GAT TGG 4621
Val Phe Asp Ser Ser Ile Ile Leu Thr Glu Thr Ile Ala Ile Asp Trp
1505 1510 1515
GTA GGT CGT AAT CTT TAC TGG ACA GAC TAT GCT CTG GAA ACA ATT GAA 4669
Val Gly Arg Asn Leu Tyr Trp Thr Asp Tyr Ala Leu Glu Thr Ile Glu
1520 1525 1530
GTC TCC AAA ATT GAT GGG AGC CAC AGG ACT GTG CTG ATT AGT AAA AAC 4717
Val Ser Lys Ile Asp Gly Ser His Arg Thr Val Leu Ile Ser Lys Asn
1535 1540 1545 1550
CTA ACA AAT CCA AGA GGA CTA GCA TTA GAT CCC AGA ATG AAT GAG CAT 4765
Leu Thr Asn Pro Arg Gly Leu Ala Leu Asp Pro Arg Met Asn Glu His
1555 1560 1565
CTA CTG TTC TGG TCT GAC TGG GGC CAC CAC CCT CGC ATC GAG CGA GCC 4813
Leu Leu Phe Trp Ser Asp Trp Gly His His Pro Arg Ile Glu Arg Ala
1570 1575 1580
AGC ATG GAC GGC AGC ATG CGC ACT GTC ATT GTC CAG GAC AAG ATC TTC 4861
Ser Met Asp Gly Ser Met Arg Thr Val Ile Val Gln Asp Lys Ile Phe
1585 1590 1595
TGG CCC TGC GGC TTA ACT ATT GAC TAC CCC AAC AGA CTG CTC TAC TTC 4909
Trp Pro Cy5 Gly Leu Thr Ile Asp Tyr Pro Asn Arg Leu Leu Tyr Phe
1600 1605 1610
CA 0220~648 1997-0~-20
WO 96/15801 PCT/US95/15203
ATG GAC TCC TAT CTT GAT TAC ATG GAC TTT TGC GAT TAT AAT GGA CAC 4957
Met Asp Ser Tyr Leu Asp Tyr Met Asp Phe Cys Asp Tyr Asn Gly His
1615 1620 1625 1630
5 CAT CGG AGA CAG GTG ATA GCC AGT GAT TTG ATT ATA CGG CAC CCC TAT 5005
His Arg Arg Gln Val Ile Ala Ser Asp Leu Ile Ile Arg His Pro Tyr
1635 1640 1645
GCC CTA ACT CTC TTT GAA GAC TCT GTG TAC TGG ACT GAC CGT GCT ACT S053
0 Ala Leu Thr Leu Phe Glu Asp Ser Val Tyr Trp Thr Asp Arg Ala Thr
1650 1655 1660
CGT CGG GTT ATG CGA GCC AAC AAG TGG CAT GGA GGG AAC CAG TCA GTT 510.1
Arg Arg Val Met Arg Ala Asn Lys Trp His Gly Gly Asn Gln Ser Val
1665 1670 1675
GTA ATG TAT AAT ATT CAA TGG CCC CTT GGG ATT GTT GCG GTT CAT CCT 5149
Val Met Tyr Asn Ile Gln Trp Pro Leu Gly Ile Val Ala Val His Pro
1680 1685 1690
TCG AAA CAA CCA AAT TCT GTG AAT CCA TGT GCC TTT TCC CGC TGC AGC 5197
Ser Lys Gln Pro Asn Ser Val Asn Pro Cys Ala Phe Ser Arg Cys Ser
1695 1700 1705 1710
25 CAT CTC TGC CTG CTT TCC TCA CAG GGG CCT CAT TTT TAC TCC TGT GTT 5245
His Leu Cys Leu Leu Ser Ser Gln Gly Pro His Phe Tyr Ser Cys Val
1715 1720 1725
TGT CCT TCA GGA TGG AGT CTG TCT CCT GAT CTC CTG AAT TGC TTG AGA 5293
30 Cys Pro Ser Gly Trp Ser Leu Ser Pro Asp Leu Leu Asn Cys Leu Arg
1730 1735 1740
GAT GAT CAA CCT TTC TTA ATA ACT GTA AGG CAA CAT ATA ATT TTT GGA 5341
Asp Asp Gln Pro Phe Leu Ile Thr Val Arg Gln His Ile Ile Phe Gly
1745 1750 1755
ATC TCC CTT AAT CCT GAG GTG AAG AGC AAT GAT GCT ATG GTC CCC ATA 5389
Ile Ser Leu Asn Pro Glu Val Lys Ser Asn Asp Ala Met Val Pro Ile
1760 1765 1770
GCA GGG ATA CAG AAT GGT TTA GAT GTT GAA TTT GAT GAT GCT GAG CAA 5437
Ala Gly Ile Gln Asn Gly Leu Asp Val Glu Phe Asp Asp Ala Glu Gln
1775 1780 1785 1790
45 TAC ATC TAT TGG GTT GAA AAT CCA GGT GAA ATT CAC AGA GTG AAG ACA 5485
Tyr Ile Tyr Trp Val Glu Asn Pro Gly Glu Ile His Arg Val Lys Thr
1795 1800 1805
GAT GGC ACC AAC AGG ACA GTA TTT GCT TCT ATA TCT ATG GT.G GGG CCT 5533
50 Asp Gly Thr Asn Arg Thr Val Phe Ala Ser Ile Ser Met Val Gly Pro
1810 1815 1820
TCT ATG AAC CTG GCC TTA GAT TGG ATT TCA AGA AAC CTT TAT TCT ACC 5581
Ser Met Asn Leu Ala Leu Asp Trp Ile Ser Arg Asn Leu Tyr Ser Thr
1825 1830 1835
AAT CCT AGA ACT CAG TCA ATC GAG GTT TTG ACA CTC CAC GGA GAT ATC 5629
Asn Pro Arg Thr Gln Ser Ile Glu Val Leu Thr Leu His Gly Asp Ile
1840 1845 1850
AGA TAC AGA AAA ACA TTG ATT GCC AAT GAT GGG ACA GCT CTT GGA GTT 5677
Arg Tyr Arg Lys Thr Leu Ile Ala Asn As~ Gly Thr Ala Leu Gly Val
1855 1860 1865 1870
CA 0220~648 l997-0~-20
W O96/15801 PCTrUS9S/15203
/ ~ ~
GGC TTT CCA ATT GGC ATA ACT GTT GAT CCT GCT CGT GGG AAG CTG TAC 5725
Gly Phe Pro Ile Gly Ile Thr Val Asp Pro Ala Arg Gly Lys Leu Tyr
1875 1880 1885
5 TGG TCA GAC CAA GGA ACT GAC AGT GGG GTT CCT GCC AAG ATC GCC AGT 5773 e
Trp Ser Asp Gln Gly Thr Asp Ser Gly Val Pro Ala Lys Ile Ala Ser
1890 1895 1900
GCT AAC ATG GAT GGC ACA TCT GTG AAA ACT CTC TTT ACT GGG AAC CTC 5821
10 Ala Asn Met Asp Gly Thr Ser Val Lys Thr Leu Phe Thr Gly Asn Leu
1905 1910 1915
GAA CAC CTG GAG TGT GTC ACT CTT GAC ATC GAA GAG CAG AAA.CTC TAC 5869
Glu His Leu Glu Cys Val Thr Leu Asp Ile Glu Glu Gln Lys Leu Tyr
1920 1925 1930
TGG GCA GTC ACT GGA AGA GGA GTG ATT GAA AGA GGA AAC GTG GAT GGA 5917
Trp Ala Val Thr Gly Arg Gly Val Ile Glu Arg Gly Asn Val Asp Gly
1935 1940 1945 l9S0
ACA GAT CGG ATG ATC CTG GTA CAC CAG CTT TCC CAC CCC TGG GGA ATT 5965
Thr Asp Arg Met Ile Leu Val His Gln Leu Ser His Pro Trp Gly Ile
1955 1960 1965
25 GCA GTC CAT GAT TCT TTC CTT TAT TAT ACT GAT GAA CAG TAT GAG GTC 6013
Ala Val His Asp Ser Phe Leu Tyr Tyr Thr Asp Glu Gln Tyr Glu Val
1970 1975 1980
ATT GAA AGA GTT GAT AAG GCC ACT GGG GCC AAC AAA ATA GTC TTG AGA 6061
30 Ile Glu Arg Val Asp Lys Ala Thr Gly Ala Asn Lys Ile Val Leu Arg
1985 1990 1995
GAT AAT GTT CCA AAT CTG AGG GGT CTT CAA GTT TAT CAC AGA CGC AAT 6109
Asp Asn Val Pro Asn Leu Arg Gly Leu Gln Val Tyr His Arg Arg Asn
2000 2005 2010
GCC GCC GAA TCC TCA AAT GGC TGT AGC AAC AAC ATG AAT GCC TGT CAG 6157
Ala Ala Glu Ser Ser Asn Gly Cys Ser Asn Asn Met Asn Ala Cys Gln
2015 2020 2025 2030
CAG ATT TGC CTG CCT GTA CCA GGA GGA TTG TTT TCC TGC GCC TGT GCC 6205
Gln Ile Cys Leu Pro Val Pro Gly Gly Leu Phe Ser Cys Ala Cys Ala
2035 2040 2045
45 ACT GGA TTT AAA CTC AAT CCT GAT AAT CGG TCC TGC TCT CCA TAT AAC 6253
Thr Gly Phe Lys Leu Asn Pro Asp Asn Arg Ser Cys Ser Pro Tyr Asn
2050 2055 2060
TCT TTC ATT GTT GTT TCA ATG CTG TCT GCA ATC AGA GGC TTT AGC TTG 6301
50 Ser Phe Ile Val Val Ser Met Leu Ser Ala Ile Arg Gly Phe Ser Leu
2065 2070 2075
GAA TTG TCA GAT CAT TCA GAA ACC ATG GTG CCG GTG GCA GGC CAA GGA 6349
Glu Leu Ser Asp His Ser Glu Thr Met Val Pro Val Ala Gly Gln Gly
2080 .2085 2090
CGA AAC GCA CTG CAT GTG GAT GTG GAT GTG TCC TCT GGC TTT ATT TAT 6397
Arg Asn Ala Leu His Val Asp Val Asp Val Ser Ser Gly Phe Ile Tyr
2095 2100 2105 2110
TGG TGT GAT TTT AGC AGC TCA GTG GCA TCT GAT AAT GCG ATC CGT AGA 6445
Trp Cys Asp Phe Ser Ser Ser Val Ala Ser Asp Asn Ala Ile Arg Arg
2115 2120 2125
_
CA 0220~648 l997-0~-20
W O 96/15801 PCT~US95/15203
ATT AAA CCA GAT GGA TCT TCT CTG ATG AAC ATT GTG ACA CAT GGA ATA 6493
Ile Lys Pro Asp Gly Ser Ser Leu Met Asn Ile Val Thr His Gly Ile
2130 2135 2140
5 GGA GAA AAT GGA GTC CGG GGT ATT GCA GTG GAT TGG GTA GCA GGA AAT 6541
Gly Glu Asn Gly Val Arg Gly Ile Ala Val Asp Trp Val Ala Gly Asn
2145 2150 2155
CTT TAT TTC ACC AAT GCC TTT GTT TCT GAA ACA CTG ATA GAA GTT CTG 6589
10 heu Tyr Phe Thr Asn Ala Phe Val Ser Glu Thr Leu Ile Glu Val Leu
2160 2165 2170
CGG ATC AAT ACT ACT TAC CGC CGT GTT CTT CTT AAA GTC ACA GTG GAC 6637
Arg Ile Asn Thr Thr Tyr Arg Arg Val Leu Leu Lys Val Thr Val Asp
2175 2180 2185 2190
ATG CCT AGG CAT ATT GTT GTA GAT CCC AAG AAC AGA TAC CTC TTC TGG 6685
Met Pro Arg ~is Ile Val Val Asp Pro Lys Asn Arg Tyr Leu Phe Trp
2195 2200 2205
GCT GAC TAT GGG CAG AGA CCA AAG ATT GAG CGT TCT TTC CTT GAC TGT 6733
Ala Asp Tyr Gly Gln Arg Pro Lys Ile Glu Arg Ser Phe Leu Asp Cys
2210 2215 2220
25 ACC AAT CGA ACA GTG CTT GTG TCA GAG GGC ATT GTC ACA CCA CGG GGC 6781
Thr Asn Arg Thr Val Leu Val Ser Glu Gly Ile Val Thr Pro Arg Gly
2225 2230 2235
TTG GCA GTG GAC CGA AGT GAT GGC TAC GTT TAT TGG GTT GAT GAT TCT 6829
30 Leu Ala Val Asp Arg Ser Asp Gly Tyr Val Tyr Trp Val Asp Asp Ser
2240 2245 2250
TTA GAT ATA ATT GCA AGG ATT CGT ATC AAT GGA GAG AAC TCT GAA GTG 6877
Leu Asp Ile Ile Ala Arg Ile Arg Ile Asn Gly Glu Asn Ser Glu Val
2255 2260 2265 2270
ATT CGT TAT GGC AGT CGT TAC CCA ACT CCT TAT GGC ATC ACT GTT TTT 6925
Ile Arg Tyr Gly Ser Arg Tyr Pro Thr Pro Tyr Gly Ile Thr Val Phe
2275 2280 2285
GAA AAT TCT ATC ATA TGG GTA GAT AGG AAT TTG AAA AAG ATC TTC CAA 6973 .
Glu Asn Ser Ile Ile Trp Val Asp Arg Asn Leu Lys Lys Ile Phe Gln
2290 2295 2300
45 GCC AGC AAG GAA CCA GAG AAC ACA GAG CCA CCC ACA GTG ATA AGA GAC 7021
Ala Ser Lys Glu Pro Glu Asn Thr Glu Pro Pro Thr Val Ile Arg Asp
2305 2310 2315
AAT ATC AAC TGG CTA AGA GAT GTG ACC ATC TTT GAC AAG CAA GTC CAG 7069
50 Asn Ile Asn Trp Leu Arg Asp Val Thr Ile Phe Asp Lys Gln Val Gln
2320 2325 2330
CCC CGG TCA CCA GCA GAG GTC AAC AAC AAC CCT TGC TTG GAA AAC AAT 7117
Pro Arg Ser Pro Ala Glu Val Asn Asn Asn Pro Cys Leu Glu Asn Asn
2335 2340 2345 2350
GGT GGG TGC TCT CAT CTC TGC TTT GCT CTG CCT GGA TTG CAC ACC CCA 7165
Gly Gly Cys Ser His Leu Cys Phe Ala Leu Pro Gly Leu His Thr Pro
2355 2360 2365
AAA TGT GAC TGT GCC TTT GGG ACC CTG CAA AGT GAT GGC AAG AAT TGT 7213
Lys Cys Asp Cys Ala Phe Gly Thr Leu Gln Ser Asp Gly Lys Asn Cys
2370 2375 2380
CA 0220~648 1997-0~-20
WO 96/lS801 PCTIUS95/15203
/~
GCC ATT TCA ACA GAA AAT TTC CTC ATC TTT GCC TTG TCT AAT TCC TTG 7261
Ala Ile Ser Thr Glu Asn Phe Leu Ile Phe Ala Leu Ser Asn Ser Leu
2385 2390 2395
5 AGA AGC TTA CAC TTG GAC CCT GAA AAC CAT AGC CCA CCT TTC CAA ACA 7309
Arg Ser Leu His Leu Asp Pro Glu Asn His Ser Pro Pro Phe Gln Thr
2400 2405 2410
.ATA AAT GTG GAA AGA ACT GTC ATG TCT CTA GAC TAT GAC AGT GTA AGT 7357
0 Ile Asn Val Glu Ar~ Thr Val Met Ser Leu Asp Tyr Asp Ser Val Ser
2415 2420 2425 2430
GAT AGA ATC TAC TTC ACA CAA AAT TTA GCC TCT GGA GTT GGA CAG ATT 7405
Asp Arg Ile Tyr Phe Thr Gln Asn Leu Ala Ser Gly Val Gly Gln Ile
2435 2440 2445
TCC TAT GCC ACC CTG TCT TCA GGG ATC CAT ACT CCA ACT GTC ATT GCT 7453
Ser Tyr Ala Thr Leu Ser Ser Gly Ile His Thr Pro Thr Val Ile Ala
2450 2455 2460
TCA GGT ATA GGG ACT GCT GAT GGC ATT GCC TTT GAC TGG ATT ACT AGA 7501
Ser Gly Ile Gly Thr Ala Asp Gly Ile Ala Phe Asp Trp Ile Thr Arg
2465 2470 2475
25 AGA ATT TAT TAC AGT GAC TAC CTC AAC CAG ATG ATT AAT TCC ATG GCT 7549
Arg Ile Tyr Tyr Ser Asp Tyr Leu Asn Gln Met Ile Asn Ser Met Ala
2480 2485 2490
GAA GAT GGG TCT AAC CGC ACT GTG ATA GCC CGC GTT CCA AAA CCA AGA 7597
30 Glu.Asp Gly Ser Asn Arg Thr Val Ile Ala Arg Val Pro Lys Pro Arg
2495 2500 2505 2510
GCA ATT GTG TTA GAT CCC TGC CAA GGG TAC CTG TAC TGG GCT GAC TGG 7645
Ala Ile Val Leu Asp Pro Cys Gln Gly Tyr Leu Tyr Trp Ala Asp Trp
2515 2520 2525
GAT ACA CAT GCC AAA ATC GAG AGA GCC ACA TTG GGA GGA AAC TTC CGC 7693
Asp Thr His Ala Lys Ile Glu Arg Ala Thr Leu Gly Gly Asn Phe Arg
2530 2535 2540
GTA CCC ATT GTG AAC AGC AGT CTG GTC ATG CCC AGT GGG CTG ACT CTG 7741
Val Pro Ile Val Asn Ser Ser Leu Val Met Pro Ser Gly Leu Thr Leu
2545 2550 2555
45 GAC TAT GAA GAG GAC CTT CTC TAC TGG GTG GAT GCT AGT CTG CAG AGG 7789
Asp Tyr Glu Glu Asp Leu Leu Tyr Trp Val Asp Ala Ser Leu Gln Arg
2560 2565 2570
ATT GAA CGC AGC ACT CTG ACG GGC GTG GAT CGT GAA GTC ATT GTC AAT 7837
50 Ile Glu Arg Ser Thr Leu Thr Gly Val Asp Arg Glu Val Ile Val Asn
2575 2580 2585 2590
GCA GCC GTT CAT GCT TTT GGC TTG ACT CTC TAT GGC CAG TAT ATT TAC 7885
Ala Ala Val His Ala Phe Gly Leu Thr Leu Tyr Gly Gln Tyr Ile Tyr
2595 2600 2605
TGG ACT GAC TTG TAC ACA CAA AGA ATT TAC CGA GCT AAC AAA TAT GAC 7933
Trp Thr Asp Leu Tyr Thr Gln Arg Ile~Tyr Arg Ala Asn Lys Tyr Asp
2610 2615 2620
GGG TCA GGT CAG ATT GCA ATG ACC ACA AAT TTG CTC TCC CAG CCC AGG 7981
Gly Ser Gly Gln Ile Ala Met Thr Thr Asn Leu Leu Ser Gln Pro Arg
2625 2630 . 2635
CA 0220~648 1997-05-20
W O 96/lS801 PCT~US95J15203
GGA ATC AAC ACT GTT GTG AAG AAC CAG AAA CAA CAG TGT AAC AAT CCT 8029
Gly Ile Asn Thr Val Val Lys Asn Gln Lys Gln Gln Cys Asn Asn Pro
2640 2645 2650
TGT GAA CAG TTT AAT GGG GGC TGC AGC CAT ATC TGT GCA CCA GGT CCA 8077
Cys Glu Gln Phe Asn Gly Gly Cys Ser.His Ile Cys Ala Pro Gly Pro
2655 2660 2665 2670
AAT GGT GCC GAG TGC CAG TGT CCA CAT GAG GGC AAC TGG TAT TTG GCC 8125
0 Asn Gly Ala Glu Cys Gln Cys Pro His Glu Gly Asn Trp Tyr Leu Ala
2675 2680 2685
AAC AAC AGG AAG CAC TGC ATT GTG GAC AAT GGT GAA CGA TGT GGT GCA 8173
Asn Asn Arg Lys His Cys Ile Val Asp Asn Gly Glu Arg Cys Gly Ala
2690 2695 2700
TCT TCC TTC ACC TGC TCC AAT GGG CGC TGC ATC TCG GAA GAG TGG AAG 8221
Ser Ser Phe Thr Cys Ser Asn Gly Arg Cys Ile Ser Glu Glu Trp Lys
2705 2710 2715
TGT GAT AAT GAC AAC GAC TGT GGG GAT GGC AGT GAT GAG ATG GAA AGT 8269
Cys Asp Asn Asp Asn Asp Cys Gly Asp Gly Ser Asp Glu Met Glu Ser
2720 2725 2730
2 5 GTC TGT GCA CTT CAC ACC TGC TCA CCG ACA GCC TTC ACC TGT GCC AAT 8317
Val Cys Ala Leu His Thr Cys Ser Pro Thr Ala Phe Thr Cys Ala Asn
2735 2740 2745 2750
GGG CGA TGT GTC CAA TAC TCT TAC CGC TGT GAT TAC TAC AAT GAC TGT 8365
3 0 Gly Arg Cys Val Gln Tyr Ser Tyr Arg Cys Asp Tyr Tyr Asn Asp Cys
2755 2760 2765
GGT GAT GGC AGT GAT GAG GCA GGG TGC CTG TTC AGG GAC TGC AAT GCC 8413
Gly Asp Gly Ser Asp Glu Ala Gly Cys Leu Phe Arg Asp Cys Asn Ala
2770 2775 2780
ACC ACG GAG TTT ATG TGC AAT AAC AGA AGG TGC ATA CCT CGT GAG TTT 8461
Thr Thr Glu Phe Met Cys Asn Asn Arg Arg Cys Ile Pro Arg Glu Phe
2785 2790 2795
ATC TGC AAT GGT GTA GAC AAC TGC CAT GAT AAT AAC ACT TCA GAT GAG 8509
Ile Cys Asn Gly Val Asp Asn Cys His Asp Asn Asn Thr Ser Asp Glu
2800 2805 2810
AAA AAT TGC CCT GAT CGC ACT TGC CAG TCT GGA TAC ACA AAA TGT CAT 8557
Lys Asn Cys Pro Asp Arg Thr Cys Gln Ser Gly Tyr Thr Lys Cys His
2815 2820 2825 2830
AAT TCA AAT ATT TGT ATT CCT CGC GTT TAT TTG TGT GAC GGA GAC AAT 8605
Asn Ser Asn Ile Cys Ile Pro Arg Val Tyr Leu Cys Asp Gly Asp Asn
2835 2840 2845
GAC TGT GGA GAT AAC AGT GAT GAA AAC CCT ACT TAT TGC ACC ACT CAC 8653
Asp Cys Gly Asp Asn Ser Asp Glu Asn Pro Thr Tyr Cys Thr Thr His
- 55 2850 2855 2860
ACG TGC AGC AGC AGT GAG TTC CAA TGC ACA TCT GGG CGC TGT ATT CCT 8701
Thr Cys Ser Ser Ser Glu Phe Gln Cys Thr Ser Gly Arg Cys Ile Pro
2865 2870 2875
CAA CAT TGG TAT TGT GAT CAA GAA ACA GAT TGT TTT GAT GCC TCT GAT 8749
Gln His Trp Tyr Cys Asp Gln Glu Thr Asp Cys Phe Asp Ala Ser Asp
2880 28~5 2890
-
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
GAA CCT GCC TCT TGT GGT CAC TCT GAG CGA ACA TGC CTA GCT GAT GAG 8797
Glu Pro Ala Ser Cys Gly His Ser Glu Arg Thr Cys Leu Ala Asp Glu
2895 2900 2905 2910
TTC AAG TGT GAT GGT GGG AGG TGC ATC CCA AGC GAA TGG ATC TGT GAC 8845
Phe Lys Cys Asp Gly Gly Arg Cys Ila Pro Ser Glu Trp Ile Cys Asp
2915 2920 2925
GGT GAT AAT GAC TGT GGG GAT ATG AGT GAC GAG GAT AAA AGG CAC CAG 8893
0 Gly Asp Asn Asp Cys Gly Asp Met Ser Asp Glu Asp Lys Arg His Gln
2930 2935 2940
TGT CAG AAT CAA AAC TGC TCG GAT TCC GAG TTT CTC TGT GTA AAT GAC 8941
Cys Gln Asn Gln Asn Cys Ser Asp Ser Glu Phe Leu Cys Val Asn Asp
2945 2950 2955
AGA CCT CCG GAC AGG AGG TGC ATT CCC CAG TCT TGG GTC TGT GAT GGC 8989
Arg Pro Pro Asp Arg Arg Cys Ile Pro Gln Ser Trp Val Cys Asp Gly
2960 2965 2970
GAT GTG GAT TGT ACT GAC GGC TAC GAT GAG AAT CAG AAT TGC ACC AGG 9037
Asp Val Asp Cys Thr Asp Gly Tyr Asp Glu Asn Gln Asn Cys Thr Arg
2975 2980 2985 2990
2 5 AGA ACT TGC TCT GAA AAT GAA TTC ACC TGT GGT TAC GGA CTG TGT ATC 9085
Arg Thr Cys Ser Glu Asn Glu Phe Thr Cys Gly Tyr Gly Leu Cys Ile
2995 3000 3005
CCA AAG ATA TTC AGG TGT GAC CGG CAC AAT GAC TGT GGT GAC TAT AGC 9133
Pro Lys Ile Phe Arg Cys Asp Arg His Asn Asp Cys Gly Asp Tyr Ser
3010 3015 3020
GAC GAG AGG GGC TGC TTA TAC CAG ACT TGC CAA CAG AAT CAG TTT ACC 9181
Asp Glu Arg Gly Cys Leu Tyr Gln Thr Cys Gln Gln Asn Gln Phe Thr
3025 3030 3035
TGT CAG AAC GGG CGC TGC ATT AGT AAA ACC TTC GTC TGT GAT GAG GAT 9229
Cys Gln Asn Gly Arg Cys Ile Ser Lys Thr Phe Val Cys Asp Glu Asp
3040 3045 3050
AAT GAC TGT GGA GAC GGA TCT GAT GAG CTG ATG CAC CTG TGC CAC ACC 9277
Asn Asp Cys Gly Asp Gly Ser Asp Glu Leu Met His Leu Cys His Thr
3055 3060 3065 3070
CCA GAA CCC ACG TGT CCA CCT CAC GAG TTC AAG TGT GAC AAT GGG CGC 9325
. Pro Glu Pro Thr Cys Pro Pro His Glu Phe Lys Cys Asp Asn Gly Arg
3075 3080 3085
TGC ATC GAG ATG ATG AAA CTC TGC AAC CAC CTA GAT GAC TGT TTG GAC 9373
Cys Ile Glu Met Met Lys Leu Cys Asn His Leu Asp Asp Cys Leu Asp
3090 3095 3100
AAC AGC GAT GAG AAA GGC TGT GGC ATT AAT GAA TGC CAT GAC CCT TCA 9421
Asn Ser Asp Glu Lys Gly Cys Gly Ile Asn Glu Cys His Asp Pro Ser
3105 3110 3115
ATC AGT GGC TGC GAT CAC AAC TGC ACA GAC ACC TTA ACC AGT TTC TAT 9469
Ile Ser Gly Cys Asp His Asn Cys Thr Asp Thr Leu Thr Ser Phe Tyr
3120 3125 3130
TGT TCC TGT CGT CCT GGT TAC AAG CTC ATG TCT GAC AAG CGG ACT TGT 9517
Cys Ser Cys Arg Pro Gly Tyr Lys Leu Met Ser Asp Lys Arg Thr Cys
3135 3140 3145 315Q
CA 0220~648 1997-0~-20
W O 96115801 PCTrUS95115203
1~ 3
GTT GAT ATT GAT GAA TGC ACA GAG ATG CCT TTT GTC TGT AGC CAG AAG 9 565
Val Asp Ile Asp Glu Cys Thr Glu Met Pro Phe Val Cys Ser Gln Lys
3155 3160 3165
5 TGT GAG AAT GTA ATA GGC TCC TAC ATC TGT AAG TGT GCC CCA GGC TAC 9613
Cys Glu Asn Val Ile Gly Ser Tyr Ile Cys Lys Cys Ala Pro Gly Tyr
3170 3175 3180
CTC CGA GAA CCA GAT GGA AAG ACC TGC CGG CAA AAC AGT AAC ATC GAA 9661
0 Leu Arg Glu Pro Asp Gly Lys Thr Cys Arg Gln Asn Ser As~ Ile Glu
3185 3190 3195
CCC TAT CTC ATT TTT AGC AAC CGT TAC TAT TTG AGA AAT TTA ACT ATA 9 709
Pro Tyr Leu Ile Phe Ser Asn Arg Tyr Tyr Leu Arg Asn Leu Thr Ile
3200 3205 3210
GAT GGC TAT TTT TAC TCC CTC ATC TTG GAA GGA CTG GAC AAT GTT GTG 9757
Asp Gly Tyr Phe Tyr Ser Leu Ile Leu Glu Gly Leu Asp Asn Val Val
3215 3220 3225 3230
GCA TTA GAT TTT GAC CGA GTA GAG AAG AGA TTG TAT TGG ATT GAT ACA 980 5
Ala Leu Asp Phe Asp Arg Val Glu Lys Arg Leu Tyr Trp Ile Asp Thr
3235 3240 3245
25 CAG AGG CAA GTC ATT GAG AGA ATG TTT CTG AAT AAG ACA AAC AAG GAG 9 853
Gln Arg Gln Val Ile Glu Arg Met Phe Leu Asn Lys Thr Asn Lys Glu
3250 3255 3260
ACA ATC ATA AAC CAC AGA CTA CCA GCT GCA GAA AGT CTG GCT GTA GAC 990l
30 Thr Ile Ile Asn His Arg Leu Pro Ala Ala Glu Ser Leu Ala Val Asp
3265 3270 3275
TGG GTT TCC AGA AAG CTC TAC TGG TTG GAT GCC CGC CTG GAT GGC CTC 9949
Trp Val Ser Arg Lys Leu Tyr Trp Leu Asp Ala Arg Leu Asp Gly Leu
3280 3285 3290
TTT GTC TCT GAC CTC AAT GGT GGA CAC CGC CGC ATG CTG GCC CAG CAC 999 7
Phe Val Ser Asp Leu Asn Gly Gly His Arg Arg Met Leu Ala Gln His
3295 3300 3305 3310
TGT GTG GAT GCC AAC AAC ACC TTC TGC TTT GAT AAT CCC AGA GGA CTT 10045
Cys Val Asp Ala Asn Asn Thr Phe Cys Phe Asp Asn Pro Arg Gly Leu
3315 3320 3325
GCC CTT CAC CCT CAA TAT GGG TAC CTC TAC TGG GCA GAC TGG GGT CAC lO09 3
Ala Leu His Pro Gln Tyr Gly Tyr Leu Tyr Trp Ala Asp Trp Gly His
3330 3335 33~0
CGC GCA TAC ATT GGG AGA GTA-GGC ATG GAT GGA ACC AAC AAG TCT GTG lOl4l
Arg Ala Tyr Ile Gly Arg Val Gly Met Asp Gly Thr Asn Lys Ser Val
3345 3350 3355
ATA ATC TCC ACC AAG TTA GAG TGG CCT AAT GGC ATC ACC ATT GAT TAC 10189
Ile Ile Ser Thr Lys Leu Glu Trp Pro Asn Gly Ile Thr Ile Asp Tyr
3360 3365 3370
ACC AAT GAT CTA CTC TAC TGG GCA GAT GCC CAC CTG GGT TAC ATA GAG 10237
Thr Asn Asp Leu Leu Tyr Trp Ala Asp Ala His Leu Gly Tyr Ile Glu
3375 3380 3385 3390
TAC TCT GAT TTG GAG GGC CAC CAT CGA CAC ACG GTG TAT GAT GGG GCA lO 285
Tyr Ser Asp Leu Glu Gly His His Arg His Thr Val Tyr Asp Gly Ala
3395 3400 3405
CA 0220~648 1997-OS-20
W O96115801 PCTrUS95115203
J~ ~/
CTG CCT CAC CCT TTC GCT ATT ACC ATT TTT GAA GAC ACT ATT TAT TGG 10333
Leu Pro His Pro Phe Ala Ile Thr Ile Phe Glu Asp Thr Ile Tyr Trp
3410 3415 3420
ACA GAT TGG AAT ACA AGG ACA GTG GAA AAG GGA AAC AAA TAT GAT GGA 10381
Thr Asp Trp Asn Thr Arg Thr Val Glu Lys Gly Asn Lys Tyr Asp Gly
3425 3430 3435
TCA AAT AGA CAG ACA CTG GTG AAC ACA ACA CAC AGA CCA TTT GAC ATC 10429
0 Ser Asn Arg Gln Thr Leu Val Asn Thr Thr His Arg Pro Phe Asp Ile
3440 3445 3450
CAT GTG TAC CAT CCA TAT AGG CAG CCC ATT GTG AGC AAT CCC TGT GGT 10477
His Val Tyr His Pro Tyr Arg Gln Pro Ile Val Ser Asn Pro Cys Gly
3455 3460 3465 3470
ACC AAC AAT GGT GGC TGT TCT CAT CTC TGC CTC ATC AAG CCA GGA GGA 10525
Thr Asn Asn Gly Gly Cys Ser His Leu Cys Leu Ile Lys Pro Gly Gly
3475 3480 3485
AAA GGG TTC ACT TGC GAG TGT CCA GAT GAC TTC CGC ACC CTT CAG CTG 10573
Lys Gly Phe Thr Cys Glu Cys Pro Asp Asp Phe Arg Thr Leu Gln Leu
3490 3495 3500
AGT GGC AGC ACC TAC TGC ATG CCC ATG TGC TCC AGC ACC CAG TTC CTG 10621
Ser Gly Ser Thr Tyr Cys Met Pro Met Cys Ser Ser Thr Gln Phe Leu
3505 3510 3515
TGC GCT AAC AAT GAA AAG TGC ATT CCT ATC TGG TGG AAA TGT GAT GGA 10669
3 0 Cys Ala Asn Asn Glu Lys Cys Ile Pro Ile Trp Trp Lys Cys Asp Gly
3520 3525 3530
CAG AAA GAC TGC TCA GAT GGC TCT GAT GAA CTG GCC CTT TGC CCG CAG 10717
Gln Lys Asp Cys Ser Asp Gly Ser Asp Glu Leu Ala Leu Cys Pro Gln
3535 3540 3545 3550
CGC TTC TGC CGA CTG GGA CAG TTC CAG TGC AGT GAC GGC AAC TGC ACC 10765
Arg Phe Cys Arg Leu Gly Gln Phe Gln Cys Ser Asp Gly Asn Cys Thr
3555 3560 3565
AGC CCG CAG ACT TTA TGC AAT GCT CAC CAA AAT TGC CCT GAT GGG TCT 10813
Ser Pro Gln Thr Leu Cys Asn Ala His Gln Asn Cys Pro Asp Gly Ser
3570 3575 3580
4 5 GAT GAA GAC CGT CTT CTT TGT GAG AAT CAC CAC TGT GAC TCC AAT GAA 10861
Asp Glu Asp Arg Leu Leu Cys Glu Asn His His Cys Asp Ser Asn Glu
3585 3590 3595
TGG CAG TGC GCC AAC AAA CGT TGC ATC CCA GAA TCC TGG CAG TGT GAC l O 909
Trp Gln Cys Ala Asn Lys Arg Cys Ile Pro Glu Ser Trp Gln Cys Asp
3600 3605 3610
ACA TTT AAC GAC TGT GAG GAT AAC TCA GAT GAA GAC AGT TCC CAC TGT 10957
Thr Phe Asn Asp Cys Glu Asp Asn Ser Asp Glu Asp Ser Ser His Cys
3615 3620 3625 3630
GCC AGC AGG ACC TGC CGG CCG GGC CAG TTT CGG TGT GCT AAT GGC CGC 11005
Ala Ser Arg Thr Cys Arg Pro Gly Gln Phe Arg Cys Ala Asn Gly Arg
3635 3640 3645
TGC ATC CCG CAG GCC TGG AAG TGT GAT GTG GAT AAT GAT TGT GGA GAC 11053
Cys Ile Pro Gln Ala Trp Lys Cys Asp Val Asp Asn Asp Cys Gly Asp
3650 3655 3660
CA 0220~648 1997-0~-20
Wo 96/1~801 PCTIUS95/15203
CAC TCG GAT GAG CCC ATT GAA GAA TGC ATG AGC TCT GCC CAT CTC TGT 11101
His Ser Asp Glu Pro Ile Glu Glu Cys Met Ser Ser Ala EIis Leu Cys
3665 3670 3675
GAC AAC TTC ACA GAA TTC AGC TGC AAA ACA AAT TAC CGC TGC ATC CCA 11149
Asp Asn Phe Thr Glu Phe Ser Cys Lys Thr Asn Tyr Arg Cys Ile Pro
3680 3685 3690
AAG TGG GCC GTG TGC AAT GGT GTA GAT GAC TGC AGG GAC AAC AGT GAT 11197
0 Lys Trp Ala Val Cys Asn Gly Val Asp Asp Cys Arg Asp Asn Ser Asp
3695 3700 3705 3710
GAG CAA GGC TGT GAG GAG AGG ACA TGC CAT CCT GTG GGG GAT TTC CGC 11245
Glu Gln Gly Cys Glu Glu Arg Thr Cys His Pro Val Gly Asp Phe Arg
3715 3720 3725
TGT AAA AAT CAC CAC TGC ATC CCT CTT CGT TGG CAG TGT GAT GGG CAA 11293
Cys Lys Asn His His Cys Ile Pro Leu Arg Trp Gln Cys Asp Gly Gln
3730 3735 3740
AAT GAC TGT GGA GAT AAC TCA GAT GAG GAA AAC TGT GCT CCC CGG GAG 11341
Asn Asp Cys Gly Asp Asn Ser Asp Glu Glu Asn Cys Ala Pro Arg Glu
3745 3750 3755
TGC ACA GAG AGC GAG TTT CGA TGT GTC AAT CAG CAG TGC ATT CCC TCG 11389
Cys Thr Glu Ser Glu Phe Arg Cys Val Asn Gln Gln Cys Ile Pro Ser
3760 3765 3770
CGA TGG ATC TGT GAC CAT TAC AAC GAC TGT GGG GAC AAC TCA GAT GAA 11437
Arg Trp Ile Cys Asp His Tyr Asn Asp Cys Gly Asp Asn Ser Asp Glu
3775 3780 3785 3790
CGG GAC TGT GAG ATG AGG ACC TGC CAT CCT GAA TAT TTT CAG TGT ACA 11485
Arg Asp Cys Glu Met Arg Thr Cys His Pro Glu Tyr Phe Gln Cys Thr
3795 3800 3805
AGT GGA CAT TGT GTA CAC AGT GAA CTG AAA TGC GAT GGA TCC GCT GAC 11533
Ser Gly His Cys Val His Ser Glu Leu IJYS Cys Asp Gly Ser Ala Asp
3810 3815 3820
TGT TTG GAT GCG TCT GAT GAA GCT GAT TGT CCC ACA CGC TTT CCT GAT 11581
Cys Leu Asp Ala Ser Asp Glu Ala Asp Cys Pro Thr Arg Phe Pro Asp
3825 3830 3835
4 5 GGT GCA TAC TGC CAG GCT ACT ATG TTC GAA TGC AAA AAC CAT GTT TGT 11629
Gly Ala Tyr Cys Gln Ala Thr Met Phe Glu Cys Lys Asn His Val Cys
3840 3845 3850
ATC CCG CCA TAT TGG AAA TGT GAT GGC GAT GAT GAC TGT GGC GAT GGT 11677
I le Pro Pro Tyr Trp Lys Cys Asp Gly Asp Asp Asp Cys Gly Asp Gly
3855 3860 3865 3870
TCA GAT GAA GAA CTT CAC CTG TGC TTG GAT GTT CCC TGT AAT TCA CCA 11725
Ser Asp Glu Glu Leu His Leu Cys ~eu Asp Val Pro Cys Asn Ser Pro
3875 . 3880 3885
AAC CGT TTC CGG TGT GAC AAC AAT CGC TGC ATT TAT AGT CAT GAG GTG 11773
Asn Arg Phe Arg Cys Asp Asn Asn Arg Cys Ile Tyr Ser His Glu Val
3890 3895 3900
TGC AAT GGT GTG GAT GAC TGT GGA GAT GGA ACT GAT GAG ACA GAG GAG 11821
Cys Asn Gly Val Asp Asp Cys Gly Asp Gly Thr Asp Glu Thr Glu Glu
3905 3910 3915
CA 0220~648 1997-0~-20
W O 96/15801 PCTrUS95/15203
~b2 6
CAC TGT AGA AAA CCG ACC CCT AAA CCT TGT ACA GAA TAT GAA TAT AAG 11869
His Cys Arg Lys Pro Thr Pro Lys Pro Cys Thr Glu Tyr Glu Tyr Lys
3920 3925 3930
TGT GGC AAT GGG CAT TGC ATT CCA CAT GAC AAT GTG TGT GAT GAT GCC 11917
Cys Gly Asn Gly His Cys Ile Pro His Asp Asn Val Cys Asp Asp Ala
3935 3940 3945 3950
GAT GAC TGT GGT GAC TGG TCC GAT GAA CTG GGT TGC AAT AAA GGA AAA 11965
0 Asp Asp Cys Gly Asp Trp Ser Asp Glu Leu Gly Cys Asn Lys Gly Lys
. 3955 3960 3965
GAA AGA ACA TGT GCT GAA AAT ATA TGC GAG CAA AAT TGT ACC CAA TTA 12013
Glu Arg Thr Cys Ala Glu Asn Ile Cys Glu Gln Asn Cys Thr Gln Leu
3970 3975 3980
AAT GAA GGA GGA TTT ATC TGC TCC TGT ACA GCT GGG TTC GAA ACC AAT 12061
Asn Glu Gly Gly Phe Ile Cys Ser Cys Thr Ala Gly Phe Glu Thr Asn
3985 3990 3995
GTT TTT GAC AGA ACC TCC TGT CTA GAT ATC AAT GAA TGT GAA CAA TTT 12109
Val Phe Asp Arg Thr Ser Cys Leu Asp Ile Asn Glu Cys Glu Gln Phe
4000 4005 4010
2 5 GGG ACT TGT CCC CAG CAC TGC AGA AAT ACC AAA GGA AGT TAT GAG TGT 12157
Gly Thr Cys Pro Gln His Cys Arg Asn Thr Lys Gly Ser Tyr Glu Cys
4015 4020 4025 4030
GTC TGT GCT GAT GGC TTC ACG TCT ATG AGT GAC CGC CCT GGA AAA CGA 12205
3 0 Val Cys Ala Asp Gly Phe Thr Ser Met Ser Asp Arg Pro Gly Lys Arg
4035 4040 4045
TGT GCA GCT GAG GGT AGC TCT CCT TTG TTG CTA CTG CCT GAC AAT GTC 12253
Cys Ala Ala Glu Gly Ser Ser Pro Leu Leu Leu Leu Pro Asp Asn Val
4050 4055 4060
CGA ATT CGA AAA TAT AAT CTC TCA TCT GAG AGG TTC TCA GAG TAT CTT 12301
Arg Ile Arg Lys Tyr Asn Leu Ser Ser Glu Arg Phe Ser Glu Tyr Leu
4065 4070 ` 4075
CAA GAT GAG GAA TAT ATC CAA GCT GTT GAT TAT GAT TGG GAT CCC RAG 12349
Gln Asp Glu Glu Tyr Ile Gln Ala Val Asp Tyr Asp Trp Asp Pro Xaa
4080 4085 4090
GAC ATA GGC CTC AGT GTT GTG TAT TAC ACT GTG CGA GGG GAG GGC TCT 12397
Asp Ile Gly Leu Ser Val Val Tyr Tyr Thr Val Arg Gly Glu Gly Ser
4095 4100 4105 411Q
AGG TTT GGT GCT ATC AAA CGT GCC TAC ATC CCC AAC TTT GAA TCC GGC 12445
Arg Phe Gly Ala Ile Lys Arg Ala Tyr Ile Pro Asn Phe Glu Ser Gly
4115 4120 4125
CGC AAT AAT CTT GTG CAG GAA GTT GAC CTG AAA CTG AAA TAC GTA ATG 12493
Arg Asn Asn Leu Val Gln Glu Val Asp Leu Lys Leu Lys Tyr Val Met
4130 , 4135 4140
CAG CCA GAT GGA ATA GCA GTG GAC TGG GTT GGA AGG CAT ATT TAC TGG 12541
Gln Pro Asp Gly Ile Ala Val Asp Trp Val Gly Arg His Ile Tyr Trp
4145 4150 4155
TCA GAT GTC AAG AAT AAA CGC ATT GAG GTG GCT AAA CTT GAT GGA AGG 12589
Ser Asp Val Lys Asn Lys Arg Ile Glu Val Ala Lys Leu Asp Gly Arg
4160 4165 4170
CA 0220~648 1997-0~-20
WO 96/15801 - PCT/US95115203
/~ '7
TAC AGA AAG TGG CTG ATT TCC ACT GAC CTG GAC CAA CCA GCT GCT ATT 12637
Tyr Arg Lys Trp Leu Ile Ser Thr Asp Leu Asp Gln Pro Ala Ala Ile
4175 4180 4185 4190
GCT GTG AAT CCC AAA CTA GGG CTT ATG TTC TGG ACT GAC TGG GGA AAG 12685
Ala Val Asn Pro Lys Leu Gly Leu Met Phe Trp Thr Asp Trp Gly Lys
4195 4200 4205
.GAA CCT AAA MTC GAG TCT GCC TGG ATG AAT GGA GAG GAC CGC AAC ATC 12733
0 Glu Pro Lys Xaa Glu Ser Ala Trp Met Asn Gly Glu Asp Arg Asn Ile
4210 4215 4220
CTG GTT TTC GAG GAC CTT GGT TGG CCA ACT GGC CTT TCT ATC GAT TAT 12i81
Leu Val Phe Glu Asp Leu Gly Trp Pro Thr Gly Leu Ser Ile Asp Tyr
4225 4230 4235
TTG AAC AAT GAC CGA ATC TAC TGG AGT GAC TTC AAG GAG GAC GTT ATT 12829
Leu Asn Asn Asp Arg Ile Tyr Trp Ser Asp Phe Lys Glu Asp Val Ile
4240 4245 4250
GAA ACC ATA AAA TAT GAT GGG ACT GAT AGG AGA GTC ATT GCA AAG GAA 12877
Glu Thr Ile Lys Tyr Asp Gly Thr Asp Arg Arg Val Ile Ala Lys Glu
4255 4260 4265 4270
GCA ATG AAC CCT TAC AGC CTG GAC ATC TTT GAA GAC CAG TTA TAC TGG 12925
Ala Met Asn Pro Tyr Ser Leu Asp Ile Phe Glu Asp Gln Leu Tyr Trp
4275 4280 4285
ATA TCT AAG GAA AAG GGA GAA GTA TGG AAA CAA AAT AAA TTT GGG CAA 12973
Ile Ser Lys Glu Lys Gly Glu Val Trp Lys Gln Asn Lys Phe Gly Gln
4290 4295 4300
GGA AAG AAA GAG AAA ACG CTG GTA GTG AAC CCT TGG CTC ACT CAA GTT 13021
Gly Lys Lys Glu Lys Thr Leu Val Val Asn Pro Trp Leu Thr Gln Val
4305 4310 4315
CGA ATC TTT CAT CAA CTC AGA TAC AAT AAG TCA GTG CCC AAC CTT TGC 13069
Arg Ile Phe His Gln Leu Arg Tyr Asn Lys Ser Val Pro Asn Leu Cys
4320 4325 4330
AAA CAG ATC TGC AGC CAC CTC TGC CTT CTG AGA CCT GGA GGA TAC AGC 13117
Lys Gln Ile Cys Ser His Leu Cys Leu Leu Arg Pro Gly Gly Tyr Ser
4335 4340 4345 4350
TGT GCC TGT CCC CAA GGC TCC AGC TTT ATA GAG GGG AGC ACC ACT GAG 13165
Cys Ala Cys Pro Gln Gly Ser Ser Phe Ile Glu Gly Ser Thr Thr Glu
4355 4360 4365
TGT GAT GCA GCC ATY GAA CTG CCT ATC AAC CTG CCC CCC CCA TGC AGG 13213
Cys Asp Ala Ala Ile Glu Leu Pro Ile Asn Leu Pro Pro Pro Cys Arg
4370 4375 4380
TGC ATG CAC GGA GGA AAT TGC TAT TTT GAT GAG ACT GAC CTC CCC AAA 13261
Cys Met His Gly Gly Asn Cys Tyr Phe Asp Glu Thr Asp Leu Pro Lys
_ 55 4385 4390 4395
TGC AAG TGT CCT AGC GGC TAC ACC GGA AAA TAT TGT GAA ATG GCG TTT 13309
Cys Lys Cys Pro Ser Gly Tyr Thr Gly Lys Tyr Cys Glu Met Ala Phe
4400 4405 4410
TCA AAA GGC ATC TCT CCA GGA ACA ACC GCA GTA GCT GTG CTG TTG ACA 13357
Ser Lys Gly Ile Ser Pro Gly Thr Thr Ala Val Ala Val Leu Leu Thr
4415 4420 4425 443
CA 0220~648 1997-0~-20
W O 96/15801 PCTrUS95/lS203
r~
ATC CTC TTG ATC GTC GTA ATT GGA GCT CTG GCA ATT GCA GGA TTC TTC 13405
Ile Leu Leu Ile Val Val Ile Gly Ala Leu Ala Ile Ala Gly Phe Phe
4435 4440 4445
CAC TAT AGA AGG ACC GGC TCC CTT TTG CCT GCT CTG CCC AAG CTG CCA 13453
His Tyr Arg Arg Thr Gly Ser Leu Leu Pro Ala Leu Pro Lys Leu Pro
4450 4455 4460
AGC TTA AGC AGT CTC GTC AAG CCC TCT GAA AAT GGG AAT GGG GTG ACC 13501
Ser Leu Ser Ser Leu Val Lys Pro Ser Glu Asn Gly Asn Gly Val Thr
4465 4470 4475
TTC AGA TCA GGG GCA GAT CTT AAC ATG GAT ATT GGA GTG TCT GGT TTT 13549
Phe Arg Ser Gly Ala Asp Leu Asn Met Asp Ile Gly Val Ser Gly Phe
4480 4485 4490
GGA CCT GAG ACT GCT ATT GAC AGG TCA ATG GCA ATG AGT GAA GAC TTT 13597
Gly Pro Glu Thr Ala Ile Asp Arg Ser Met Ala Met Ser Glu Asp Phe
4495 4500 4505 4510
GTC ATG GAA ATG GGG AAG CAG CCC ATA ATA TTT GAA AAC CCA ATG TAC 13645
Val Met Glu Met Gly Lys Gln Pro Ile Ile Phe Glu Asn Pro Met Tyr
4515 4520 4525
TCA GCC AGA GAC AGT GCT GTC AAA GTG GTT CAG CCA ATC CAG GTG ACT 13693
Ser Ala Arg Asp Ser Ala Val Lys Val Val Gln Pro Ile Gln Val Thr
4530 4535 4540
GTA TCT GAA AAT GTG GAT AAT AAG AAT TAT GGA AGT CCC ATA AAC CCT 13741
Val Ser Glu Asn Val Asp Asn Lys Asn Tyr Gly Ser Pro Ile Asn Pro
4545 4550 4555
TCT GAG ATA GTT CCA GAG ACA AAC CCA ACT TCA CCA GCT GCT GAT GGA 13789
Ser Glu Ile Val Pro Glu Thr Asn Pro Thr Ser Pro Ala Ala Asp Gly
4560 4565 4570
ACT CAG GTG ACA AAA TGG AAT CTC TTC AAA CGA AAA TCT AAA CAA ACT 13837
Thr Gln Val Thr Lys Trp Asn Leu Phe Lys Arg Lys Ser Lys Gln Thr
4575 4580 4585 4590
ACC AAC TTT GAA AAT CCA ATC TAT GCA CAG ATG GAG AAC GAG CAA AAG 13885
Thr Asn Phe Glu Asn Pro Ile Tyr Ala Gln Met Glu Asn Glu Gln Lys
4595 4600 4605
GAA AGT GTT GCT GCG ACA CCA CCT CCA TCA CCT TCG CTC CCT GCT AAG 13933
Glu Ser Val Ala Ala Thr Pro Pro Pro Ser Pro Ser Leu Pro Ala Lys
4610 4615 4620
CCT AAG CCT CCT TCG AGA AGA GAC CCA ACT CCA ACC TAT TCT GCA ACA 13981
Pro Lys Pro Pro Ser Arg Arg Asp Pro Thr Pro Thr Tyr Ser Ala Thr
4625 4630 4635
GAA GAC ACT TTT AAA GAC ACC GCA AAT CTT GTT AAA GAA GAC TCT GAA 14029
Glu Asp Thr Phe Lys Asp Thr Ala Asn ~eu Val Lys Glu Asp Ser Glu
4640 4645 4650
GTA TAG CTATACC 14042
Val
4655
(2) INFORMATION FOR SEQ ID NO:86:
(i) SEQUENCE CHARACTERISTICS:
CA 0220~648 l997-0S-20
W O96115801 PCTrUS95115203
t~7
(A) LENGTH: 4656 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: l inear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:86:
Met Asp Arg Gly Pro Ala Ala Val Ala Cys Thr Leu Leu Leu Ala Leu
0 1 5 10 15
Val Ala Cys Leu Ala Pro Ala Ser Gly Gln Glu Cys Asp Ser Ala His
20 25 30
15 Phe Arg Cys Gly Ser Gly His Cys Ile Pro Ala Asp Trp Arg Cys Asp
35 40 45
Gly Thr Lys Asp Cys Ser Asp Asp Ala Asp Glu Ile Gly Cys Ala Val
50 55 60
Val Thr Cys Gln Gln Gly Tyr Phe Lys Cys Gln Ser Glu Gly Gln Cys
65 70 75 80
Ile Pro Ser Ser Trp Val Cys Asp Gln Asp Gln Asp Cys Asp Asp Gly
85 90 95
Ser Asp Glu Arg Gln Asp Cys Ser Gln Ser Thr Cys Ser Ser His Gln
100 105 110
30 Ile Thr Cys Ser Asn Gly Gln Cys Ile Pro Ser Glu Tyr Arg Cys Asp
115 120 125
His Val Arg Asp Cys Pro Asp Gly Ala Asp Glu Asn Asp Cys Gln Tyr
130 135 1~0
Pro Thr Cys Glu Gln Leu Thr Cys Asp Asn Gly Ala Cys Tyr Asn Thr
145 150 155 160
Ser Gln Lys Cys Asp Trp Lys Val Asp Cys Arg Asp Ser Ser Asp Glu
165 170 175
Ile Asn Cys Thr Glu Ile Cys Leu His Asn Glu Phe Ser Cys Gly Asn
180 185 190
45 Gly Glu Cys Ile Pro Arg Ala Tyr Val Cys Asp His Asp Asn Asp Cys
195 200 205
Gln Asp Gly Ser Asp Glu His Ala Cys Asn Tyr Pro Thr Cys Gly Gly
210 215 220
Tyr Gln Phe Thr Cys Pro Ser Gly Arg Cys Ile Tyr Gln Asn Trp Val
225 230 235 240
Cys Asp Gly Glu Asp Asp Cys Lys Asp Asn Gly Asp Glu Asp Gly Cys
245 250 255
Glu Ser Gly Pro His Asp Val His I,ys Cys Ser Pro Arg Glu Trp Ser
260 265 270
0 Cys Pro Glu Ser Gly Arg Cys Ile Ser Ile Tyr Lys Val Cys Asp Gly
275 280 285
Ile Leu Asp Cys Pro Gly Arg Glu Asp Glu Asn Asn Thr Ser Thr Gly
2g0 295 300
.
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
1~
Lys Tyr Cys Ser Met Thr Leu Cys Ser Ala Leu Asn Cys Gln Tyr Gln
305 310 315 320
Cys His Glu Thr Pro Tyr Gly Gly Ala Cys Phe Cys Pro Pro Gly Tyr
325 330 335
Ile Ile Asn His Asn Asp Ser Arg Thr Cys Val Glu Phe Asp Asp Cys
340 345 350
Gln Ile Trp Gly Ile Cys Asp Gln Lys Cys Glu Ser Arg Pro Gly Arg
355 360 365
His Leu Cys His Cys Glu Glu Gly Tyr Ile Leu Glu Arg Gly Gln Tyr
370 375 380
Cys Lys Ala Asn Asp Ser Phe Gly Glu Ala Ser Ile Ile Phe Ser Asn
385 390 395 400
2 0 Gly Arg Asp Leu Leu Ile Gly Asp Ile His Gly Arg Ser Phe Arg Ile
405 410 415
Leu Val Glu Ser Gln Asn Arg Gly Val Ala Val Gly Val Ala Phe His
420 425 430
2S
Tyr His Leu Gln Arg Val Phe Trp Thr Asp Thr Val Gln Asn Lys Val
435 440 445
Phe Ser Val Asp Ile Asn Gly Leu Asn Ile Gln Glu Val Leu Asn Val
. 450 455 460
Ser Val Glu Thr Pro Glu Asn Leu Ala Val Asp Trp Val Asn Asn Lys
465 470 475 480
Ile Tyr Leu Val Glu Thr Lys Val Asn Arg Ile Asp Met Val Asn Leu
485 490 495
Asp Gly Ser Tyr Arg Val Thr Leu Ile Thr Glu Asn Leu Gly His Pro
500 505 510
Arg Gly Ile Ala Val Asp Pro Thr Val Gly Tyr Leu Phe Phe Ser Asp
515 520 525
Trp Glu Ser Leu Ser Gly Glu Pro Lys Leu Glu Arg Ala Phe Met Asp
530 535 540
Gly Ser Asn Arg Lys Asp Leu Val Lys Thr Lys Leu Gly Trp Pro Ala
545 550 555 560
Gly Val Thr Leu Asp Met Ile Ser Lys Arg Val Tyr Trp Val Asp Ser
565 570 575
Arg Phe Asp Tyr Ile Glu Thr Val Thr Tyr Asp Gly Ile Gln Arg Lys
580 585 590
Thr Val Val His Gly Gly Ser Leu Ile Pro His Pro Phe Gly Val Ser
595 600 605
Leu Phe Glu Gly Gln Val Phe Phe Thr Asp Trp Thr Lys Met Ala Val
610 615 620
Leu Lys Ala Asn Lys Phe Thr Glu Thr Asn Pro Gln Val Tyr Tyr Gln
625 630 635 640
CA 02205648 1997-0~-20
WO 96/1~801 PCTIUS95115203
131
Ala Ser Leu Arg Pro Tyr Gly Val Thr Val Tyr His Ser Leu Arg Gln
645 650 655
Pro Tyr Ala Thr Asn Pro Cys Lys Asp Asn Asn Gly Gly Cys Glu Gln
660 665 670
Val Cys Val Leu Ser His Arg Thr Asp Asn Asp Gly Leu Gly Phe Arg
675 680 685
0 Cys Lys Cys Thr Phe Gly Phe Gln Leu Asp Thr Asp Glu Arg His Cys
690 695 700
Ile Ala Val Gln Asn Phe Leu Ile Phe Ser Ser Gln Val Ala Ile Arg
705 710 715 720
Gly Ile Pro Phe Thr Leu Ser Thr Gln Glu Asp Val Met Val Pro Val
725 730 735
Ser Gly Asn Pro Ser Phe Phe Val Gly Ile Asp Phe Asp Ala Gln Asp
740 745 750
Ser Thr Ile Phe Phe Ser Asp Met Ser Lys His Met Ile Phe Lys Gln
755 760 765
Lys Ile Asp Gly Thr Gly Arg Glu Ile Leu Ala Ala Asn Arg Val Glu
770 775 780
Asn Val Glu Ser Leu Ala Phe Asp Trp Ile Ser Lys Asn Leu Tyr Trp
785 790 795 800
Thr Asp Ser His Tyr Lys Ser Ile Ser Val Met Arg Leu Ala Asp Lys
805 810 815
Thr Arg Arg Thr Val Val Gln Tyr Leu Asn Asn Pro Arg Ser Val Val
820 825 830
Val His Pro Phe Ala Gly Tyr Leu Phe Phe Thr Asp Trp Phe Arg Pro
835 840 845
Ala Lys Ile Met Arg Ala Trp Ser Asp Gly Ser His Leu Leu Pro Val
850 855 860
Ile Asn Thr Thr Leu Gly Trp Pro Asn Gly Leu Ala Ile Asp Trp Ala
865 870 875 880
Ala Ser Arg Leu Tyr Trp Val Asp Ala Tyr Phe Asp Lys Ile Glu His
885 890 895
Ser Thr Phe Asp Gly Leu Asp Arg Arg Arg Leu Gly His Ile Glu Gln
900 905 910
Met Thr His Pro Phe Gly Leu Ala Ile PheGly Glu His Leu Phe Phe
915 920 925
55 Thr Asp Trp Arg Leu Gly Ala Ile Ile Arg Val Arg Lys Ala Asp Gly
930 935 940
Gly Glu Met Thr Val Ile Arg Ser Gly Ile Ala Tyr Ile Leu His Leu
945 950 955 960
Lys Ser Tyr Asp Val Asn I le Gln Thr Gly Ser Asn Ala Cys Asn Gln
965 970 975
Pro Thr E~is Pro Asn Gly Asp Cys Ser His Phe Cys Phe Pro Val Pro
CA 0220~648 l997-OS-20
W O96/15801 PCTAUS95/15203
~3 2_
980 985 ggo
Asn Phe Gln Arg Val Cys Gly Cys Pro Tyr Gly Met Arg Leu Ala Ser
995 1000 1005
Asn His Leu Thr Cys Glu Gly Asp Pro. Thr Asn Glu Pro Pro Thr Glu
1010 1015 1020
Gln Cys Gly Leu Phe Ser Phe Pro Cys Lys Asn Gly Arg Cys Val Pro
1025 1030 1035 1040
Asn Tyr Tyr Leu Cys Asp Gly Val Asp Asp Cys His Asp Asn Ser Asp
1045 1050 1055
5 Glu Gln I,eu Cys Gly Thr Leu Asn Asn Thr Cys Ser Ser Ser Ala Phe
1060 1065 1070
Thr Cys Gly His Gly Glu Cys Ile Pro Ala His Trp Arg Cys Asp Lys
1075 1080 1085
Arg Asn Asp Cys Val Asp Gly Ser Asp Glu His Asn Cys Pro Thr His
1090 1095 1100
Ala Pro Ala Ser Cys Leu Asp Thr Gln Tyr Thr Cys Asp Asn His Gln
1105 lllo 1115 1120
Cys Ile Ser Lys Asn Trp Val Cys Asp Thr Asp Asn Asp Cys Gly Asp
1125 1130 1135
3 0 Gly Ser Asp Glu Lys Asn Cys Asn Ser Thr Glu Thr Cys Gln Pro Ser
1140 1145 1150
Gln Phe Asn Cys Pro Asn His Arg Cys Ile Asp Leu Ser Phe Val Cys
1155 1160 1165
Asp Gly Asp Lys Asp Cys Val Asp Gly Ser Asp Glu Val Gly Cys Val
1170 1175 1180
Leu Asn Cys Thr Ala Ser Gln Phe Lys Cys Ala Ser Gly Asp Lys Cys
1185 1190 1195 1200
Ile Gly Val Thr Asn Arg Cys Asp Gly Val Phe Asp Cys Ser Asp Asn
1205 1210 1215
Ser Asp Glu Ala Gly Cys Pro Thr Arg Pro Pro Gly Met Cys His Ser
1220 1225 1230
Asp Glu Phe Gln Cys Gln Glu Asp Gly Ile Cys Ile Pro Asn Phe Trp
1235 1240 1245
Glu Cys Asp Gly His Pro Asp Cys Leu Tyr Gly Ser Asp Glu His Asn
1250 1255 1260
Ala Cys Val Pro Lys Thr Cys Pro Ser Ser Tyr Phe His Cys Asp Asn
1265 1270 1275 1280
Gly Asn Cys Ile His Arg Xaa Trp Leu Cys Asp Arg Asp Asn Asp Cys
1285 1290 1295
0 Gly Asp Met Ser Asp Glu Lys Asp Cys Pro Thr Gln Pro Phe Arg Cys
1300 1305 131Q
Pro Ser Trp Gln Trp Gln Cys Leu Gly His Asn Ile Cys Val Asn Leu
1315 1320 1325
CA 0220~648 l997-0~-20
WO 96/l58Ol PCT/US95115203
I ~33
Ser Val Val Cys Asp Gly Ile Phe Asp Cys Pro Asn Gly Thr Asp Glu
1330 1335 1340
Ser Pro Leu Cys Asn Gly Asn Ser Cys Ser Asp Phe Asn Gly Gly Cys
,, 1345 1350 1355 1360
Thr His Glu Cys Val Gln Glu Pro Phe Gly Ala Lys Cys Leu Cys Pro
1365 1370 1375
10 '
Leu Gly Phe Leu Leu Ala Asn Asp Ser Lys Thr Cys Glu Asp I le Asp
1380 1385 1390
Glu Cys Asp Ile Leu Gly Ser Cys Ser Gln His Cys Tyr Asn Met Arg
1395 1400 1405
Gly Ser Phe Arg Cys Ser Cys Asp Thr Gly Tyr Met Leu Glu Ser Asp
1410 1415 1420
Gly Arg Thr Cys Lys Val Thr Ala Ser Glu Ser Leu Leu Leu Leu Val
1425 1430 1435 1440
Ala Ser Gln Asn Lys Ile Ile Ala Asp Ser Val Thr Ser Gln Val His
1445 1450 lg55
Asn Ile Tyr Ser Leu Val Glu Asn Gly Ser Tyr Ile Val Ala Val Asp
1460 1465 1470
Phe Asp Ser Ile Ser Gly Arg Ile Phe Trp Ser Asp Ala Thr Gln Gly
1475 1480 1485
Lys Thr Trp Ser Ala Phe Gln Asn Gly Thr Asp Arg Arg Val Val Phe
1490 1495 1500
3 5 Asp Ser Ser Ile Ile Leu Thr Glu Thr Ile Ala Ile Asp Trp Val Gly
1505 1510 1515 1520
Arg Asn Leu Tyr Trp Thr Asp Tyr Ala Leu Glu Thr Ile Glu Val Ser
1525 1530 1535
Lys Ile Asp Gly Ser His Arg Thr Val Leu Ile Ser Lys Asn Leu Thr
1540 1545 1550
Asn Pro Arg Gly Leu Ala Leu Asp Pro Arg Met Asn Glu His Leu Leu
1555 1560 1565
Phe Trp Ser Asp Trp Gly His His Pro Arg Ile Glu Arg Ala Ser Met
1570 1575 1580
Asp Gly Ser Met Arg Thr Val Ile Val Gln Asp Lys Ile Phe Trp Pro
1585 1590 1595 1600
Cys Gly Leu Thr Ile Asp Tyr Pro Asn Arg Leu Leu Tyr Phe Me'c Asp
1605 1610 1615
Ser Tyr Leu Asp Tyr Met Asp Phe Cys Asp Tyr Asn Gly His His Arg
1620 1625 1630
Arg Gln Val Ile Ala Ser Asp Leu Ile Ile Arg His Pro Tyr Ala Leu
1635 1640 1645
Thr Leu Phe Glu Asp Ser Val Tyr Trp Thr Asp Arg Ala Thr Arg Arç~
1650 1655 1660
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
Val Met Arg Ala Asn Lys Trp His Gly Gly Asn Gln Ser Val Val Met
1665 1670 1675 1680
Tyr Asn Ile Gln Trp Pro Leu Gly Ile Val Ala Val His Pro Ser Lys
1685 1690 1695 t
Gln Pro Asn Ser Val Asn Pro Cys Ala Phe Ser Arg Cys Ser His Leu
1700 1705 1710
0 Cys Leu Leu Ser Ser Gln Gly Pro His Phe Tyr Ser Cys Val Cys Pro
1715 1720 1725
Ser Gly Trp Ser Leu Ser Pro Asp Leu Leu Asn Cys Leu Arg Asp Asp
1730 1735 1740
Gln Pro Phe Leu Ile Thr Val Arg Gln His Ile Ile Phe Gly Ile Ser
1745 1750 1755 1760
Leu Asn Pro Glu Val Lys Ser Asn Asp Ala.Met Val Pro Ile Ala Gly
1765 1770 1775
Ile Gln Asn Gly Leu Asp Val Glu Phe Asp Asp Ala Glu Gln Tyr Ile
1780 1785 1790
Tyr Trp Val Glu Asn Pro Gly Glu Ile His Arg Val Lys Thr Asp Gly
1795 1800 1805
Thr Asn Arg Thr Val Phe Ala Ser Ile Ser Met Val Gly Pro Ser Met
1810 1815 1820
Asn Leu Ala Leu Asp Trp I le Ser Arg Asn Leu Tyr Ser Thr Asn Pro
1825 1830 1835 1840
Arg Thr Gln Ser Ile Glu Val Leu Thr Leu His Gly Asp Ile Arg Tyr
1845 1850 1855
Arg Lys Thr Leu Ile Ala Asn Asp Gly Thr Ala Leu Gly Val Gly Phe
1860 1865 1870
Pro Ile Gly Ile Thr Val Asp Pro Ala Arg Gly Lys Leu Tyr Trp Ser
1875 1880 1885
Asp Gln Gly Thr Asp Ser Gly Val Pro Ala Lys Ile Ala Ser Ala Asn
1890 1895 1900
Met Asp Gly Thr Ser Val Lys Thr Leu Phe Thr Gly Asn Leu Glu His
1905 1910 1915 1920
Leu Glu Cys Val Thr Leu Asp Ile Glu Glu Gln Lys Leu Tyr Trp Ala
1925 1930 1935
Val Thr Gly Arg Gly Val Ile Glu Arg Gly Asn Val Asp Gly Thr Asp
1940 1945 1950
55 Arg Met Ile Leu Val His Gln Leu Ser His Pro Trp Gly Ile Ala Val
1955 1960 1965
His Asp Ser Phe Leu Tyr Tyr Thr Asp Glu Gln Tyr Glu Val Ile Glu
1970 1975 1980
Arg Val Asp Lys Ala Thr Gly Ala Asn Lys Ile Val Leu Arg Asp Asn
1985 1990 1995 2000
Val Pro Asn Leu Arg Gly Leu Gln Val Tyr His Arg Arg Asn Ala Ala
CA 0220~648 1997-Os-20
W os6lls8ol PCTrUS95/15203
2005 2010 2015
Glu Ser Ser Asn Gly Cys Ser Asn Asn Met Asn Ala Cys Gln Gln Ile
2020 2025 2030
Cys Leu Pro Val Pro Gly Gly Leu Phe Ser Cys Ala Cys Ala Thr Gly
2035 2040 20gS
Phe Lys ~eu Asn Pro Asp Asn Arg Ser Cys Ser Pro Tyr Asn Ser Phe
0 2050 2055 2060
Ile Val Val Ser Met Leu Ser Ala Ile Arg Gly Phe Ser Leu~Glu Leu
2065 2070 2075 2080
lS Ser Asp His Ser Glu Thr Met Val Pro Val Ala Gly Gln Gly Arg Asn
2085 2090 2095
Ala Leu His Val Asp Val Asp Val Ser Ser Gly Phe Ile Tyr Trp Cys
2100 2105 2110
Asp Phe Ser Ser Ser Val Ala Ser Asp Asn Ala Ile Ar~ Arg Ile Lys
2115 2120 2125
Pro Asp Gly Ser Ser Leu Met Asn Ile Val Thr His Gly Ile Gly Glu
2130 2135 2140
Asn Gly Val Arg Gly Ile Ala Val Asp Trp Val Ala Gly Asn Leu Tyr
2145 2150 2155 2160
Phe Thr Asn Ala Phe Val Ser Glu Thr Leu Ile Glu Val Leu Arg Ile
2165 2170 2175
Asn Thr Thr Tyr Arg Arg Val Leu Leu Lys Val Thr Val Asp Met Pro
2180 2185 2190
Arg His Ile Val Val Asp Pro Lys Asn Arg Tyr Leu Phe Trp Ala Asp
2195 2200 2205
Tyr Gly Gln Arg Pro Lys Ile Glu Arg Ser Phe Leu Asp Cys Thr Asn
2210 2215 2220
Arg Thr Val Leu Val Ser Glu Gly Ile Val Thr Pro Arg Gly Leu Ala
2225 2230 2235 2240
Val Asp Arg Ser Asp Gly Tyr Val Iyr Trp Val Asp Asp Ser Leu Asp
2245 2250 2255
Ile Ile Ala Arg Ile Arg Ile Asn Gly Glu Asn Ser Glu Val Ile Arg
2260 2265 2270
Tyr Gly Ser Arg Tyr Pro Thr Pro Tyr Gly Ile Thr Val Phe Glu Asn
2275 2280 2285
Ser Ile Ile Trp Val Asp Arg Asn Leu Lys Lys Ile Phe Gln Ala Ser
- 55 2290 2295 2300
Lys Glu Pro Glu Asn Thr Glu Pro Pro Thr Val Ile Arg Asp Asn Ile
2305 2310 2315 2320
60 Asn Trp Leu Arg Asp Val Thr Ile Phe Asp Lys Gln Val Gln Pro Arg
2325 2330 2335
Ser Pro Ala Glu Val Asn Asn Asn Pro CyS Leu Glu Asn Asn Gly Gly
2340 2345 2350
CA 0220~648 l997-0~-20
WO 96115801 PCTlUS95/l5203
13G
Cys Ser His Leu Cys Phe Ala Leu Pro Gly Leu His Thr Pro Lys Cys
2355 2360 2365
Asp Cys Ala Phe Gly Thr Leu Gln Ser Asp Gly Lys Asn Cys Ala I le
2370 2375 . 2380
Ser Thr Glu Asn Phe Leu Ile Phe Ala Leu Ser Asn Ser Leu Arg Ser
2385 2390 2395 2400
Leu His Leu Asp Pro Glu Asn His Ser Pro Pro Phe Gln Thr Ile Asn
2405 2410 2415
Val Glu Arg Thr Val Met Ser Leu Asp Tyr Asp Ser Val Ser Asp Arg
2420 2425 2430
Ile Tyr Phe Thr Gln Asn Leu Ala Ser Gly Val Gly Gln Ile Ser Tyr
2435 2440 2445
Ala Thr Leu Ser Ser Gly Ile His Thr Pro Thr Val Ile Ala Ser Gly
2450 2455 2460
Ile Gly Thr Ala Asp Gly Ile Ala Phe Asp Trp Ile Thr Arg Arg Ile
2465 2470 2475 2480
Tyr Tyr Ser Asp Tyr Leu Asn Gln Met Ile Asn Ser Met Ala Glu Asp
2485 2490 2495
Gly Ser Asn Arg Thr Val Ile Ala Arg Val Pro Lys Pro Arg Ala Ile
2500 2505 2510
Val Leu Asp Pro Cys Gln Gly Tyr Leu Tyr Trp Ala Asp Trp Asp Thr
2515 2520 2525
His Ala Lys Ile Glu Arg Ala Thr Leu Gly Gly Asn Phe Arg Val Pro
2530 2535 2540
Ile Val Asn Ser Ser Leu Val Met Pro Ser Gly Leu Thr Leu Asp Tyr
2545 2550 2555 2560
Glu Glu Asp Leu Leu Tyr Trp Val Asp Ala Ser Leu Gln Arg Ile Glu
2565 2570 2575
Arg Ser Thr Leu Thr Gly Val Asp Arg Glu Val Ile Val Asn Ala Ala
2580 2585 2590
Val His Ala Phe Gly Leu Thr Leu Tyr Gly Gln Tyr Ile Tyr Trp Thr
2595 2600 2605
Asp Leu Tyr Thr Gln Arg Ile Tyr Arg Ala Asn Lys Tyr Asp Gly Ser
2610 2615 2620
Gly Gln Ile Ala Met Thr Thr Asn Leu Leu Ser Gln Pro Arg Gly Ile
2625 2630 2635 2640
Asn Thr Val Val Lys Asn Gln Lys Gln Gln Cys Asn Asn Pro Cys Glu
2645 2650 2655
Gln Phe Asn Gly Gly Cys Ser His Ile Cys Ala Pro Gly Pro Asn Gly
2660 2665 2670
Ala Glu Cys Gln Cys Pro His Glu Gly Asn Trp Tyr Leu Ala Asn Asn
2675 2680 2685
CA 0220~648 l997-0~-20
WO 96/15801 PCTIUS95/15203
J37
Arg Lys His Cys Ile Val Asp Asn Gly Glu Arg Cys Gly Ala Ser Ser
2690 2695 2700
Phe Thr Cys Ser Asn Gly Arg Cys Ile Ser Glu Glu Trp Lys Cys Asp
270S 2710 2715 2720
Asn Asp Asn Asp Cys Gly Asp Gly Ser Asp Glu Met Glu Ser Val Cys
2725 2730 2735
0 Ala Leu His Thr Cys Ser Pro Thr Ala Phe Thr Cys Ala Asn Gly Arg
2740 2745 2750
Cys Val Gln Tyr Ser Tyr Arg Cys Asp Tyr Tyr Asn Asp Cys Gly Asp
2755 2760 2765
Gly Ser Asp Glu Ala Gly Cys Leu Phe Arg Asp Cys Asn Ala Thr Thr
2770 2775 2780
Glu Phe Met Cys Asn Asn Arg Arg Cys Ile Pro Arg Glu Phe Ile Cys
20 2785 2790 2795 2800
Asn Gly Val Asp Asn Cys His Asp Asn Asn Thr Ser Asp Glu Lys Asn
2805 2810 2815
25 Cys Pro Asp Arg Thr Cys Gln Ser Gly Tyr Thr Lys Cys His Asn Ser
2820 2825 2830
Asn Ile Cys Ile Pro Arg Val Tyr Leu Cys Asp Gly Asp Asn Asp Cys
2835 2840 2845
Gly Asp Asn Ser Asp Glu Asn Pro Thr Tyr Cys Thr Thr His Thr Cys
2850 2855 2860
Ser Ser Ser Glu Phe Gln Cys Thr Ser Gly Arg Cys Ile Pro Gln His
35 2865 2870 2875 2880
Trp Tyr Cys Asp Gln Glu Thr Asp Cys Phe Asp Ala Ser Asp Glu Pro
2885 2890 2895
40 Ala Ser Cys Gly His Ser Glu Arg Thr Cys Leu Ala Asp Glu Phe Lys
2900 2905 2910
Cys Asp Gly Gly Arg Cys I le Pro Ser Glu Trp I le Cys Asp Gly Asp
2915 2920 2925
Asn Asp Cys Gly Asp Met Ser Asp Glu Asp Lys Arg His Gln Cys Gln
2930 2935 2940
Asn Gln Asn Cys Ser Asp Ser Glu Phe Leu Cys Val Asn Asp Arg Pro
50 2945 2950 2955 2960
Pro Asp Arg Arg Cys Ile Pro Gln Ser Trp Val Cys Asp Gly Asp Val
2965 2970 2975
5 Asp Cys Thr Asp Gly Tyr Asp Glu Asn Gln Asn Cys Thr Arg Arg Thr
2980 2985 2990
Cys Ser Glu Asn Glu Phe Thr Cys Gly Tyr Gly Leu Cys Ile Pro Lys
2995 3000 3005
Ile Phe Arg Cys Asp Arg His Asn Asp Cys Gly Asp Tyr Ser Asp Glu
3010 3015 3020
Arg Gly Cys Leu Tyr Gln Thr Cys Gln Gln Asn Gln Phe Thr Cys Gln
CA 0220~648 1997-0~-20
WO 96/1~801 PCT/US95/15203
1~&'
3025 3030 3035 3040
Asn Gly Arg Cys Ile Ser Lys Thr Phe Val Cys Asp Glu Asp Asn Asp
30g5 3050 30S5
Cys Gly Asp Gly Ser Asp Glu Leu Met His Leu Cys His Thr Pro Glu
3060 3065 3070
Pro Thr Cys Pro Pro His Glu Phe Lys Cys Asp Asn Gly Arg Cys Ile
0 3075 3080 3085
Glu Met Met Lys Leu Cys Asn His Leu Asp Asp Cys Leu Asp Asn Ser
3090 3095 3100
Asp Glu Lys Gly Cys Gly Ile Asn Glu Cys His Asp Pro Ser Ile Ser
3105 3110 3115 3120
Gly Cys Asp His Asn Cys Thr Asp Thr Leu Thr Ser Phe Tyr Cys Ser
3125 3130 3135
Cys Arg Pro Gly Tyr Lys Leu Met Ser Asp Lys Arg Thr Cys Val Asp
3140 3145 3150
Ile Asp Glu Cys Thr Glu Met Pro Phe Val Cys Ser Gln Lys Cys Glu
3155 3160 3165
Asn Val Ile Gly Ser Tyr Ile Cys Lys Cys Ala Pro Gly Tyr Leu Arg
3170 3175 3180
3 0 Glu Pro Asp Gly Lys Thr Cys Arg Gln Asn Ser Asn Ile Glu Pro Tyr
3185 3190 3195 3200
Leu Ile Phe Ser Asn Arg Tyr Tyr Leu Arg Asn Leu Thr Ile Asp Gly
3205 3210 3215
Tyr Phe Tyr Ser Leu Ile Leu Glu Gly Leu Asp Asn Val Val Ala Leu
3220 3225 3230
Asp Phe Asp Arg Val Glu Lys Arg Leu Tyr Trp Ile Asp Thr Gln Arg
3235 3240 3245
Gln Val Ile Glu Arg Met Phe Leu Asn Lys Thr Asn Lys Glu Thr Ile
3250 3255 3260
Ile Asn His Arg Leu Pro Ala Ala Glu Ser Leu Ala Val Asp Trp Val
3265 3270 3275 3280
Ser Arg Lys Leu Tyr Trp Leu Asp Ala Arg Leu Asp Gly Leu Phe Val
3285 3290 . 3295
Ser Asp Leu Asn Gly Gly His Arg Arg Met Leu Ala Gln His Cys Val
3300 3305 3310
Asp Ala Asn Asn Thr Phe Cys Phe Asp Asn Pro Arg Gly Leu Ala Leu
3315 3320 3325
His Pro Gln Tyr Gly Tyr Leu Tyr Trp Ala Asp Trp Gly His Arg Ala
3330 3335 3340
60 Tyr Ile Gly Arg Val Gly Met Asp Gly Thr Asn Lys Ser Val Ile Ile
3345 3350 3355 3360
Ser Thr Lys Leu Glu Trp Pro Asn Gly Ile Thr Ile Asp Tyr Thr Asn
3365 3370 3375
CA 0220~648 1997-0~-20
Wo 96/15801 PCT/US95115203
13q
Asp Leu Leu Tyr Trp Ala Asp Ala His Leu Gly Tyr Ile Glu Tyr Ser
3380 3385 3390
Asp Leu Glu Gly His His Arg His Thr Val Tyr Asp Gly Ala Leu Pro
3395 3400 . 3405
His Pro Phe Ala Ile Thr Ile Phe Glu Asp Thr Ile Tyr Trp Thr Asp
3410 3415 3420
Trp Asn Thr Arg Thr Val Glu Lys Gly Asn Lys Tyr Asp Gly Ser Asn
3425 3430 3435 3440
Arg Gln Thr Leu Val Asn Thr Thr His Arg Pro Phe Asp Ile His Val
3445 3450 3455
Tyr His Pro Tyr Arg Gln Pro Ile Val Ser Asn Pro Cys Gly Thr Asn
3460 3465 3470
Asn Gly Gly Cys Ser His Leu Cys Leu Ile Lys Pro Gly Gly Lys Gly
3475 3480 3485
Phe Thr Cys Glu Cys Pro Asp Asp Phe Arg Thr Leu Gln Leu Ser Gly
3490 3495 3500
Ser Thr Tyr Cys Met Pro Met Cys Ser Ser Thr Gln Phe Leu Cys Ala
3505 3510 3515 3520
Asn Asn Glu ~ys Cys Ile Pro Ile Trp Trp Lys Cys Asp Gly Gln Lys
3525 3530 3535
Asp Cys Ser Asp Gly Ser Asp Glu Leu Ala Leu Cys Pro Gln Arg Phe
3540 ~545 3550
3 5 Cys Arg Leu Gly Gln Phe Gln Cys Ser Asp Gly Asn Cys Thr Ser Pro
3555 3560 3565
Gln Thr Leu Cys Asn Ala His Gln Asn Cys Pro Asp Gly Ser Asp Glu
3570 3575 3580
Asp Arg Leu Leu Cys Glu Asn His His Cys Asp Ser Asn Glu Trp Gln
3585 3590 3595 3600
Cys Ala Asn Lys Arg Cys Ile Pro Glu Ser Trp Gln Cys Asp Thr Phe
3605 3610 3615
Asn Asp Cys Glu Asp Asn Ser Asp Glu Asp Ser Ser His Cys Ala Ser
3620 3625 3630
50 Arg Thr Cys Arg Pro Gly Gln Phe Arg Cys Ala Asn Gly Arg Cys Ile
3635 3640 3645
Pro Gln Ala Trp Lys Cys Asp Val Asp Asn Asp Cys Gly Asp His Ser
3650 3655 3660
Asp Glu Pro Ile Glu Glu Cys Met Ser Ser Ala His Leu Cys Asp Asn
3665 3670 3675 3680
Phe Thr Glu Phe Ser Cys Lys Thr Asn Tyr Arg Cys Ile Pro Lys Trp
3685 3690 3695
Ala Val Cys Asn Gly Val Asp Asp Cys Arg Asp Asn Ser Asp Glu Gln
3700 3705 3710
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
Gly Cys Glu Glu Arg Thr Cys His Pro Val Gly Asp Phe Arg Cys Lys
3715 3720 3725
Asn His His Cys Ile Pro Leu Arg Trp Gln Cys Asp Gly Gln Asn Asp
3730 3735 3740
Cys Gly Asp Asn Ser Asp Glu Glu Asn Cys Ala Pro Arg Glu Cys Thr
3745 3750 3755 3760
Glu Ser Glu Phe Arg Cys Val Asn Gln Gln Cys Ile Pro Ser Arg Trp
3765 3770 3775
,
Ile Cys Asp His Tyr Asn Asp Cys Gly Asp Asn Ser Asp Glu Arg Asp
3780 3785 3790
Cys Glu Met Arg Thr Cys His Pro Glu Tyr Phe Gln Cys Thr Ser Gly
3795 3800 3805
His Cys Val His Ser Glu Leu Lys Cys Asp Gly Ser Ala Asp Cys Leu
3810 3815 3820
Asp Ala Ser Asp Glu Ala Asp Cys Pro Thr Arg Phe Pro Asp Gly Ala
3825 3830 3835 3840
Tyr Cys Gln Ala Thr Met Phe Glu Cys Lys Asn His Val Cys Ile Pro
3845 3850 3855
Pro Tyr Trp Lys Cys Asp Gly Asp Asp Asp Cys Gly Asp Gly Ser Asp
3860 3865 3870
Glu Glu Leu His Leu Cys Leu Asp Val Pro Cys Asn Ser Pro Asn Arg
3875 3880 3885
Phe Arg Cys Asp Asn Asn Arg Cys Ile Tyr Ser His Glu Val Cys Asn
3890 3895 3900
Gly Val Asp Asp Cys Gly Asp Gly Thr Asp Glu Thr Glu Glu His Cys
3905 3910 3915 3920
Arg Lys Pro Thr Pro Lys Pro Cys Thr Glu Tyr Glu Tyr Lys Cys Gly
3925 3930 3935
Asn Gly His Cys Ile Pro His Asp Asn Val Cys Asp Asp Ala Asp Asp
3940 3945 3950
Cys Gly Asp Trp Ser Asp Glu Leu Gly Cys Asn Lys Gly Lys Glu Arg
3955 3960 3965
Thr Cys Ala Glu Asn Ile Cys Glu Gln Asn Cys Thr Gln Leu Asn Glu
3970 3975 3980
Gly Gly Phe Ile Cys Ser Cys Thr Ala Gly Phe Glu Thr Asn Val Phe
3985 3990 3995 4000
55 Asp Arg Thr Ser Cys Leu Asp Ile Asn Glu Cys Glu Gln Phe Gly Thr
4005 4010 4015
Cys Pro Gln His Cys Arg Asn Thr Lys Gly Ser Tyr Glu Cys Val Cys
4020 4025 4030
Ala Asp Gly Phe Thr Ser Met Ser Asp Arg Pro Gly Lys Arg Cys Ala
4035 4040 4045
Ala Glu Gly Ser Ser Pro Leu Leu Leu Leu Pro Asp Asn Val Arg Ile
-
CA 0220~648 l997-0~-20
WO 96115801 PCTIUS95/15203
4050 4055 4060
Arg Lys Tyr Asn Leu Ser Ser Glu Arg Phe Ser Glu Tyr Leu Gln Asp
4065 4070 4075 4080
Glu Glu Tyr Ile Gln Ala Val Asp Tyr Asp Trp Asp Pro Xaa Asp Ile
4085 4090 4095
Gly Leu Ser Val Val Tyr Tyr Thr Val Arg Gly Glu Gly Ser Arg Phe
0 4100 4105 4110
Gly Ala Ile Lys Arg Ala Tyr Ile Pro Asn Phe Glu Ser Gly Arg Asn
4115 4120 4125
Asn Leu Val Gln Glu Val Asp Leu Lys Leu Lys Tyr Val Met Gln Pro
4130 4135 4140
Asp Gly Ile Ala Val Asp Trp Val Gly Arg His Ile Tyr Trp Ser Asp
4145 4150 4155 4160
Val Lys Asn Lys Arg Ile Glu Val Ala Lys Leu Asp Gly Arg Tyr Arg
4165 4170 4175
Lys Trp Leu Ile Ser Thr Asp Leu Asp Gln Pro Ala Ala Ile Ala Val
4180 4185 4190
Asn Pro Lys heu Gly Leu Met Phe Trp Thr Asp Trp Gly Lys Glu Pro
41g5 4200 4205
Lys Xaa Glu Ser Ala Trp Met Asn Gly Glu Asp Arg Asn Ile Leu Val
4210 4215 4220
Phe Glu Asp Leu Gly Trp Pro Thr Gly Leu Ser Ile Asp Tyr Leu Asn
4225 4230 4235 4240
Asn Asp Arg Ile Tyr Trp Ser Asp Phe Lys Glu Asp Val Ile Glu Thr
4245 4250 4255
Ile Lys Tyr Asp Gly Thr Asp Arg Arg Val Ile Ala Lys Glu Ala Met
4260 4265 4270
Asn Pro Tyr Ser Leu Asp Ile Phe Glu Asp Gln Leu Tyr Trp Ile Ser
4275 4280 4285
Lys Glu Lys Gly Glu Val Trp Lys Gln Asn Lys Phe Gly Gln Gly Lys
4290 4295 4300
Lys Glu Lys Thr Leu Val Val Asn Pro Trp Leu Thr Gln Val Arg Ile
4305 4310 4315 4320
Phe His Gln Leu Arg Tyr Asn Lys Ser Val Pro Asn Leu Cys Lys Gln
4325 4330 4335
Ile Cys Ser His Leu Cys Leu Leu Arg Pro Gly Gly Tyr Ser Cys Ala
4340 4345 4350
Cys Pro Gln Gly Ser Ser Phe Ile Glu Gly Ser Thr Thr Glu Cys Asp
4355 4360 4365
60 Ala Ala Ile Glu Leu Pro Ile Asn Leu Pro Pro Pro Cys Arg Cys Met
4370 4375 4380
His Gly Gly Asn Cys Tyr Phe Asp Glu Thr Asp Leu Pro Lys Cys Lys
4385 4390 4395 440Q
_
CA 0220~648 l997-0~-20
W O96/15801 PCTrUS95/15203
Cys Pro Ser Gly Tyr Thr Gly Lys Tyr Cys Glu Met Ala Phe Ser Lys
4405 4410 4415
Gly Ile Ser Pro Gly Thr Thr Ala Val Ala Val Leu Leu Thr Ile Leu
4420 442.5 4430
Leu Ile Val Val Ile Gly Ala Leu Ala Ile Ala Gly Phe Phe His Tyr
4435 4440 4445
10 '
Arg Arg Thr Gly Ser Leu Leu Pro Ala Leu Pro Lys Leu Pro Ser Leu
4450 4455 4460
Ser Ser Leu Val Lys Pro Ser Glu Asn Gly Asn Gly Val Thr Phe Arg
4465 4470 4475 4480
Ser Gly Ala Asp Leu Asn Met Asp Ile Gly Val Ser Gly Phe Gly Pro
4485 4490 4495
Glu Thr Ala Ile Asp Arg Ser Met Ala Met Ser Glu Asp Phe Val Met
4500 4505 4510
Glu Met Gly Lys Gln Pro Ile Ile Phe Glu Asn Pro Met Tyr Ser Ala
4515 4520 4525
Arg Asp Ser Ala Val Lys Val Val Gln Pro Ile Gln Val Thr Val Ser
4530 4535 4540
Glu Asn Val Asp Asn Lys Asn Tyr Gly Ser Pro Ile Asn Pro Ser Glu
4545 4550 4555 4560
Ile Val Pro Glu Thr Asn Pro Thr Ser Pro Ala Ala Asp Gly Thr Gln
4565 4570 4575
Val Thr Lys Trp Asn Leu Phe Lys Arg Lys Ser Lys Gln Thr Thr Asn
4580 4585 4590
Phe Glu Asn Pro Ile Tyr Ala Gln Met Glu Asn Glu Gln ~ys Glu Ser
4595 4600 4605
Val Ala Ala Thr Pro Pro Pro Ser Pro Ser Leu Pro Ala Lys Pro Lys
4610 4615 4620
Pro Pro Ser Arg Arg Asp Pro Thr Pro Thr Tyr Ser Ala Thr Glu Asp
4625 4630 4635 4640
Thr Phe Lys Asp Thr Ala Asn Leu Val Lys Glu Asp Ser Glu Val *
4645 4650 4655
(2) INFORMATION FOR SEQ ID NO:87:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14080 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
CA 0220~648 l997-0~-20
WO 96/15801 PCTtUS95/15203
r Y~3
( vi ) O~IGINAL SOURCE:
(A) ORGANISM: Homo sapiens
(F) TISSUE TYPE: Kidney
( ix ) FEATURE:
" (A) NAME/KEY: CDS
(B) LOCATION: 105. .14072
(xi ) SEQUENCE: DESCRIPTION: SEQ ID NO: 87:
GCAGACCTAA AGGAGCGTTC GCTAGCAGAG GCGCTGCCGG TGCG~ il~C TACGCGCGCC 60
CACCTCCCGG GGAAGGAACG GCGAGGCCGG GGACCGTCGC GGAG ATG GAT CGC GGG 116
Met Asp Arg Gly
4660
CCG GCA GCA GTG GCG TGC ACG CTG CTC CTG GCT CTC GTC GCC TGC CTA 164
Pro Ala Ala Val Ala Cys Thr Leu Leu Leu Ala Leu Val Ala Cys Leu
4665 4670 4675
GCG CCG GCC AGT GGC CAA GAA TGT GAC AGT GCG CAT TTT CGC TGT GGA 212
Ala Pro Ala Ser Gly Gln GlU Cys Asp Ser Ala His Phe Arg Cys Gly
4680 4685 4690
AGT GGG CAT TGC ATC CCT GCA GAC TGG AGG TGT GAT GGG ACC AAA GAC 260
Ser Gly His Cys Ile Pro Ala Asp Trp Arg Cys Asp Gly Thr Lys Asp
4695 4700 4705
3 0 TGT TCA GAT GAC GCG GAT GAA ATT GGC TGC GCT GTT GTG ACC TGC CAG 308
Cys Ser Asp Asp Ala Asp Glu Ile Gly Cys Ala Val Val Thr Cys Gln
4710 4715 4720
CAG GGC TAT TTC AAG TGC CAG AGT GAG GGA CAA TGC ATC CCC AGC TCC 356
3 5 Gln Gly Tyr Phe Lys Cys Gln Ser Glu Gly Gln Cys Ile Pro Ser Ser
4725 4730 4735 4740
TGG GTG TGT GAC CAA GAT CAA GAC TGT GAT GAT GGC TCA GAT GAA CGT 404
Trp Val Cys Asp Gln Asp Gln Asp Cys Asp Asp Gly Ser Asp Glu Arg
4745 4750 4755
CAA GAT TGC TCA CAA AGT ACA TGC TCA AGT CAT CAG ATA ACA TGC TCC 452
Gln Asp Cys Ser Gln Ser Thr Cys Ser Ser His Gln I le Thr Cys Ser
4760 4765 4770
AAT GGT CAG TGT ATC CCA AGT GAA TAC AGG TGC GAC CAC GTC AGA GAC 500
Asn Gly Gln Cys Ile Pro Ser Glu Tyr Arg Cys Asp Hls Val Arg Asp
4775 4780 4785
TGC CCC GAT GGA GCT GAT GAG AAT GAC TGC CAG TAC CCA ACA TGT GAG 548
Cys Pro Asp Gly Ala Asp Glu Asn Asp Cys Gln Tyr Pro Thr Cys Glu
4790 4795 4800
CAG CTT ACT TGT GAC AAT GGG GCC TGC TAT AAC ACC AGT CAG AAG TGT 596
5 5 Gln Leu Thr Cys Asp Asn Gly Ala Cys Tyr Asn Thr Ser Gln Lys Cys
4805 4810 4815 4820
GAT TGG AAA GTT GAT TGC AGG GAC TCC TCA GAT GAA ATC AAC TGC ACT 644
Asp Trp Lys Val Asp Cys Arg Asp Ser Ser Asp Glu Ile Asn Cys Thr
4825 4830 4835
GAG ATA TGC TTG CAC AAT GAG TTT TCA TGT GGC AAT GGA GAG TGT ATC 692
Glu Ile Cys Leu His Asn Glu Phe Ser Cys Gly Asn Gly Glu Cys Ile
4840 4845 4850
CA 0220~648 l997-0~-20
WO 96/15801 PCTtUS95/15203
r~t
CCT CGT GCT TAT GTC TGT GAC CAT GAC AAT GAT TGC CAA GAC GGC AGT 740
Pro Arg Ala Tyr Val Cys Asp His Asp Asn Asp Cys Gln Asp Gly Ser
4855 4860 4865
,.
GAT GAA CAT GCT TGC AAC TAT CCG ACC TGC GGT GGT TAC CAG TTC ACT 788
Asp Glu His Ala Cys Asn Tyr Pro Thr Cys Gly Gly Tyr Gln Phe Thr
4870 4875 4880
0 TGC CCC AGT GGC CGA TGC ATT TAT CAA AAC TGG GTT TGT GAT GGA GAA 836
Cys Pro Ser Gly Arg Cys Ile Tyr Gln Asn Trp Val Cys Asp Gly Glu
48~5 4890 4895 4900
GAT GAC TGT AAA GAT AAT GGA GAT GAA GAT GGA TGT GAA AGC GGT CCT 884
Asp Asp Cys Lys Asp Asn Gly Asp Glu Asp Gly Cys Glu Ser Gly Pro
4905 4910 4915
CAT GAT GTT CAT AAA TGT TCC CCA AGA GAA TGG TCT TGC CCA GAG TCG 932
His Asp Val His Lys Cys Ser Pro Arg Glu Trp Ser Cys Pro Glu Ser
4920 4925 4930
GGA CGA TGC ATC TCC ATT TAT AAA GTT TGT GAT GGG ATT TTA GAT TGC 980
Gly Arg Cys Ile Ser Ile Tyr Lys Val Cys Asp Gly I:Le Leu Asp Cys
4935 4940 4945
CCA GGA AGA GAA GAT GAA AAC AAC ACT AGT ACC GGA AAA TAC TGT AGT 1028
Pro Gly Arg Glu Asp Glu Asn Asn Thr Ser Thr Gly Lys Tyr Cys Ser
4950 4955 4960
ATG ACT CTG TGC TCT GCC TTG AAC TGC CAG TAC CAG TGC CAT GAG ACG 1076
Met Thr Leu Cys Ser Ala Leu Asn Cys Gln Tyr Gln Cys His Glu Thr
4965 4970 4975 4980
CCG TAT GGA GGA GCG TGT TTT TGT CCC CCA GGT TAT ATC ATC AAC CAC 1124
3 5 Pro Tyr Gly Gly Ala Cys Phe Cys Pro Pro Gly Tyr Ile Ile Asn His
4985 4990 4995
AAT GAC AGC CGT ACC TGT GTT GAG TTT GAT GAT TGC CAG ATA TGG GGA 1172
Asn Asp Ser Arg Thr Cys Val Glu Phe Asp Asp Cys Gln Ile Trp Gly
5000 5005 5010
ATT TGT GAC CAG AAG TGT GAA AGC CGA CCT GGC CGT CAC CTG TGC CAC 1220
Ile Cys Asp Gln Lys Cys Glu Ser Arg Pro Gly Arg His Leu Cys His
5015 5020 5025
TGT GAA GAA GGG TAT ATC TTG GAG CGT GGA CAG TAT TGC AAA GCT AAT 1268
Cys Glu Glu Gly Tyr Ile Leu Glu Arg Gly Gln Tyr Cys Lys Ala Asn
5030 5035 5040
5 0 GAT TCC TTT GGC GAG GCC TCC ATT ATC TTC TCC AAT GGT CGG GAT TTG 1316
Asp Ser Phe Gly Glu Ala Ser Ile Ile Phe Ser Asn Gly Arg Asp Leu
5045 5050 5055 5060
TTA ATT GGT GAT ATT CAT GGA AGG AGC TTC CGG ATC CTA GTG GAG TCT 1364
Leu Ile Gly Asp Ile His Gly Arg Ser Phe Arg Ile Leu Val Glu Ser
5065 5070 5075
CAG AAT CGT GGA GTG GCC GTG GGT GTG GCT TTC CAC TAT CAC CTG CAA 1412
Gln Asn Arg Gly Val Ala Val Gly Val Ala Phe His Tyr His Leu Gln
5080 5085 5090
AGA GTT TTT TGG ACA GAC ACC GTG CAA AAT AAG GTT TTT TCA GTT GAC 1460
Arg Val Phe Trp Thr Asp Thr Val Gln Asn Lys Val Phe Ser Val Asp
5095 5100 5105
_ _ _ _ _ _ _
CA 0220~648 1997-0~-20
WO 96115801 PCTIUS95115203
~yS
ATT AAT GGT TTA AAT ATC CAA GAG GTT CTC AAT GTT TCT GTT GAA ACC 1508
Ile Asn Gly Leu Asn Ile Gln Glu Val Leu Asn Val Ser Val Glu Thr
5110 5115 5120
CCA GAG AAC CTG GCT GTG GAC TGG GTT AAT AAT AAA ATC TAT CTA GTG 1556
Pro Glu Asn Leu Ala Val Asp Trp Val Asn Asn Lys Ile Tyr Leu Val
5125 5130 5135 5140
GAA ACC AAG GTC AAC CGC ATA GAT ATG GTA AAT TTG GAT GGA AGC TAT 1604
Glu Thr Lys Val Asn Arg Ile Asp Met Val Asn Leu Asp Gly Ser Tyr
5145 5150 5155
CGG GTT ACC CTT ATA ACT GAA AAC TTG GGG CAT CCT AGA GGA ATT GCC 1652
Arg Val Thr Leu Ile Thr Glu Asn Leu Gly His Pro Arg Gly Ile Ala
5160 5165 5170~
GTG GAC CCA ACT GTT GGT TAT TTA TTT TTC TCA GAT TGG GAG AGC CTT 1700
Val Asp Pro Thr Val Gly Tyr Leu Phe Phe Ser Asp Trp Glu Ser Leu
5175 5180 5185
TCT GGG GAA CCT AAG CTG GAA AGG GCA TTC ATG GAT GGC AGC AAC CGT 1748
Ser Gly Glu Pro Lys Leu Glu Arg Ala Phe Met Asp Gly Ser Asn Arg
5190 5195 5200
AAA GAC TTG GTG AAA ACA AAG CTG GGA TGG CCT GCT GGG GTA ACT CTG 1796
Lys Asp Leu Val Lys Thr Lys Leu Gly Trp Pro Ala Gly Val Thr Leu
5205 5210 5215 5220
3 0 GAT ATG ATA TCG AAG CGT GTT TAC TGG GTT GAC TCT CGG TTT GAT TAC 1844
Asp Met Ile Ser Lys Arg Val Tyr Trp Val Asp Ser Arg Phe Asp Tyr
5225 5230 5235
ATT GAA ACT GTA ACT TAT GAT GGA ATT CAA AGG AAG ACT GTA GTT CAT 1892
3 5 Ile Glu Thr Val Thr Tyr Asp Gly Ile Gln Arg Lys Thr Val Val His
5240 5245 5250
GGA GGC TCC CTC ATT CCT CAT CCC TTT GGA GTA AGC TTA TTT GAA GGT 1940
Gly Gly Ser Leu Ile Pro His Pro Phe Gly Val Ser Leu Phe Glu Gly
5255 5260 5265
CAG GTG TTC TTT ACA GAT TGG ACA AAG ATG GCC GTG CTG AAG GCA AAC 1988
Gln Val Phe Phe Thr Asp Trp Thr Lys Met Ala Val Leu Lys Ala Asn
5270 5275 5280
AAG TTC ACA GAG ACC AAC CCA CAA GTG TAC TAC CAG GCT TCC CTG AGG 2036
Lys Phe Thr Glu Thr Asn Pro Gln Val Tyr Tyr Gln Ala Ser Leu Arg
5285 5290 5295 5300
CCC TAT GGA GTG ACT GTT TAC CAT TCC CTC AGA CAG CCC TAT GCT ACC 2084
. Pro Tyr Gly Val Thr Val Tyr His Ser Leu Arg Gln Pro Tyr Ala Thr
5305 5310 5315
AAT CCG TGT AAA GAT AAC AAT GGG GGC TGT GAG CAG GTC TGT GTT CTC 2132
5 5 Asn Pro Cys Lys Asp Asn Asn Gly Gly Cys Glu Gln Val Cys Val Leu
5320 5325 5330
AGC CAC AGA ACA GAT AAT GAT GGT TTG GGT TTC CGT TGC AAG TGC ACA 2180
Ser His Arg Thr Asp Asn Asp Gly Leu Gly Phe Arg Cys Lys Cys Thr
5335 5340 5345
TTC GGC TTC CAA CTG GAT ACA GAT GAG CGC CAC TGC ATT GCT GTT CAG 2228
Phe Gly Phe Gln Leu Asp Thr Asp Glu Arg His Cys Ile Ala Val Gln
5350 5355 536~
CA 0220~648 l997-0~-20
W O96/15801 PCTrUS95/15203
AAT TTC CTC ATT TTT TCA TCC CAA GTT GCT ATT CGT GGG ATC CCG TTC 2276
Asn Phe Leu Ile Phe Ser Ser Gln Val Ala Ile Arg Gly Ile Pro Phe
5365 5370 5375 5380
ACC TTG TCT ACC CAG GAA GAT GTC ATG GTT CCA GTT TCG GGG AAT CCT 2324
Thr Leu Ser Thr Gln Glu Asp Val Met Val Pro Val Ser Gly Asn Pro
5385 5390 5395
0 TCT TTC TTT GTC GGG ATT GAT TTT GAC GCC CAG GAC AGC ACT ATC TTT 2372
Ser Phe Phe Val Gly Ile Asp Phe Asp Ala Gln Asp Ser Thr Ile Phe
5400 5405 541D
TTT TCA GAT ATG TCA AAA CAC ATG ATT TTT AAG CAA AAG ATT GAT GGC 2420
15 Phe Ser Asp Met Ser Lys His Met Ile Phe Lys Gln Lys Ile Asp Gly
5415 5420 5425
ACA GGA AGA GAA ATT CTC GCA GCT AAC AGG GTG GAA AAT GTT GAA AGT 2468
Thr Gly Arg Glu Ile Leu Ala Ala Asn Arg Val Glu Asn Val Glu Ser
5430 5435 5440
TTG GCT TTT GAT TGG ATT TCA AAG AAT CTC TAT TGG ACA GAC TCT CAT 2516
Leu Ala Phe Asp Trp Ile Ser Lys Asn Leu Tyr Trp Thr Asp Ser His
5445 5450 5455 5460
TAC AAG AGT ATC AGT GTC ATG AGG CTA GCT GAT AAA ACG AGA CGC ACA 2564
Tyr Lys Ser Ile Ser Val Met Arg Leu Ala Asp Lys Thr Arg Arg Thr
5465 5470 5475
30 GTA GTT CAG TAT TTA AAT AAC CCA CGG TCG GTG GTA GTT CAT CCT TTT 2612
Val Val Gln Tyr Leu Asn Asn Pro Arg Ser Val Val Val His Pro Phe
5480 5485 5490
GCC GGG TAT CTA TTC TTC ACT GAT TGG TTC CGT CCT GCT AAA ATT ATG 2660
35 Ala Gly Tyr Leu Phe Phe Thr Asp Trp Phe Arg Pro Ala Lys Ile Met
5495 5500 5505
AGA GCA TGG AGT GAC GGA TCT CAC CTC TTG CCT GTA ATA AAC ACT ACT 2708
Arg Ala Trp Ser Asp Gly Ser His Leu Leu Pro Val Ile Asn Thr Thr
5510 5515 5520
CTT GGA TGG CCC AAT GGC TTG GCC ATC GAT TGG GCT GCT TCA CGA TTG 2756
Leu Gly Trp Pro Asn Gly Leu Ala Ile Asp Trp Ala Ala Ser Arg Leu
5525 5530 5535 5540
TAC TGG GTA GAT GCC TAT TTT GAT AAA ATT GAG CAC AGC ACC TTT GAT 2804
Tyr Trp Val Asp Ala Tyr Phe Asp Lys Ile Glu His Ser Thr Phe Asp
5545 5550 5555
50 GGT TTA GAC AGA AGA AGA CTG GGC CAT ATA GAG CAG ATG ACA CAT CCG 2852
Gly Leu Asp Arg Arg Arg Leu Gly His Ile Glu Gln Met Thr His Pro
5560 5565 5570
TTT GGA CTT GCC ATC TTT GGA GAG CAT TTA TTT TTT ACT GAC TGG AGA 2900
55 Phe Gly Leu Ala Ile Phe Gly Glu His Leu Phe Phe Thr Asp Trp Arg
5575 5580 5585
CTG GGT GCC ATT ATT CGA GTC AGG AAA GCA GAT GGT GGA GAA ATG ACA 2948
Leu Gly Ala Ile Ile Arg Val Arg ~y5 Ala Asp Gly Gly Glu Met Thr
5590 5595 5600
GTT ATC CGA AGT GGC ATT GCT TAC ATA CTG CAT TTG AAA TCG TAT GAT 2996
Val Ile Arg Ser Gly Ile Ala Tyr Ile Leu His Leu Lys Ser Tyr Asp
5605 5610 5615 5620
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
GTC AAC ATC CAG ACT GGT TCT AAC GCC TGT AAT CAA CCC ACG CAT CCT 3044
Val Asn Ile Gln Thr Gly Ser Asn Ala Cys Asn Gln Pro Thr His Pro
5625 5630 5635
AAC GGT GAC TGC AGC CAC TTC TGC TTC CCG GTG CCA AAT TTC CAG CGA 3092
Asn Gly Asp Cys Ser His Phe Cys Phe Pro Val Pro Asn Phe Gln Arg
5640 5645 5650
10 GTG TGT GGG TGC CCT TAT GGA ATG AGG CTG GCT TCC AAT CAC TTG ACA 3140
- Val Cys Gly Cys Pro Tyr Gly Met Arg Leu Ala Ser Asn His Leu Thr
5655 5660 5665
TGC GAG GGG GAC CCA ACC AAT GAA CCA CCC ACG GAG CAG TGT GGC TTA 3188
15 Cys Glu Gly Asp Pro Thr Asn Glu Pro Pro Thr GlU Gln Cys Gly Leu
5670 5675 5680
TTT TCC TTC CCC TGT AAA AAT GGC AGA TGT GTG CCC AAT TAC TAT CTC 3236
Phe Ser Phe Pro Cys Lys Asn Gly Arg Cys Val Pro Asn Tyr Tyr Leu
20 5685 5690 5695 5700
TGT GAT GGA GTC GAT GAT TGT CAT GAT AAC AGT GAT GAG CAA CTA TGT 3284
Cys Asp Gly Val Asp Asp Cys His Asp Asn Ser Asp Glu Gln Leu Cys
5705 5710 5715 .
GGC ACA CTT AAT AAT ACC TGT TCA TCT TCG GCG TTC ACC TGT GGC CAT 3332
Gly Thr Leu Asn Asn Thr Cys Ser Ser Ser Ala Phe Thr Cys Gly His
5720 5725 5730
3 0 GGG GAG TGC ATT CCT GCA CAC TGG CGC TGT GAC AAA CGC AA~ GAC TGT 3380
Gly Glu Cys Ile Pro Ala His Trp Arg Cys Asp Lys Arg Asn Asp Cys
5735 5740 5745
GTG GAT GGC AGT GAT GAG CAC AAC TGC CCC ACC CAC GCA CCT GCT TCC 3428
3 5 Val Asp Gly Ser Asp Glu His Asn Cys Pro Thr His Ala Pro Ala Ser
5750 5755 5760
TGC CTT GAC ACC CAA TAC ACC TGT GAT AAT CAC CAG TGT ATC TCA AAG 3476
Cys Leu Asp Thr Gln Tyr Thr Cys Asp Asn His Gln Cys Ile Ser Lys
40 5765 5770 5775 5780
AAC TGG GTC TGT GAC ACA GAC AAT GAT TGT GGG GAT GGA TCT GAT GAA 3524
Asn Trp Val Cys Asp Thr Asp Asn Asp Cys Gly Asp Gly Ser Asp Glu
5785 5790 5795
AAG AAC TGC AAT TCG ACA GAG ACA TGC CAA CCT AGT CAG TTT AAT TGC 3572
Lys Asn Cys Asn Ser Thr Glu Thr Cys Gln Pro Ser Gln Phe Asn Cys
5800 5805 5810
5 0 CCC AAT CAT CGA TGT ATT GAC CTA TCG TTT GTC TGT GAT GGT GAC AAG 3620
Pro Asn His Arg Cys Ile Asp Leu Ser Phe Val Cys Asp Gly Asp Lys
5815 5820 5825
GAT TGT GTT GAT GGA TCT GAT GAG GTT GGT TGT GTA TTA AAC TGT ACT 3668
5 5 Asp Cys Val Asp Gly Ser, Asp Glu Val Gly Cys Val Leu Asn Cys Thr
5830 5835 5840
GCT TCT CAA TTC AAG TGT GCC AGT GGG GAT AAA TGT ATT GGC GTC ACA 3716
Ala Ser Gln Phe Lys Cys Ala Ser Gly Asp Lys Cys Ile Gly Val Thr
60 5845 5850 5855 5860
AAT CGT TGT GAT GGT GTT TTT GAT TGC AGT GAC AAC TCG GAT GAA GCG 3764
Asn Arg Cys Asp Gly Val Pne Asp Cys Ser Asp Asn Ser Asp Glu Ala
5865 5870 5875
CA 0220~648 1997-OS-20
W O96/15801 PCTrUS95/15203
GGC TGT CCA ACC AGG CCT CCT GGT ATG TGC CAC TCA GAT GAA TTT CAG 3812
Gly Cys Pro Thr Arg Pro Pro Gly Met Cys His Ser Asp Glu Phe Gln
5880 5885 5890
TGC CAA GAA GAT GGT ATC TGC ATC CCG AAC TTC TGG GAA TGT GAT GGG 3860
Cys Gln Glu Asp Gly Ile Cys Ile Pro Asn Phe Trp Glu Cys Asp Gly
5895 5900 5905
0 CAT CCA GAC TGC CTC TAT GGA TCT GAT GAG CAC AAT GCC TGT GTC CCC 3908
His Pro Asp Cys Leu Tyr Gly Ser Asp Glu His Asn Ala Cys Val Pro
5910 5915 5920
AAG ACT TGC CCT TCA TCA TAT TTC CAC TGT GAC AAC GGA AAC TGC ATC 3956
15 Lys Thr Cys Pro Ser Ser Tyr Phe His Cys Asp Asn Gly Asn Cys Ile
5925 5930 5935 5940
CAC AGG GCA TGG CTC TGT GAT CGG GAC AAT GAC TGC GGG GAT ATG AGT 4004
His Arg Ala Trp Leu Cys Asp Arg Asp Asn Asp Cys Gly Asp Met Ser
5945 5950 5955
GAT GAG AAG GAC TGC CCT ACT CAG CCC TTT CGC TGT CCT AGT TGG CAA 4052
Asp Glu Lys Asp Cys Pro Thr Gln Pro Phe Arg Cys Pro Ser Trp Gln
5960 5965 5970
TGG CAG TGT CTT GGC CAT AAC ATC TGT GTG AAT CTG AGT GTA GTG TGT 4100
Trp Gln Cys Leu Gly His Asn Ile Cys Val As,n Leu Ser Val Val Cys
5975 5980 5985
GAT .GGC ATC TTT GAC TGC CCC AAT GGG ACA GAT GAG TCC CCA CTT TGC 4148
Asp Gly Ile Phe Asp Cys Pro Asn Gly Thr Asp Glu Ser Pro Leu Cys
5990 5995 6000
AAT GGG AAC AGC TGC TCA GAT TTC AAT GGT GGT TGT ACT CAC GAG TGT 4196
3 5 Asn Gly Asn Ser Cys Ser Asp Phe Asn Gly Gly Cys Thr His Glu Cys
6005 6010 6015 6020
GTT CAA GAG CCC TTT GGG GCT AAA TGC CTA TGT CCA TTG GGA TTC TTA 4244
Val Gln Glu Pro Phe Gly Ala Lys Cys Leu Cys Pro Leu Gly Phe Leu
6025 6030 6035
CTT GCC AAT GAT TCT AAG ACC TGT GAA GAC ATA GAT GAA TGT GAT ATT 4292
Leu Ala Asn Asp Ser Lys Thr Cys Glu Asp Ile Asp Glu Cys Asp Ile
6040 6045 6050
CTA GGC TCT TGT AGC CAG CAC TGT TAC AAT ATG AGA GGT TCT TTC CGG 4340
Leu Gly Ser Cys Ser Gln His Cys Tyr Asn Met Arg Gly Ser Phe Arg
6055 6060 6065
5 0 TGC TCG TGT GAT ACA GGC TAC ATG TTA GAA AGT GAT GGG AGG ACT TGC 4388
Cys Ser Cys Asp Thr Gly Tyr Met Leu Glu Ser Asp Gly Arg Thr Cys
6070 6075 6080
AAA GTT ACA GCA TCT GAG AGT CTG CTG TTA CTT GTG GCA AGT CAG AAC 4436
Lys Val Thr Ala Ser Glu Ser Leu Leu Leu Leu Val Ala Ser Gln Asn
6085 6090 6095 6100
AAA ATT ATT GCC GAC AGT GTC ACC TCC CAG GTC CAC AAT ATC TAT TCA 4484
Lys Ile Ile Ala Asp Ser Val Thr Ser Gln Val His Asn Ile Tyr Ser
6105 6110 ~ 6115
TTG GTC GAG AAT GGT TCT TAC ATT GTA GCT GTT GAT TTT GAT TCA ATT 4532
I.eu Val Glu Asn Gly Ser Tyr Ile Val Ala Val Asp Phe Asp Ser Ile
6120 6125 6130
CA 0220~648 l997-0~-20
.,
WO 96/15801 PCT/US9~/15203
AGT GGT CGT ATC TTT TGG TCT GAT GCA ACT CAG GGT AAA ACC TGG AGT 4580
Ser Gly Arg Ile Phe Trp Ser Asp Ala Thr Gln Gly Lys Thr Trp Ser
6135 6140 6145
GCG TTT CAA AAT GGA ACG GAC AGA AGA GTG GTA TTT GAC AGT AGC ATC 4628
Ala Phe Gln Asn Gly Thr Asp Arg Arg Val Val Phe Asp Ser Ser Ile
6150 6155 6160
0 ATC TTG ACT GAA ACT ATT GCA ATA GAT TGG GTA GGT CGT AAT CTT TAC 4676
Ile Leu Thr Glu Thr Ile Ala Ile Asp Trp Val Gly Arg Asn Leu Tyr
6165 6170 6175 6180
TGG ACA GAC TAT GCT CTG GAA ACA ATT GAA GTC TCC AAA ATT GAT GGG 4724
Trp Thr Asp Tyr Ala Leu Glu Thr Ile Glu Val Ser Lys Ile Asp Gly
6185 6190 6195
AGC CAC AGG ACT GTG CTG ATT AGT AAA AAC CTA ACA AAT CCA AGA GGA 4772
Ser His Arg Thr Val Leu Ile Ser Lys Asn Leu Thr Asn Pro Arg Gly
6200 6205 6210
CTA GCA TTA GAT CCC AGA ATG AAT GAG CAT CTA CTG TTC TGG TCT GAC 4820
Leu Ala Leu Asp Pro Arg Met Asn Glu His Leu Leu Phe Trp Ser Asp
6215 6220 6225
TGG GGC CAC CAC CCT CGC ATC GAG CGA GCC AGC ATG GAC GGC AGC ATG 4868
Trp Gly His His Pro Arg Ile G1U Arg Ala Ser Met Asp Gly Ser Met
6230 6235 6240
3 0 CGC ACT GTC ATT GTC CAG GAC AAG ATC TTC TGG CCC TGC GGC TTA ACT 4916
Arg Thr Val Ile Val Gln Asp Lys Ile Phe Trp Pro Cys Gly Leu Thr
6245 6250 6255 6260
ATT GAC TAC CCC AAC AGA CTG CTC TAC TTC ATG GAC TCC TAT CTT GAT 4964
3 5 Ile Asp Tyr Pro Asn Arg Leu Leu Tyr Phe Met Asp Ser Tyr Leu Asp
6265 6270 6275
TAC ATG GAC TTT TGC GAT TAT AAT GGA CAC CAT CGG AGA CAG GTG ATA 5012
Tyr Met Asp Phe Cys Asp Tyr Asn Gly His His Arg Arg Gln Val Ile
6280 6285 6290
GCC AGT GAT TTG ATT ATA CGG CAC CCC TAT GCC CTA ACT CTC TTT GAA 5060
Ala Ser Asp Leu Ile Ile Arg His Pro Tyr Ala Leu Thr Leu Phe Glu
6295 6300 6305
GAC TCT GTG TAC TGG ACT GAC CGT GCT ACT CGT CGG GTT ATG CGA GCC 5108
Asp Ser Val Tyr Trp Thr Asp Arg Ala Thr Arg Arg Val Met Arg Ala
6310 6315 6320
5 Q AAC AAG TGG CAT GGA GGG AAC CAG TCA GTT GTA ATG TAT AAT ATT CAA 5156
Asn Lys Trp His Gly Gly Asn Gln Ser Val Val Met Tyr Asn Ile Gln
6325 6330 6335 6340
TGG CCC CTT GGG ATT GTT GCG GTT CAT CCT TCG AAA CAA CCA AAT TCC 5204
5 5 Trp Pro Leu Gly Ile Val Ala Val His Pro Ser Lys Gln Pro Asn Ser
6345 ~ 6350 6355
GTG AAT CCA TGT GCC TTT TCC CGC TGC AGC CAT CTC TGC CTG CTT TCC 5252
Val Asn Pro Cys Ala Phe Ser Arg Cys Ser His Leu Cys Leu Leu Ser
6360 6365 6370
TCA CAG GGG CCT CAT TTT TAC TCC TGT GTT TGT CCT TCA GGA TGG AGT 5300
Ser Gln Gly Pro His Phe Tyr Ser Cys Val Cys Pro Ser Gly Trp Ser
6375 6380 6385
CA 02205648 1997-0~-20
W 096/1580l PCTrUS95/15203
/5-D
CTG TCT CCT GAT CTC CTG AAT TGC TTG AGA GAT GAT CAA CCT TTC TTA 5348
Leu Ser Pro Asp Leu Leu Asn Cys Leu Arg Asp Asp Gln Pro Phe Leu
6390 6395 6400
ATA ACT GTA AGG CAA CAT ATA ATT TTT GGA ATC TCC CTT AAT CCT GAG 5396
Ile Thr Val Arg Gln His Ile Ile Phe Gly Ile Ser Leu Asn Pro Glu
6405 6410 6415 6420
. 10 GTG AAG AGC AAT GAT GCT ATG GTC CCC ATA GCA GGG ATA CAG AAT GGT 5444
Val Lys Ser Asn Asp Ala Met Val Pro Ile Ala Gly Ile Gln Asn Gly
6425 6430 6435
TTA GAT GTT GAA TTT GAT GAT GCT GAG CAA TAC ATC TAT TGG GTT GAA 5492
15 Leu Asp Val Glu Phe Asp Asp Ala Glu Gln Tyr Ile Tyr Trp Val Glu
6440 6445 6450
AAT CCA GGT GAA ATT CAC AGA GTG AAG ACA GAT GGC ACC AAC AGG ACA 5540
Asn Pro Gly Glu Ile His Arg Val Lys Thr Asp Gly Thr Asn Arg Thr
6455 6460 6465
GTA TTT GCT TCT ATA TCT ATG GTG GGG CCT TCT ATG AAC CTG GCC TTA 5588
Val Phe Ala Ser Ile Ser Met Val Gly Pro Ser Met Asn Leu Ala Leu
6470 6475 6480
GAT TGG ATT TCA AGA AAC CTT TAT TCT ACC AAT CCT AGA ACT CAG TCA 5636
Asp Trp Ile Ser Arg Asn Leu Tyr Ser Thr Asn Pro Arg Thr Gln Ser
6485 6490 6495 6500
30 ATC GAG GTT TTG ACA CTC CAC GGA GAT ATC AGA TAC AGA AAA ACA TTG 5684
Ile Glu Val Leu Thr Leu His Gly Asp Ile Arg Tyr Arg Lys Thr Leu
6505 6510 6515
ATT GCC AAT GAT GGG ACA GCT CTT GGA GTT GGC TTT CCA ATT GGC ATA 5732
35 Ile Ala Asn Asp Gly Thr Ala Leu Gly Val Gly Phe Pro Ile Gly Ile
6520 6525 6530
ACT GTT GAT CCT GCT CGT GGG AAG CTG TAC TGG TCA GAC CAA GGA ACT 5780
Thr Val Asp Pro Ala Arg Gly Lys Leu Tyr Trp Ser Asp Gln Gly Thr
6535 6540 6545
GAC AGT GGG GTT CCT GCC AAG ATC GCC AGT GCT AAC ATG GAT GGC ACA 5828
Asp Ser Gly Val Pro Ala Lys Ile Ala Ser Ala Asn Met Asp Gly Thr
6550 6555 6560
TCT GTG AAA ACT CTC TTT ACT GGG AAC CTC GAA CAC CTG GAG TGT GTC 5876
Ser Val Lys Thr Leu Phe Thr Gly Asn Leu Glu His Leu Glu Cys Val
6565 6570 6575 6580
50 ACT CTT GAC ATC GAA GAG CAG AAA CTC TAC TGG GCA GTC ACT GGA AGA 5924
Thr Leu Asp Ile Glu Glu Gln Lys Leu Tyr Trp Ala Val Thr Gly Arg
6585 6590 6595
GGA GTG ATT GAA AGA GGA AAC GTG GAT GGA ACA GAT CGG ATG ATC CTG 5972
55 Gly Val Ile Glu Arg Gly Asn Val Asp Gly Thr Asp Arg Met Ile Leu
6600 6605 6610
GTA CAC CAG CTT TCC CAC CCC TGG GGA ATT GCA GTC CAT GAT TCT TTC 6020
Val His Gln Leu Ser His Pro Trp Gly Ile Ala Val kis Asp Ser Phe
6615 6620 6625
CTT TAT TAT ACT GAT GAA CAG TAT GAG GTC ATT GAA AGA GTT GAT AAG 6068
Leu Tyr Tyr Thr Asp Glu Gln Tyr Glu Val Ile Glu Arg Val Asp Lys
6630 6635 6640
CA 0220~648 l997-OS-20
W O 96/lS801 PCTrUS9~/lS203
lS/
GCC ACT GGG GCC AAC AAA ATA GTC TTG AGA GAT AAT GTT CCA AAT CTG 6116
Ala Thr Gly Ala Asn Lys Ile Val Leu Arg Asp Asn Val Pro Asn Leu
. 6645 6650 6655 6660
AGG GGT CTT CAA GTT TAT CAC AGA CGC AAT GCC GCC GAA TCC TCA AAT 6164
Arg Gly Leu Gln Val Tyr His Arg Arg Asn Ala Ala Glu Ser Ser Asn
6665 6670 6675
0 GGC TGT AGC AAC AAC ATG AAT GCC TGT CAG CAG ATT TGC CTG CCT GTA 6212
Gly Cys Ser Asn Asn Met Asn Ala Cys Gln Gln Ile Cys Leu Pro Val
6680 6685 6690
CCA GGA GGA TTG TTT TCC TGC GCC TGT GCC ACT GGA TTT AAA CTC AAT 6260
15 Pro Gly Gly Leu Phe Ser Cys Ala Cys Ala Thr Gly Phe Lys Leu Asn
6695 6700 6705
CCT GAT AAT CGG TCC TGC TCT CCA TAT AAC TCT TTC ATT GTT GTT TCA 6308
Pro Asp Asn Arg Ser Cys Ser Pro Tyr Asn Ser Phe Ile Val Val Ser
6710 6715 6720
ATG CTG TCT GCA ATC AGA GGC TTT AGC TTG GAA TTG TCA GAT CAT TCA 6356
Met Leu Ser Ala Ile Arg Gly Phe Ser Leu Glu Leu Ser Asp His Ser
6725 6730 6735 6740
GAA ACC ATG GTG CCG GTG GCA GGC CAA GGA CGA AAC GCA CTG CAT GTG 6404
Glu Thr Met Val Pro Val Ala Gly Gln Gly Arg Asn Ala Leu His Val
6745 6750 6755
30 GAT GTG GAT GTG TCC TCT GGC TTT ATT TAT TGG TGT GAT TTT AGC AGC 6452
Asp Val Asp Val Ser Ser Gly Phe Ile Tyr Trp Cys Asp Phe Ser Ser
6760 6765 6770
TCA GTG GCA TCT GAT AAT GCG ATC CGT AGA ATT AAA CCA GAT GGA TCT 6500
35 Ser Val Ala Ser Asp Asn Ala Ile Arg Arg Ile Lys Pro Asp Gly Ser
6775 6780 6785
TCT CTG ATG AAC ATT GTG ACA CAT GGA ATA GGA GAA AAT GGA GTC CGG 6548
Ser Leu Met Asn Ile Val Thr His Gly Ile Gly Glu Asn Gly Val Arg
6790 6795 6800
GGT ATT GCA GTG GAT TGG GTA GCA GGA AAT CTT TAT TTC ACC AAT GCC 6596
Gly Ile Ala Val Asp Trp Val Ala Gly Asn Leu Tyr Phe Thr Asn Ala
6805 6810 6815 6820
TTT GTT TCT GAA ACA CTG ATA GAA GTT CTG CGG ATC AAT ACT ACT TAC 6644
Phe Val Ser Glu Thr Leu Ile Glu Val Leu Arg Ile Asn Thr Thr Tyr
6825 6830 6835
50 CGC CGT GTT CTT CTT AAA GTC ACA GTG GAC ATG CCT AGG CAT ATT GTT 6692
Arg Arg Val Leu Leu Lys Val Thr Val Asp Met Pro Arg His Ile Val
6840 6845 6850
GTA GAT CCC AAG AAC AGA TAC CTC TTC TGG GCT GAC TAT GGG CAG AGA 6740
55 Val Asp Pro Lys Asn Arg Tyr Leu Phe Trp Ala Asp Tyr Gly Gln Arg
6855 6860 6865
CCA AAG ATT GAG CGT TCT TTC CTT GAC TGT ACC AAT CGA ACA GTG CTT 6788
Pro Lys Ile Glu Arg Ser Phe Leu Asp Cys Thr Asn Arg Thr Val Leu
6870 6875 6880
GTG TCA GAG GGC ATT GTC ACA CCA CGG GGC TTG GCA GTG GAC CGA AGT 6836
Val Ser Glu Gly Ile Val Thr Pro Arg Gly Leu Ala Val Asp Arg Ser
6885 6890 6895 6900
CA 0220~648 l997-0~-20
WO 96/1~i801 PCT/US95/15203
/,s--.æ
GAT GGC TAC GTT TAT TGG GTT GAT GAT TCT TTA GAT ATA ATT GCA AGG 6884
Asp Gly Tyr Val Tyr Trp Val Asp Asp Ser Leu Asp Ile Ile Ala Arg
6905 6910 6915
ATT CGT ATC AAT GGA GAG AAC TCT GAA GTG ATT CGT TAT GGC AGT CGT 6932
Ile Arg Ile Asn Gly Glu Asn Ser Glu Val Ile Arg Tyr Gly Ser Arg
6920 6925 6930
TAC CCA ACT CCT TAT GGC ATC ACT GTT TTT GAA AAT TCT ATC ATA TGG 6980
Tyr Pro Thr Pro Tyr Gly Ile Thr Val Phe Glu Asn Ser Ile Ile Trp
6935 6940 6945
GTA GAT AGG AAT TTG AAA AAG ATC TTC CAA GCC AGC AAG GAA CCA GAG 7028
Val Asp Arg Asn Leu Lys Lys Ile Phe Gln Ala Ser Lys Glu Pro Glu
6950 6955 6960
AAC ACA GAG CCA CCC ACA GTG ATA AGA GAC AAT ATC AAC TGG CTA AGA 7076
Asn Thr Glu Pro Pro Thr Val Ile Arg Asp Asn Ile Asn Trp Leu Arg
6965 6970 6975 6980
GAT GTG ACC ATC TTT GAC AAG CAA GTC CAG CCC CGG TCA CCA GCA GAG 7124
Asp Val Thr Ile Phe Asp Lys Gln Val Gln Pro Arg Ser Pro Ala Glu
6985 6990 6995
GTC AAC AAC AAC CCT TGC TTG GAA AAC AAT GGT GGG TGC TCT CAT CTC 7172
Val Asn Asn Asn Pro Cys Leu Glu Asn Asn Gly Gly Cys Ser His Leu
7000 7005 7010
3 0 TGC TTT GCT CTG CCT GGA TTG CAC ACC CCA AAA TGT GAC TGT GCC TTT 7220
Cys Phe Ala Leu Pro Gly Leu His Thr Pro Lys Cys Asp Cys Ala Phe
7015 7020 7025
GGG ACC CTG CAA AGT GAT GGC AAG AAT TGT GCC ATT TCA ACA GAA AAT 7268
3 5 Gly Thr Leu Gln Ser Asp Gly Lys Asn Cys Ala Ile Ser Thr Glu Asn
7030 7035 7040
TTC CTC ATC TTT GCC TTG TCT AAT TCC TTG AGA AGC TTA CAC TTG GAC 7316
Phe Leu Ile Phe Ala Leu Ser Asn Ser Leu Arg Ser Leu His Leu Asp
7045 7050 7055 7060
CCT GAA AAC CAT AGC CCA CCT TTC CAA ACA ATA AAT GTG GAA AGA ACT 7364
Pro Glu Asn His Ser Pro Pro Phe Gln Thr Ile Asn Val Glu Arg Thr
7065 7070 7075
GTC ATG TCT CTA GAC TAT GAC AGT GTA AGT GAT AGA ATC TAC TTC ACA 7412
Val Met Ser Leu Asp Tyr Asp Ser Val Ser Asp Arg Ile Tyr Phe Thr
7080 7085 7090
5 0 CAA AAT TTA GCC TCT GGA GTT GGA CAG ATT TCC TAT GCC ACC CTG TCT 746 G
Gln Asn Leu Ala Ser Gly Val Gly Gln Ile Ser Tyr Ala Thr Leu Ser
7095 . 7100 7105
TCA GGG ATC CAT ACT CCA ACT GTC ATT GCT TCA GGT ATA GGG ACT GCT 7508
Ser Gly Ile His Thr Pro Thr Val Ile Ala Ser Gly Ile Gly Thr Ala
7110 7115 7120
GAT GGC ATT GCC TTT GAC TGG ATT ACT AGA AGA ATT TAT TAC AGT GAC 7556
Asp Gly Ile Ala Phe Asp Trp Ile Thr Arg Arg Ile Tyr Tyr Ser Asp
7125 7130 7135 7140
TAC CTC AAC CAG ATG ATT AAT TCC ATG GCT GAA GAT GGG TCT AAC CGC 7604
Tyr Leu Asn Gln Met Ile Asn Ser Met Ala Glu Asp Gly Ser Asn Arg
7145 7150 7155
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
/~
ACT GTG ATA GCC CGC GTT CCA AAA CCA AGA GCA ATT GTG TTA GAT CCC 7652
Thr Val Ile Ala Arg Val Pro Lys Pro Arg Ala Ile Val Leu Asp Pro
7160 7165 7170
,, TGC CAA GGG TAC CTG TAC TGG GCT GAC TGG GAT ACA CAT GCC AAA ATC 7700
Cys Gln Gly Tyr Leu Tyr Trp Ala Asp Trp Asp Thr His Ala Lys Ile
7175 7180 7185
10 GAG AGA GCC ACA TTG GGA GGA AAC TTC CGG GTA CCC ATT GTG AAC AGC 7748
Glu Arg Ala Thr Leu Gly Gly Asn Phe Arg Val Pro Ile Val Asn Ser
7190 7195 7200
AGT CTG GTC ATG CCC AGT GGG CTG ACT CTG GAC TAT GAA GAG GAC CTT 7796
15 Ser Leu Val Met Pro Ser Gly Leu Thr Leu Asp Tyr Glu Glu Asp Leu
7205 7210 7215 7220
CTC TAC TGG GTG GAT GCT AG~ CTG CAG AGG ATT GAA CGC AGC ACT CTG 7844
Leu Tyr Trp Val Asp Ala Ser Leu Gln Arg Ile Glu Arg Ser Thr Leu
7225 7230 7235
ACG GGC GTG GAT CGT GAA GTC ATT GTC AAT GCA GCC GTT CAT GCT TTT 7892
Thr Gly Val Asp Arg Glu Val Ile Val Asn Ala Ala Val His Ala Phe
7240 7245 7250
GGC TTG ACT CTC TAT GGC CAG TAT ATT TAC TGG ACT GAC TTG TAC ACA 7940
Gly Leu Thr Leu Tyr Gly Gln Tyr Ile Tyr Trp Thr Asp Leu Tyr Thr
7255 7260 7265
3 0 CAA AGA ATT TAC CGA GCT AAC AAA TAT GAC GGG TCA GGT CAG ATT GCA 7988
Gln Arg Ile Tyr Arg Ala Asn Lys Tyr Asp Gly Ser Gly Gln Ile Ala
7270 7275 7280
ATG ACC ACA AAT TTG CTC TCC CAG CCC AGG GGA ATC AAC ACT GTT GTG 8036
3 5 Met Thr Thr Asn Leu Leu Ser Gln Pro Arg Gly Ile Asn Thr Val Val
7285 7290 7295 7300
AAG AAC CAG AAA CAA CAG TGT AAC AAT CCT TGT GAA CAG TTT AAT GGG 8084
Lys Asn Gln Lys Gln Gln Cys Asn Asn Pro Cys Glu Gln Phe Asn Gly
7305 7310 7315
GGC TGC AGC CAT ATC TGT GCA CCA GGT CCA AAT GGT GCC GAG TGC CAG 8132
Gly Cys Ser His Ile Cys Ala Pro Gly Pro Asn Gly Ala Glu Cys Gln
7320 7325 7330
TGT CCA CAT GAG GGC AAC TGG TAT TTG GCC AAC AAC AGG AAG CAC TGC 8180
Cys Pro His Glu Gly Asn Trp Tyr Leu Ala Asn Asn Arg Lys His Cys
7335 7340 7345
50 ATT GTG GAC AAT GGT GAA CGA TGT GGT GCA TCT TCC TTC ACC TGC TCC 8228
Ile Val Asp Asn Gly Glu Arg Cys Gly Ala Ser Ser Phe Thr Cys Ser
7350 7355 7360
AAT GGG CGC TGC ATC TCG GAA GAG TGG AAG TGT GAT AAT GAC AAC GAC 8276
55 Asn Gly Arg Cys Ile Ser Glu Glu Trp Lys Cys Asp Asn Asp Asn Asp
7365 7370 7375 7380
TGT GGG GAT GGC AGT GAT GAG ATG GAA AGT GTC TGT GCA CTT CAC ACC 8324
Cys Gly Asp Gly Ser Asp Glu Met Glu Ser Val Cys Ala Leu His Thr
7385 7390 7395
TGC TCA CCG ACA GCC TTC ACC TGT GCC AAT GGG CGA TGT GTC CAA TAC 8372
Cys Ser Pro Thr Ala Phe Thr Cys Ala Asn Gly Arg Cys Val Gln Tyr
7400 7405 7410
CA 0220S648 1997-OS-20
W O96/15801 PCTrUS95/15203
1~--S/
TCT TAC CGC TGT GAT TAC TAC AAT GAC TGT GGT GAT GGC AGT GAT GAG 8420
Ser Tyr Arg Cys Asp Tyr Tyr Asn Asp Cys Gly Asp Gly Ser Asp Glu
7415 7420 7425
GCA GGG TGC CTG TTC AGG GAC TGC AAT GCC ACC ACG GAG TTT ATG TGC 8468
Ala Gly Cys ~eu Phe Arg Asp Cys Asn Ala Thr Thr Glu Phe Met Cys
7430 7435 7440
10 AAT AAC AGA AGG TGC ATA CCT CGT GAG TTT ATC TGC AAT GGT GTA GAC 8516
Asn Asn Arg Arg Cys Ile Pro Arg Glu Phe Ile Cys Asn Gly Val Asp
7445 7450 7455 7460
AAC TGC CAT GAT AAT AAC ACT TCA GAT GAG AAA AAT TGC CCT GAT CGC 8564
15 Asn Cys His Asp Asn Asn Thr Ser Asp Glu Lys Asn Cys Pro Asp Arg
7465 7470 7475
ACT TGC CAG TCT GGA TAC ACA AAA TGT CAT AAT TCA AAT ATT TGT ATT 8612
Thr Cys Gln Ser Gly Tyr Thr Lys Cys His Asn Ser Asn Ile Cys Ile
7480 7485 7490
CCT CGC GTT TAT TTG TGT GAC GGA GAC AAT GAC TGT GGA GAT AAC AGT 8660
Pro Arg Val Tyr Leu Cys Asp Gly Asp Asn Asp Cys Gly Asp Asn Ser
7495 7500 7505
GAT GAA AAC CCT ACT TAT TGC ACC ACT CAC ACA TGC AGC AGC AGT GAG 8708
Asp Glu Asn Pro Thr Tyr Cys Thr Thr His Thr Cys Ser Ser Ser Glu
7510 7515 7520
30 TTC CAA TGC GCA TCT GGG CGC TGT ATT CCT CAA CAT TGG TAT TGT GAT 8756
Phe Gln Cys Ala Ser Gly Arg Cys Ile Pro Gln His Trp Tyr Cys Asp
7525 7530 7535 7540
CAA GAA ACA GAT TGT TTT GAT GCC TCT GAT GAA CCT GCC TCT TGT GGT 8804
3 5 Gln Glu Thr Asp Cys Phe Asp Ala Ser Asp Glu Pro Ala Ser Cys Gly
7545 7550 7555
CAC TCT GAG CGA ACA TGC CTA GCT GAT GAG TTC AAG TGT GAT GGT GGG 8852
His Ser Glu Arg Thr Cys Leu Ala Asp Glu Phe Lys Cys Asp Gly Gly
7560 7565 7570
AGG TGC ATC CCA AGC GAA TGG ATC TGT GAC GGT GAT AAT GAC TGT GGG 8900
Arg Cys Ile Pro Ser Glu Trp Ile Cys Asp Gly Asp Asn Asp Cys Gly
7575 7580 7585
GAT ATG AGT GAC GAG GAT AAA AGG CAC CAG TGT CAG AAT CAA AAC TGC 8948
Asp Met Ser Asp Glu Asp Lys Arg His Gln Cys Gln Asn Gln Asn Cys
7590 7595 7600
50 TCG GAT TCC GAG TTT CTC TGT GTA AAT GAC AGA CCT CCG GAC AGG AGG 8996
Ser Asp Ser Glu Phe Leu Cys Val Asn Asp Arg Pro Pro Asp Arg Arg
7605 7610 7615 7620
TGC ATT CCC CAG TCT TGG GTC TGT GAT GGC GAT GTG GAT TGT ACT GAC 9044
55 Cys Ile Pro Gln Ser TrR Val Cys Asp Gly Asp Val Asp Cys Thr Asp
7625 7630 7635
GGC TAC GAT GAG AAT CAG AAT TGC ACC AGG AGA ACT TGC TCT GAA AAT 9092
Gly Tyr Asp Glu Asn Gln Asn Cys Thr Arg Arg Thr Cys Ser Glu Asn
7640 7645 7650
GAA TTC ACC TGT GGT TAC GGA CTG TGT ATC CCA AAG ATA TTC AGG TGT 9140
Glu Phe Thr Cys Gly Tyr Gly Leu Cys Ile Pro Lys Ile Phe Arg Cys
7655 7660 7665
CA 0220~648 l997-0~-20
WO 96/15801 PCTtUS95/15203
GAC CGG CAC AAT GAC TGT GGT GAC TAT AGC GAC GAG AGG GGC TGC TTA 9188
Asp Arg His Asn Asp Cys Gly Asp Tyr Ser Asp Glu Arg Gly Cys Leu
7670 7675 7680
TAC CAG ACT TGC CAA CAG AAT CAG TTT ACC TGT CAG AAC GGG CGC TGC 9236
Tyr Gln Thr Cys Gln Gln Asn Gln Phe Thr Cys Gln Asn Gly Arg Cys
7685 7690 7695 7700
0 ATT AGT AAA ACC TTC GTC TGT GAT GAG GAT AAT GAC TGT GGA GAC GGA 9284
Ile Ser Lys Thr Phe Val Cys Asp Glu Asp Asn Asp Cys Gly Asp Gly
7705 7710 7715
TCT GAT GAG CTG ATG CAC CTG TGC CAC ACC CCA GAA CCC ACG TGT CCA 9332
Ser Asp Glu Leu Met His Leu Cys His Thr Pro Glu Pro Thr Cys Pro
7720 7725 7730
CCT CAC GAG TTC AAG TGT GAC AAT GGG CGC TGC ATC GAG ATC- ATG AAA 9380
Pro His Glu Phe Lys Cys Asp Asn Gly Arg Cys Ile Glu Met Met Lys
7735 7740 7745
CTC TGC AAC CAC CTA GAT GAC TGT TTG GAC AAC AGC GAT GAG AAA GGC 9428
Leu Cys Asn His Leu Asp Asp Cys Leu Asp Asn Ser Asp Glu Lys Gly
7750 7755 7760
TGT GGC ATT AAT GAA TGC CAT GAC CCT TCA ATC AGT GGC TGC GAT CAC 9476
Cys Gly Ile Asn Glu Cys His Asp Pro Ser Ile Ser Gly Cys Asp His
7765 7770 7775 7780
3 0 AAe TGC ACA GAC ACC TTA ACC AGT TTC TAT TGT TCC TGT CGT CCT GGT 9524
Asn Cys Thr Asp Thr Leu Thr Ser Phe Tyr Cys Ser Cys Arg Pro Gly
7785 7790 7795
TAC AAG CTC ATG TCT GAC AAG CGG ACT TGT GTT GAT ATT GAT GAA TGC 9572
3 5 Tyr Lys Leu Met Ser Asp Lys Arg Thr Cys Val Asp Ile Asp Glu Cys
7800 7805 7810
ACA GAG ATG CCT TTT GTC TGT AGC CAG AAG TGT GAG AAT GTA ATA GGC 9620
Thr Glu Met Pro Phe Val Cys Ser Gln Lys Cys Glu Asn Val Ile Gly
7815 7820 7825
TCC TAC ATC TGT AAG TGT GCC CCA GGC TAC CTC CGA GAA CCA GAT GGA 9668
Ser Tyr Ile Cys Lys Cys Ala Pro Gly Tyr Leu Arg Glu Pro Asp Gly
7830 7835 7840
AAG ACC TGC CGG CAA AAC AGT AAC ATC GAA CCC TAT CTC ATT TTT AGC 9716
Lys Thr Cys Arg Gln Asn Ser Asn Ile Glu Pro Tyr Leu Ile Phe Ser
7845 7850 7855 7860
AAC CGT TAC TAT TTG AGA AAT TTA ACT ATA GAT GGC TAT TTT TAC TCC 9764
Asn Arg Tyr Tyr Leu Arg Asn Leu Thr Ile Asp Gly Tyr Phe Tyr Ser
7865 7870 7875
CTC ATC TTG GAA GGA CTG GAC AAT GTT GTG GCA TTA GAT TTT GAC CGA 981 Z
- 55 Leu Ile Leu Glu Gly Leu Asp Asn Val Val Ala Leu Asp Phe Asp Arg
7880 7885 7890
GTA GAG AAG AGA TTG TAT TGG ATT GAT ACA CAG AGG CAA GTC ATT GAG 9860
Val Glu Lys Arg Leu Tyr Trp Ile Asp Thr Gln Arg Gln Val Ile Glu
7895 7900 7905
AGA ATG TTT CTG AAT AAG ACA AAC AAG GAG ACA ATC ATA AAC CAC AGA 9908
Arg Met Phe Leu Asn Lys Thr Asn Lys Glu Thr Ile Ile Asn His Arg
7910 7915 7920
_
CA 0220~648 l997-0~-20
W O96/15801 PCT~US95115203
CTA CCA GCT GCA GAA AGT CTG GCT GTA GAC TGG GTT TCC AGA AAG CTC 9956
Leu Pro Ala Ala Glu Ser Leu Ala Val Asp Trp Val Ser Arg Lys Leu
7925 7930 7935 7940
TAC TGG TTG GAT GCC CGC CTG GAT GGC CTC TTT GTC TCT GAC CTC AAT 10004
Tyr Trp Leu Asp Ala Arg Leu Asp Gly ~eu Phe Val Ser Asp Leu Asn
7945 7950 7955
10 GGT GGA CAC CGC CGC ATG CTG GCC CAG CAC TGT GTG GAT GCC AAC AAC 10052
Gly Gly His Arg Arg Met Leu Ala Gln His Cys Val Asp Ala Asn Asn
7960 7965 7970
ACC TTC TGC TTT GAT AAT CCC AGA GGA CTT GCC CTT CAC CCT CAA TAT 10100
15 Thr Phe Cys Phe Asp Asn Pro Arg Gly Leu Ala Leu His Pro Gln Tyr
7975 7980 7985
GGG TAC CTC TAC TGG GCA GAC TGG GGT CAC CGC GCA TAC ATT GGG AGA 10148
Gly Tyr Leu Tyr Trp Ala Asp Trp Gly His Arg Ala Tyr Ile Gly Arg
7990 7995 8000
GTA GGC ATG GAT GGA ACC AAC AAG TCT GTG ATA ATC TCC ACC AAG TTA 10196
Val Gly Met Asp Gly Thr Asn Lys Ser Val Ile Ile Ser Thr Lys Leu
8005 8010 8015 8020
GAG TGG CCT AAT GGC ATC ACC ATT GAT TAC ACC AAT GAT CTA CTC TAC 10244
Glu Trp Pro Asn Gly Ile Thr Ile Asp Tyr Thr Asn Asp Leu Leu Tyr
8025 8030 8035
TGG GCA GAT GCC CAC CTG GGT TAC ATA GAG TAC TCT GAT TTG GAG GGC 10292
Trp Ala Asp Ala His Leu Gly Tyr Ile Glu Tyr Ser Asp Leu Glu Gly
8040 8045 8050
CAC CAT CGA CAC ACG GTG TAT GAT GGG GCA CTG CCT CAC CCT TTC GCT 10340
His His Arg His Thr Val Tyr Asp Gly Ala Leu Pro His Pro Phe Ala
8055 8060 8065
ATT ACC ATT TTT GAA GAC ACT ATT TAT TGG ACA GAT TGG AAT ACA AGG 10388
Ile Thr Ile Phe Glu Asp Thr Ile Tyr Trp Thr Asp Trp Asn Thr Arg
8070 8075 8080
ACA GTG GAA AAG GGA AAC AAA TAT GAT GGA TCA AAT AGA CAG ACA CTG lQ436
Thr Val Glu Lys Gly Asn Lys Tyr Asp Gly Ser Asn Arg Gln Thr Leu
8085 8090 8095 8100
GTG AAC ACA ACA CAC AGA CCA TTT GAC ATC CAT GTG TAC CAT CCA TAT 10484
Val Asn Thr Thr His Arg Pro Phe Asp Ile His Val Tyr His Pro Tyr
8105 8110 8115
AGG CAG CCC ATT GTG AGC AAT CCC TGT GGT ACC AAC AAT GGT GGC TGT 10532
. Arg Gln Pro Ile Val Ser Asn Pro Cys Gly Thr Asn Asn Gly Gly Cys
8120 8125 8130
TCT CAT CTC TGC CTC ATC AAG CCA GGA GGA AAA GGG TTC ACT TGC GAG 10580
Ser His Leu Cys Leu Ile Lys Pro Gly Gly Lys Gly Phe Thr Cys Glu
8135 8140 8145
TGT CCA GAT GAC TTC CGC ACC CTT CAA CTG AGT GGC AGC ACC TAC TGC 10628
Cys Pro Asp Asp Phe Arg Thr Leu Gln Leu Ser Gly Ser Thr Tyr Cys
8150 8155 8160
ATG CCC ATG TGC TCC AGC ACC CAG TTC CTG TGC GCT AAC AAT GAA AAG 10676
Met Pro Met Cys Ser Ser Thr Gln Phe Leu Cys Ala Asn Asn Glu Lys
8165 8170 8175 8180
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
~ s77
TGC ATT CCT ATC TGG TGG AAA TGT GAT GGA CAG AAA GAC TGC TCA GAT 10724
Cys Ile Pro Ile Trp Trp Lys Cys Asp Gly Gln Lys Asp Cys Ser Asp
8185 8190 8195
GGC TCT GAT GAA CTG GCC CTT TGC CCG CAG CGC TTC TGC CGA CTG GGA 10772
Gly Ser Asp Glu Leu Ala Leu Cys Pro Gln Arg Phe Cys Arg Leu Gly
8200 8205 8210
CAG TTC CAG TGC AGT GAC GGC AAC TGC ACC AGC CCG CAG ACT TTA TGC 10820
Gln Phe Gln Cys Ser Asp Gly Asn Cys Thr Ser Pro Gln Thr Leu Cys
8215 8220 8225 ' ..
AAT GCT CAC CAA AAT TGC CCT GAT GGG TCT GAT GAA GAC CGT CTT CTT 10868
Asn Ala His Gln Asn Cys Pro Asp Gly Ser Asp Glu Asp Arg Leu Leu
8230 8235 8240
TGT GAG AAT CAC CAC TGT GAC TCC AAT GAA TGG CAG TGC GCC AAC AAA 10916
Cys Glu Asn His His Cys Asp Ser Asn Glu Trp Gln Cys Ala Asn Lys
8245 8250 8255 8260
CGT TGC ATC CCA GAA TCC TGG CAG TGT GAC ACA TTT AAC GAC TGT GAG 10964
Arg Cys Ile Pro Glu Ser Trp Gln Cys Asp Thr Phe Asn Asp Cys Glu
8265 8270 8275
GAT AAC TCA GAT GAA GAC AGT TCC CAC TGT GCC AGC AGG ACC TGC CGG 11012
Asp Asn Ser Asp Glu Asp Ser Ser His Cys Ala Ser Arg Thr Cys Arg
8280 8285 8290
3 0 CCG GGC CAG TTT CGG TGT GCT AAT GGC CGC TGC ATC CCG CAG GCC TGG 11060
Pro Gly Gln Phe Arg Cys Ala Asn Gly Arg Cys Ile Pro Gln Ala Trp
8295 8300 8305
AAG TGT GAT GTG GAT AAT GAT TGT GGA GAC CAC TCG GAT GAG CCC ATT 11108
3 5 Lys Cys Asp Val Asp Asn Asp Cys Gly Asp His Ser Asp Glu Pro Ile
8310 8315 8320
GAA GAA TGC ATG AGC TCT GCC CAT CTC TGT GAC AAC TTC ACA GAA TTC 11156
Glu Glu Cys Met Ser Ser Ala His Leu Cys Asp Asn Phe Thr Glu Phe
8325 8330 8335 8340
AGC TGC AAA ACA AAT TAC CGC TGC ATC CCA AAG TGG GCC GTG TGC AAT 11204
Ser Cys Lys Thr Asn Tyr Arg Cys Ile Pro Lys Trp Ala Val Cys Asn
8345 8350 8355
GGT GTA GAT GAC TGC AGG GAC AAC AGT GAT GAG CAA GGC TGT GAG GAG 11252
Gly Val Asp Asp Cys Arg Asp Asn Ser Asp Glu Gln Gly Cys Glu Glu
8360 8365 8370
AGG ACA TGC CAT CCT GTG GGG GAT TTC CGC TGT AAA AAT CAC CAC TGC 11300
Arg Thr Cys His Pro Val Gly Asp Phe Ar~ Cys Lys Asn His His Cys
8375 8380 8385
ATC CCT CTT CGI~ TGG CAG TGT GAT GGG CAA AAT GAC TGT GGA GAT AAC 11348
Ile Pro Leu Arg Trp Gln Cys Asp Gly Gln Asn Asp Cys Gly Asp Asn
8390 8395 8400
TCA GAT GAG GAA AAC TGT GCT CCC CGG GAG TGC ACA GAG AGC GAG TTT 11396
Ser Asp Glu Glu Asn Cys Ala Pro Arg Glu Cys Thr Glu Ser Glu Phe
8405 8410 8415 8420
CGA TGT GTC AAT CAG CAG TGC ATT CCC TCG CGA TGG ATC TGT GAC CAT 11444
Arg Cys Val Asn Gln Gln Cys Ile Pro Ser Arg Trp Ile Cys Asp His
8425 843 Q 8435
CA 0220~648 l997-0~-20
WO 96115801 PCTtUS95/15203
TAC AAC GAC TGT GGG GAC AAC TCA GAT GAA CGG GAC TGT GAG ATG AGG 11492
Tyr Asn Asp Cys Gly Asp Asn Ser Asp Glu Arg Asp Cys Glu Met Arg
8440 . 8445 8450
ACC TGC CAT CCT GAA TAT TTT CAG TGT ACA AGT GGA CAT TGT GTA CAC 11540
Thr Cys His Pro Glu Tyr Phe Gln Cys Thr Ser Gly His Cys Val His
8455 8460 8465
AGT GAA CTG AAA TGC GAT GGA TCC GCT GAC TGT TTG GAT GCG TCT GAT 11588
Ser Glu Leu Lys Cys Asp Gly Ser Ala Asp Cys Leu Asp Ala Ser Asp
8470 ' 8475 8480
GAA GCT GAT TGT CCC ACA CGC TTT CCT GAT GGT GCA TAC TGC CAG GCT 11636
Glu Ala Asp Cys Pro Thr Arg Phe Pro Asp Gly Ala Tyr Cys Gln Ala
8485 8490 8495 8500
ACT ATG TTC GAA TGC AAA AAC CAT GTT TGT ATC CCG CCA TAT TGG AAA 11684
Thr Met Phe Glu Cys Lys Asn His Val Cys Ile Pro Pro Tyr Trp Lys
8505 8510 8515
TGT GAT GGC GAT GAT GAC TGT GGC GAT GGT TCA GAT GAA GAA CTT CAC 11732
Cys Asp Gly Asp Asp Asp Cys Gly Asp Gly Ser Asp Glu Glu Leu His
8520 8525 8530
CTG TGC TTG GAT GTT CCC TGT AAT TCA CCA AAC CGT TTC CGG TGT GAC 11780
Leu Cys Leu Asp Val Pro Cys Asn Ser Pro Asn Arg Phe Arg Cys Asp
8535 8540 8545
3 0 AAC AAT CGC TGC ATT TAT AGT CAT GAG GTG TGC AAT GGT GTG GAT GAC 11828
Asn Asn Arg Cys Ile Tyr Ser His Glu Val Cys Asn Gly Val Asp Asp
8550 8555 8560
TGT GGA GAT GGA ACT GAT GAG ACA GAG GAG CAC TGT AGA AAA CCG ACC 11876
3 5 Cys Gly Asp Gly Thr Asp Glu Thr Glu Glu His Cys Arg Lys Pro Thr
8565 8570 8575 858D
CCT AAA CCT TGT ACA GAA TAT GAA TAT AAG TGT GGC AAT GGG CAT TGC 11924
Pro Lys Pro Cys Thr Glu Tyr Glu Tyr Lys Cys Gly Asn Gly His Cys
8585 8590 8595
ATT CCA CAT GAC AAT GTG TGT GAT GAT GCC GAT GAC TGT GGT GAC TGG 11972
Ile Pro His Asp Asn Val Cys Asp Asp Ala Asp Asp Cys Gly Asp Trp
8600 8605 8610
TCC GAT GAA CTG GGT TGC AAT AAA GGA AAA GAA AGA ACA TGT GCT GAA 12020
Ser Asp Glu Leu Gly Cys Asn Lys Gly Lys Glu Arg Thr Cys Ala Glu
8615 8620 8625
5 0 AAT ATA TGC GAG CAA AAT TGT ACC CAA TTA AAT GAA GGA GGA TTT ATC 12068
Asn Ile Cys Glu Gln Asn Cys Thr Gln Leu Asn Glu Gly Gly Phe Ile
8630 8635 8640
TGC TCC TGT ACA GCT GGG TTC GAA ACC AAT GTT TTT GAC AGA ACC TCC 12116
5 5 Cys Ser Cys Thr Ala Gly Phe Glu Thr Asn Val Phe Asp Arg Thr Ser
8645 8650 8655 8660
TGT CTA GAT ATC AAT GAA TGT GAA CAA TTT GGG ACT TGT CCC CAG CAC 12164
Cys Leu Asp Ile Asn Glu Cys Glu Gln Phe Gly Thr Cys Pro Gln His
8665 8670 8675
TGC AGA AAT ACC AAA GGA AGT TAT GAG TGT GTC TGT G"T GAT GGC TTC 12212
Cys Arg Asn Thr Lys Gly Ser Tyr Glu Cys Val Cys Ala Asp Gly Phe
8680 8685 8690
CA 0220~648 l997-0~-20
W O 96/15801 PCT~US95/15203
ACG TCT ATG AGT GAC CGC CCT GGA AAA CGA TGT GCA GCT GAG GGT AGC 12260
Thr Ser Met Ser Asp Arg Pro Gly Lys Arg Cys Ala Ala Glu Gly Ser
86g5 8700 8705
TCT CCT TTG TTG CTA CTG CCT GAC AAT GTC CGA ATT CGA AAA TAT AAT 12308
Ser Pro Leu Leu Leu Leu Pro Asp Asn Val Arg Ile Arg Lys Tyr Asn
8710 8715 8720
0 CTC TCA TCT GAG AGG TTC TCA GAG TAT CTT CAA GAT GAG GAA TAT ATC 12356
Leu Ser Ser Glu Arg Phe Ser Glu Tyr Leu Gln Asp Glu Glu Tyr Ile
8725 8730 8735 8740
CAA GCT GTT GAT TAT GAT TGG GAT CCC GAG GAC ATA GGC CTC AGT GTT 12404
Gln Ala Val Asp Tyr Asp Trp Asp Pro Glu Asp Ile Gly Leu Ser Val
8745 8750 8755
GTG TAT TAC ACT GTG CGA GGG GAG GGC TCT AGG TTT GGT GCT ATC AAA 12452
Val Tyr Tyr Thr Val Arg Gly Glu Gly Ser Arg Phe Gly Ala Ile Lys
8760 8765 8770
CGT GCC TAC ATC CCC AAC TTT GAA TCC GGC CGC AAT AAT CTT GTG CAG 12500
Arg Ala Tyr Ile Pro Asn Phe Glu Ser Gly Arg Asn Asn Leu Val Gln
8775 8780 8785
GAA GTT GAC CTG AAA CTG AAA TAC GTA ATG CAG CCA GAT GGA ATA GCA 12548
Glu Val Asp Leu Lys Leu Lys Tyr Val Met Gln Pro Asp Gly Ile Ala
8790 8795 8800
G~G GAC TGG GTT GGA AGG CAT ATT TAC TGG TCA GAT GTC AAG AAT AAA 12596
Val Asp Trp Val Gly Arg His Ile Tyr Trp Ser Asp Val Lys Asn Lys
8805 8810 8815 8820
CGC ATT GAG GTG GCT AAA CTT GAT GGA AGG TAC AGA AAG TGG CTG ATT 12644
Arg Ile Glu Val Ala Lys Leu Asp Gly Arg Tyr Arg Lys Trp Leu Ile
8825 8830 8835
TCC ACT GAC CTG GAC CAA CCA GCT GCT ATT GCT GTG AAT CCC AAA CTA 12692
Ser Thr Asp Leu Asp Gln Pro Ala Ala Ile Ala Val Asn Pro Lys Leu
8840 8845 8850
GGG CTT ATG TTC TGG ACT GAC TGG GGA AAG GAA CCT AAA MTC GAG TCT 12740
Gly Leu Met Phe Trp Thr Asp Trp Gly Lys Glu Pro Lys Xaa Glu Ser
8855 8860 8865
GCC TGG ATG AAT GGA GAG GAC CGC AAC ATC CTG GTT TTC GAG GAC CTT 12788
Ala Trp Met Asn Gly Glu Asp Arg Asn Ile Leu Val Phe Glu Asp Leu
8870 8875 8880
GGT TGG CCA ACT GGC CTT TCT ATC GAT TAT TTG AAC AAT GAC CGA ATC 12836
Gly Trp Pro Thr Gly Leu Ser Ile Asp Tyr Leu Asn Asn Asp Arg Ile
8885 . 8890 8895 8900
TAC TGG AGT GAC TTC AAG GAG GAC GTT ATT GAA ACC ATA AAA TAT GAT 12884
Tyr Trp Ser Asp Phe Lys Glu Asp Val Ile Glu Thr Ile Lys Tyr Asp
8905 8910 8915
GGG ACT GAT AGG AGA GTC ATT GCA AAG GAA GCA ATG AAC CCT TAC AGC 12932
Gly Thr Asp Arg Arg Val Ile Ala Lys Glu Ala Met Asn Pro Tyr Ser
8920 8925 8930
CTG GAC ATC TTT GAA GAC CAG TTA TAC TGG ATA TCT AAG GAA AAG GGA 12980
Leu Asp Ile Phe Glu Asp Gln Leu Tyr Trp Ile Ser Lys Glu Lys Gly
8935 8940 8945
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
/~
GAA GTA TGG AAA CAA AAT AAA TTT GGG CAA GGA AAG AAA GAG AAA ACG 13028
Glu Val Trp I.ys Gln Asn IJYS Phe Gly Gln Gly Lys Lys Glu Lys Thr
8950 8955 8960
CTG GTA GTG AAC CCT TGG CTC ACT CAA GTT CGA ATC TTT CAT CAA CTC 13076
Leu Val Val Asn Pro Trp Leu Thr Gln Val Arg Ile Phe His Gln Leu
8965 8970 8975 8980
0 AGA TAC AAT AAG TCA GTG CCC AAC CTT TGC AAA CAG ATC TGC AGC CAC 13124
. Arg Tyr Asn Lys Ser Val Pro Asn Leu Cys Lys Gln Ile Cys Ser His
8985 8990 8995
CTC TGC CTT CTG AGA CCT GGA GGA TAC AGC TGT GCC TGT CCC CAA GGC 13172
Leu Cys Leu Leu Arg Pro Gly Gly Tyr Ser Cys Ala Cys Pro Gln Gly
9000 9005 9010
TCC AGC TTT ATA GAG GGG AGC ACC ACT GAG TGT GAT GCA GCC ATC GAA 13220
Ser Ser Phe Ile Glu Gly Ser Thr Thr Glu Cys Asp Ala Ala Ile Glu
9015 9020 9025
CTG CCT ATC AAC CTG CCC CCC CCA TGC AGG TGC ATG CAC GGA GGA AAT 13268
~eu Pro Ile Asn Leu Pro Pro Pro Cys Arg Cys Met His Gly Gly Asn
9030 9035 9040
TGC TAT TTT GAT GAG ACT GAC CTC CCC AAA TGC AAG TGT CCT AGC GGC 13316
Cys Tyr Phe Asp Glu Thr Asp ~eu Pro Lys Cys Lys Cys Pro Ser Gly
9045 9050 9055 9060
TAC ACC GGA AAA TAT TGT GAA ATG GCG TTT TCA AAA GGC ATC TCT CCA 1336a~
Tyr Thr Gly Lys Tyr Cys Glu Met Ala Phe Ser Lys Gly Ile Ser Pro
9065 9070 9075
GGA ACA ACC GCA GTA GCT GTG CTG TTG ACA ATC CTC TTG ATC GTC GTA 13412
3 5 Gly Thr Thr Ala Val Ala Val l~eu Leu Thr Ile Leu Leu Ile Val Val
9080 9085 9090
ATT GGA GCT CTG GCA ATT GCA GGA TTC TTC CAC TAT AGA AGG ACC GGC 13460
Ile Gly Ala ~eu Ala Ile Ala Gly Phe Phe His Tyr Arg Arg Thr Gly
9095 9100 9105
TCC CTT TTG CCT GCT CTG CCC AAG CTG CCA AGC TTA AGC AGT CTC &TC 13508
Ser Leu Leu Pro Ala Leu Pro Lys Leu Pro Ser Leu Ser Ser Leu Val
9110 9115 9120
AAG CCC TCT GAA AAT GGG AAT GGG GTG ACC TTC AGA TCA GGG GCA GAT 13556
Lys Pro Ser Glu Asn Gly Asn Gly Val Thr Phe Arg Ser Gly Ala Asp
9125 9130 9135 9140
5.0 CTT AAC ATG GAT ATT GGA GTG TCT GGT TTT GGA CCT GAG ACT GCT ATT 13604
Leu Asn Met Asp Ile Gly Val Ser Gly Phe Gly Pro Glu Thr Ala Ile
9145 9150 9155
GAC AGG TCA ATG GCA ATG AGT GAA GAC TTT GTC ATG GAA ATG GGG AAG 1365
Asp Arg Ser Met Ala Met Ser Glu Asp Phe Val Met Glu Met Gly Lys
9160 9165 9170
CAG CCC ATA ATA TTT GAA AAC CCA ATG TAC TCA GCC AGA GAC AGT GCT 13700
Gln Pro Ile Ile Phe Glu Asn Pro Met Tyr Ser Ala Arg Asp Ser Ala
9175 9180 9185
GTC AAA GTG GTT CAG CCA ATC CAG GTG ACT GTA TCT GAA AAT GTG GAT 13748
Val Lys Val Val Gln Pro Ile Gln Val Th- Val Ser Glu Asn Val Asp
9190 9195 920~
CA 0220~648 l997-0~-20
W O96/15801 PCTrUS95/lS203
/~l
AAT AAG AAT TAT GGA AGT CCC ATA AAC CCT TCT GAG ATA GTT CCA GAG 13796
Asn Lys Asn Tyr Gly Ser Pro Ile Asn Pro Ser Glu Ile Val Pro Glu
s 9205 9210 9215 9220
ACA AAC CCA ACT TCA CCA GCT GCT GAT GGA ACT CAG GTG ACA AAA TGG 13844
Thr Asn Pro Thr Ser Pro Ala Ala Asp Gly Thr Gln Val Thr Lys Trp
9225 9230 9235
10 AAT CTC TTC AAA CGA AAA TCT AAA CAA ACT ACC AAC TTT GAA AAT CCA 13892
Asn Leu Phe Lys Arg Lys Ser Lys Gln Thr Thr Asn Phe Glu Asn Pro
9240 9245 9250
ATC TAT GCA CAG ATG GAG AAC GAG CAA AAG GAA AGT GTT GCT GCG ACA 13940
Ile Tyr Ala Gln Met Glu Asn Glu Gln Lys Glu Ser Val AIa Ala Thr
9255 9260 9Z65
CCA CCT CCA TCA CCT TCG CTC CCT GCT AAG CCT AAG CCT CCT TCG AGA 13988
Pro Pro Pro Ser Pro Ser Leu Pro Ala Lys Pro Lys Pro Pro Ser Arg
9270 9275 9280
AGA GAC CCA ACT CCA ACC TAT TCT GCA ACA GAA GAC ACT TTT AAA GAC 14036
Arg Asp Pro Thr Pro Thr Tyr Ser Ala Thr Glu Asp Thr Phe Lys Asp
9285 9290 9295 9300
ACC GCA AAT CTT GTT AAA GAA GAC TCT GAA GTA TAG CTATACCA 14080
Thr Ala Asn Leu Val Lys Glu Asp Ser Glu Val *
9305 9310
(2) INFORMATION FOR SEQ ID NO:88:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 4656 amino acids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:88:
Met Asp Arg Gly Pro Ala Ala Val Ala Cys Thr Leu Leu Leu Ala Leu
1 5 10 15
Val Ala Cys Leu Ala Pro Ala Ser Gly Gln Glu Cys Asp Ser Ala His
20 25 30
Phe Arg Cys Gly Ser Gly His Cys Ile Pro Ala Asp Trp Arg Cys Asp
35 40 45
Gly Thr Lys Asp Cys Ser Asp Asp Ala Asp Glu Ile Gly Cys Ala Val
50 55 60
Val Thr Cys Gln Gln Gly Tyr Phe Lys Cys Gln Ser Glu Gly Gln Cys
65 7p 75 80
Ile Pro Ser Ser Trp Val Cys Asp Gln Asp Gln Asp Cys Asp Asp Gly
Ser Asp Glu Arg Gln Asp Cys Ser Gln Ser Thr Cys Ser Ser His Gln
100 105 110
Ile Thr Cys Ser Asn Gly Gln Cys Ile Pro Ser Glu Tyr Arg Cys Asp
115 120 125
CA 0220~648 l997-0~-20
WO 96115801 - PCTIUS95115203
His Val Arg Asp Cys Pro Asp Gly Ala Asp Glu Asn Asp Cys Gln Tyr
130 135 140
Pro Thr Cys Glu Gln Leu Thr Cys Asp Asn Gly Ala Cys Tyr Asn Thr t
145 150 155 160
Ser Gln Lys Cys Asp Trp Lys Val Asp Cys Arg Asp Ser Ser Asp Glu
165 170 175
Ile Asn Cys Thr Glu Ile Cys Leu His Asn Glu Phe Ser Cys Gly Asn
180 185 190
Gly Glu Cys Ile Pro Arg Ala Tyr Val Cys Asp His Asp Asn Asp Cys
195 200 205
Gln Asp Gly Ser Asp Glu His Ala Cys Asn Tyr Pro Thr Cys Gly Gly
210 215 220
Tyr Gln Phe Thr Cys Pro Ser Gly Arg Cys Ile Tyr Gln Asn Trp Val
225 230 235 240
Cys Asp Gly Glu Asp Asp Cys Lys Asp Asn Gly Asp Glu Asp Gly Cys
245 250 255
Glu Ser Gly Pro His Asp Val His Lys Cys Ser Pro Arg Glu Trp Ser
260 265 270
Cys Pro Glu Ser Gly Arg Cys Ile Ser Ile Tyr Lys Val Cys Asp Gly
275 280 285
Ile Leu Asp Cys Pro Gly Arg Glu Asp Glu Asn Asn Thr Ser Thr Gly
290 295 300
3 5 Lys Tyr Cys Ser Met Thr Leu Cys Ser Ala Leu Asn Cys Gln Tyr Gln
305 310 315 320
Cys His Glu Thr Pro Tyr Gly Gly Ala Cys Phe Cys Pro Pro Gly Tyr
325 330 335
Ile Ile Asn His Asn Asp Ser Arg Thr Cys Val Glu Phe Asp Asp Cys
340 345 350
Gln Ile Trp Gly Ile Cys Asp Gln Lys Cys Glu Ser Arg Pro Gly Arg
355 360 365
His Leu Cys His Cys Glu Glu Gly Tyr Ile Leu Glu Arg Gly Gln Tyr
370 375 380
Cys Lys Ala Asn Asp Ser Phe Gly Glu Ala Ser Ile Ile Phe Ser Asn
385 390 395 400
Gly Arg Asp Leu Leu Ile Gly Asp Ile His Gly Arg Ser Phe Arg Ile
405 410 415
Leu Val Glu Ser Gln Asn Arg Gly Val Ala Val Gly Val Ala Phe His
420 425 430
Tyr His Leu Gln Arg Val Phe Trp Thr Asp Thr Val Gln Asn Lys Val
435 440 445
Phe Ser Val Asp Ile Asn Gly Leu Asn Ile Gln Glu Val Leu Asn Val
450 455 - 460
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US9S/15203
/.~;3
Ser Val Glu Thr Pro Glu Asn Leu Ala Val Asp Trp Val Asn Asn Lys
465 470 475 480
Ile Tyr Leu Val Glu Thr Lys Val Asn Arg Ile Asp Met Val Asn Leu
485 490 495
Asp Gly Ser Tyr Arg Val Thr Leu Ile Thr Glu Asn Leu Gly His Pro
500 505 510
0 Arg Gly Ile Ala Val Asp Pro Thr Val Gly Tyr Leu Phe Phe Ser Asp
515 520 525
Trp Glu Ser Leu Ser Gly Glu Pro Lys Leu Glu Arg Ala Phe Met Asp
530 535 540
Gly Ser Asn Arg Lys Asp Leu Val Lys Thr Lys Leu Gly Trp Pro Ala
545 550 555 560
Gly Val Thr Leu Asp Met Ile Ser Lys Arg Val Tyr Trp Val Asp Ser
565 570 575
Arg Phe Asp Tyr Ile Glu Thr Val Thr Tyr Asp Gly Ile Gln Arg Lys
580 585 590
Thr Val Val His Gly Gly Ser Leu Ile Pro His Pro Phe Gly Val Ser
595 600 605
Leu Phe Glu Gly Gln Val Phe Phe Thr Asp Trp Thr Lys Met Ala Val
610 615 620
Leu Lys Ala Asn Lys Phe Thr Glu Thr Asn Pro Gln Val Tyr Tyr Gln
625 630 635 640
Ala Ser Leu Arg Pro Tyr Gly Val Thr Val Tyr His Ser Leu Arg Gln
645 650 655
Pro Tyr Ala Thr Asn Pro Cys Lys Asp Asn Asn Gly Gly Cys Glu Gln
660 665 670
Val Cys Val Leu Ser His Arg Thr Asp Asn Asp Gly Leu Gly Phe Arg
675 680 685
Cys Lys Cys Thr Phe Gly Phe Gln Leu Asp Thr Asp Glu Arg His Cys
690 695 700
Ile Ala Val Gln Asn Phe Leu Ile Phe Ser Ser Gln Val Ala Ile Arg
705 710 715 720
Gly Ile Pro Phe Thr Leu Ser Thr Gln Glu Asp Val Met Val Pro Val
725 730 735
Ser Gly Asn Pro Ser Phe Phe Val Gly Ile Asp Phe Asp Ala Gln Asp
740 745 750
5 Ser Thr Ile Phe Phe Ser Asp Met Ser Lys His Met Ile Phe Lys Gln
755 760 765
Lys Ile Asp Gly Thr Gly Arg Glu Ile Leu Ala Ala Asn Arg Val Glu
770 775 780
Asn Val Glu Ser Leu Ala Phe Asp Trp Ile Ser Lys Asn Leu Tyr Trp
785 790 795 800
Thr Asp Ser His Tyr Lys Ser Ile Ser Val Met Arg Leu Ala Asp Lys
CA 0220S648 1997-0~-20
W O96/15801 PCTrUS95/15203
/~y
805 810 815
Thr Arg Ar3 Thr Val Val Gln Tyr Leu Asn Asn Pro Arg Ser Val Val
820 825 830
Val His Pro Phe Ala Gly Tyr Leu Phe Phe Thr Asp Trp Phe Arg Pro
835 840 845
Ala Lys Ile Met Arg Ala Trp Ser Asp Gly Ser His Leu Leu Pro Val
0 850 855 860
Ile Asn Thr Thr Leu Gly Trp Pro Asn Gly Leu Ala Ile Asp Trp Ala
865 870 875 880
Ala Ser Arg Leu Tyr Trp Val Asp Ala Tyr Phe Asp Lys Ile Glu His
885 890 895
Ser Thr Phe Asp Gly Leu Asp Arg Arg Arg Leu Gly His Ile Glu Gln
900 905 910
Met Thr His Pro Phe Gly Leu Ala Ile Phe Gly Glu His Leu Phe Phe
915 920 925
Thr Asp Trp Arg Leu Gly Ala Ile Ile Arg Val Arg Lys Ala Asp Gly
930 935 940
Gly Glu Met Thr Val Ile Arg Ser Gly Ile Ala Tyr Ile Leu His Leu
945 950 955 960
Lys Ser Tyr Asp Val Asn Ile Gln Thr Gly Ser Asn Ala Cys Asn Gln
965 970 975
Pro Thr His Pro Asn Gly Asp Cys Ser His Phe Cys Phe Pro Val Pro
980 985 990
Asn Phe Gln Arg Val Cys Gly Cys Pro Tyr Gly Met Arg Leu Ala Ser
995 1000 1005
Asn His Leu Thr Cys Glu Gly Asp Pro Thr Asn Glu Pro Pro Thr Glu
1010 1015 1020
Gln Cys Gly Leu Phe Ser Phe Pro Cys Lys Asn Gly Arg Cys Val Pro
1025 1030 1035 1040
Asn Tyr Tyr Leu Cys Asp Gly Val Asp Asp Cys His Asp Asn Ser Asp
1045 1050 1055
Glu Gln Leu Cys Gly Thr Leu Asn Asn Thr Cys Ser Ser Ser Ala Phe
1060 1065 1070
Thr Cys Gly His Gly Glu Cys Ile Pro Ala His Trp Arg Cys Asp Lys
1075 1080 1085
Arg Asn Asp Cys Val Asp Gly Ser Asp Glu His Asn Cys Pro Thr His
1090 . 1095 1100
Ala Pro Ala Ser Cys IJeu Asp Thr Gln Tyr Thr Cys Asp Asn His Gln
1105 1110 1115 1120
60 Cys Ile Ser Lys Asn Trp Val Cys Asp Thr Asp Asn Asp Cys Gly Asp
1125 1130 11~5
Gly Ser Asp Glu Lys Asn Cys Asn Ser Thr Glu Thr Cys Gln Pro Ser
1140 1145 1150
CA 0220~648 l997-0~-20
WO 96/15801 PCTIUS95/15203
~6S
Gln Phe Asn Cys Pro Asn His Arg Cys Ile Asp Leu Ser Phe Val Cys
1155 1160 1165
Asp Gly Asp Lys Asp Cys Val Asp Gly Ser Asp Glu Val Gly Cys Val
1170 1175 1180
Leu Asn Cys Thr Ala Ser Gln Phe Lys Cys Ala Ser Gly Asp Lys Cys
1185 1190 1195 1200
Ile Gly Val Thr Asn Arg Cys Asp Gly Val Phe Asp Cys Ser Asp Asn
1205 1210 1215
Ser Asp Glu Ala Gly Cys Pro Thr Arg Pro Pro Gly Met Cys His Ser
1220 1225 1230
Asp Glu Phe Gln Cys Gln Glu Asp Gly Ile Cys Ile Pro Asn Phe Trp
1235 1240 1245
2 0 Glu Cys Asp Gly His Pro Asp Cys Leu Tyr Gly Ser Asp Glu His Asn
1250 1255 1260
Ala Cys Val Pro Lys Thr Cys Pro Ser Ser Tyr Phe His Cys Asp Asn
1265 1270 1275 1280
Gly Asn Cys Ile His Arg Ala Trp Leu Cys Asp Arg Asp Asn Asp Cys
1285 1290 1295
Gly Asp Met Ser Asp Glu Lys Asp Cys Pro Thr Gln Pro Phe Arg Cys
1300 1305 1310
Pro Ser Trp Gln Trp Gln Cys Leu Gly His Asn Ile Cys Val Asn Leu
1315 1320 1325
3 5 Ser Val Val Cys Asp Gly Ile Phe Asp Cys Pro Asn Gly Thr Asp Glu
1330 1335 1340
Ser Pro Leu Cys Asn Gly Asn Ser Cys Ser Asp Phe Asn Gly Gly Cys
1345 1350 1355 1360
Thr His Glu Cys Val Gln Glu Pro Phe Gly Ala Lys Cys Leu Cys Pro
1365 1370 1375
Leu Gly Phe Leu Leu Ala Asn Asp Ser Lys Thr Cys Glu Asp Ile Asp
1380 1385 1390
Glu Cys Asp Ile Leu Gly Ser Cys Ser Gln His Cys Tyr Asn Met Arg
1395 1400 1405
Gly Ser Phe Arg Cys Ser Cys Asp Thr Gly Tyr Met Leu Glu Ser Asp
1410 1415 1420
Gly Arg Thr Cys Lys Val Thr Ala Ser Glu Ser Leu Leu Leu Leu Val
1425 1430 1435 1440
- 55
Ala Ser Gln Asn Lys Ile Ile Ala Asp Ser Val Thr Ser Gln Val His
1445 1450 1455
Asn Ile Tyr Ser Leu Val Glu Asn Gly Ser Tyr Ile Val Ala Val Asp
1460 1465 1470
Phe Asp Ser Ile Ser Gly Arg Ile Phe Trp Ser Asp Ala Thr Gln Gly
1475 1480 1485
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
t66
Lys Thr Trp Ser Ala Phe Gln Asn Gly Thr Asp Arg Arg Val Val Phe
1490 1495 1500
Asp Ser Ser Ile Ile Leu Thr Glu Thr Ile Ala Ile Asp Trp Val Gly
1505 1510 1515 1520
Arg Asn Leu Tyr Trp Thr Asp Tyr Ala Leu Glu Thr Ile Glu Val Ser
lS25 1530 1535
0 Lys Ile Asp Gly Ser His Arg Thr Val Leu Ile Ser Lys Asn Leu Thr
1540 1545 1550
Asn Pro Arg Gly Leu Ala Leu Asp Pro Arg Met Asn Glu His Leu Leu
1555 1560 1565
Phe Trp Ser Asp Trp Gly His His Pro Arg Ile Glu Arg Ala Ser Met
1570 1575 1580
Asp Gly Ser Met Arg Thr Val Ile Val Gln Asp Lys Ile Phe Trp Pro
1585 1590 1595 1600
Cys Gly Leu Thr Ile Asp Tyr Pro Asn Arg Leu Leu Tyr Phe Met Asp
1605 1610 1615
Ser Tyr Leu Asp Tyr Met Asp Phe Cys Asp Tyr Asn Gly His His Arg
1620 1625 1630
Arg Gln Val Ile Ala Ser Asp Leu Ile Ile Arg His Pro Tyr Ala Leu
1635 1640 1645
Thr Leu Phe Glu Asp Ser Val Tyr Trp Thr Asp Arg Ala Thr Arg Arg
1650 1655 1660
Val Met Arg Ala Asn Lys Trp His Gly Gly Asn Gln Ser Val Val Met
1665 1670 1675 1680
Tyr Asn Ile Gln Trp Pro Leu Gly Ile Val Ala Val His Pro Ser Lys
1685 1690 1695
Gln Pro Asn Ser Val Asn Pro Cys Ala Phe Ser Arg Cys Ser His Leu
1700 1705 1710
Cys Leu Leu Ser Ser Gln Gly Pro His Phe Tyr Ser Cys Val Cys Pro
1715 1720 1725
Ser Gly Trp Ser Leu Ser Pro Asp Leu Leu Asn Cys Leu Arg Asp Asp
1730 1735 1740
Gln Pro Phe Leu Ile Thr Val Arg Gln His Ile Ile Phe Gly Ile Ser
1745 1750 1755 1760
Leu Asn Pro Glu Val Lys Ser Asn Asp Ala Met Val Pro Ile Ala Gly
1765 1770 1775
5 Ile Gln Asn Gly Leu Asp Val Glu Phe Asp Asp Ala Glu Gln Tyr Ile
1780 1785 1790
Tyr Trp Val Glu Asn Pro Gly Glu Ile His Arg Val Lys Thr Asp Gly
1795 1800 1805
Thr Asn Arg Thr Val Phe Ala Ser Ile Ser Met Val Gly Pro Ser Met
1810 1815 1820
Asn Leu Ala Leu Asp Trp I le Ser Arg Asn Leu Tyr Ser Thr Asn Pro
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
/6 7
1825 1830 1835 1840
Arg Thr Gln Ser Ile Glu Val Leu Thr Leu His Gly Asp Ile Arg Tyr
1845 1850 1855
Arg Lys Thr Leu Ile Ala Asn Asp Gly Thr Ala Leu Gly Val Gly Phe
1860 1865 1870
Pro Ile Gly Ile Thr Val Asp Pro Ala Arg Gly Lys Leu Tyr Trp Ser
0 1875 1880 1885
Asp Gln Gly Thr Asp Ser Gly Val Pro Ala Lys Ile Ala Ser Ala Asn
1890 1895 l900
Met Asp Gly Thr Ser Val Lys Thr Leu Phe Thr Gly Asn Leu Glu His
1905 1910 1915 1920
Leu Glu Cys Val Thr Leu Asp Ile Glu Glu Gln Lys Leu Tyr Trp Ala
1925 1930 1935
Val Thr Gly Arg Gly Val Ile Glu Arg Gly Asn Val Asp Gly Thr Asp
1940 1945 1950
Arg Met Ile Leu Val His Gln Leu Ser His Pro Trp Gly Ile Ala Val
1955 1960 1965
His Asp Ser Phe Leu Tyr Tyr Thr Asp Glu Gln Tyr Glu Val Ile Glu
1970 1975 1980
Arg Val Asp Lys Ala Thr Gly Ala Asn Lys Ile Val Leu Arg Asp Asn
1985 1990 1995 2000
Val Pro Asn Leu Arg Gly Leu Gln Val Tyr His Arg Arg Asn Ala Ala
2005 2010 2015
Glu Ser Ser Asn Gly Cys Ser Asn Asn Met Asn Ala Cys Gln Gln Ile
2020 2025 2030
Cys Leu Pro Val Pro Gly Gly Leu Phe Ser Cys Ala Cys Ala Thr Gly
2035 2040 2045
Phe Lys Leu Asn Pro Asp Asn Arg Ser Cys Ser Pro Tyr Asn Ser Phe
2050 2055 2060
Ile Val Val Ser Met Leu Ser Ala Ile Arg Gly Phe Ser Leu Glu Leu
2065 2070 2075 2080
Ser Asp His Ser Glu Thr Met Val Pro Val Ala Gly Gln Gly Arg Asn
2085 2090 2095
5Q
Ala Leu His Val Asp Val Asp Val Ser Ser Gly Phe Ile Tyr Trp Cys
2100 2105 2110
Asp Phe Ser Ser Ser Val Ala Ser Asp Asn Ala Ile Arg Arg Ile Lys
2115 2120 2125
Pro Asp Gly Ser Ser Leu Met Asn Ile Val Thr His Gly Ile Gly Glu
2130 2135 2140
60 Asn Gly Val Arg Gly Ile Ala Val Asp Trp Val Ala Gly Asn Leu Tyr
2145 2150 2155 2160
Phe Thr Asn Ala Phe Val Ser Glu Thr Leu Ile Glu Val Leu Arg Ile
2165 2170 2175
CA 0220~648 l997-0~-20
W O96/15801 PCTrUS95/15203
l6 8
Asn Thr Thr Tyr Arg Arg Val Leu Leu Lys Val Thr Val Asp Met Pro
2180 2185 2190
Arg His Ile Val Val Asp Pro Lys Asn Arg Tyr Leu Phe Trp Ala Asp
2195 2200 2205
Tyr Gly Gln Arg Pro Lys Ile Glu Arg Ser Phe Leu Asp Cys Thr Asn
2210 2215 2220
Arg Thr Val Leu Val Ser Glu Gly Ile Val Thr Pro Arg Gly Leu Ala 2225 2230 2235 2240
Val Asp Arg Ser Asp Gly Tyr Val Tyr Trp Val Asp Asp Ser Leu Asp
2245 2250 2255
Ile Ile Ala Arg Ile Arg Ile Asn Gly Glu Asn Ser Glu Val Ile Arg
2260 2265 2270
Tyr Gly Ser Arg Tyr Pro Thr Pro Tyr Gly Ile Thr Val Phe Glu Asn
2275 2280 2285
Ser Ile Ile Trp Val Asp Arg Asn Leu Lys Lys Ile Phe Gln Ala Ser
2290 2295 2300
Lys Glu Pro Glu Asn Thr Glu Pro Pro Thr Val Ile Arg Asp Asn Ile
2305 2310 2315 2320
Asn Trp Leu Arg Asp Val Thr Ile Phe Asp Lys Gln Val Gln Pro Arg
2325 2330 2335
Ser Pro Ala Glu Val Asn Asn Asn Pro Cys Leu Glu Asn Asn Gly Gly
2340 2345 2350
Cys Ser His Leu Cys Phe Ala Leu Pro Gly Leu His Thr Pro Lys Cys
2355 2360 2365
Asp Cys Ala Phe Gly Thr Leu Gln Ser Asp Gly Lys Asn Cys Ala Ile
2370 2375 2380
Ser Thr Glu Asn Phe Leu Ile Phe Ala Leu Ser Asn Ser Leu Arg Ser
2385 2390 2395 2400
Leu His Leu Asp Pro Glu Asn His Ser Pro Pro Phe Gln Thr Ile Asn
2405 2410 2415
Val Glu Arg Thr Val Met Ser Leu Asp Tyr Asp Ser Val Ser Asp Arg
2420 2425 2430
Ile Tyr Phe Thr Gln Asn Leu Ala Ser Gly Val Gly Gln Ile Ser Tyr
2435 2440 2445
Ala Thr Leu Ser Ser Gly Ile His Thr Pro Thr Val Ile Ala Ser Gly
2450 2455 2460
Ile Gly Thr Ala Asp Gly Ile Ala Phe Asp Trp Ile Thr Arg Arg Ile
2465 2470 2475 2480
Tyr Tyr Ser Asp Tyr ~eu Asn Gln Met Ile Asn Ser Met Ala Glu Asp
2485 2490 2495
Gly Ser Asn Arg Thr Val Ile Ala Arg Val Pro Lys Pro Arg Ala Ile
2500 2505 2510
CA 0220~648 l997-0~-20
WO 96/15801 PCTIUS95/15203
/6~
Val Leu Asp Pro Cys Gln Gly Tyr Leu Tyr Trp Ala Asp Trp Asp Thr
2515 2520 2525
His Ala Lys Ile Glu Arg Ala Thr Leu Gly Gly Asn Phe Arg Val Pro
2530 2535 2540
Ile Val Asn Ser Ser Leu Val Met Pro Ser Gly Leu Thr Leu Asp Tyr
2545 2550 2555 2560
10 Glu Glu Asp Leu Leu Tyr Trp Val Asp Ala Ser Leu Gln Arg Ile Glu
2565 2570 2575
Arg Ser Thr Leu Thr Gly Val Asp Arg Glu Val Ile Val Asn Ala Ala
2580 2585 2590
Val His Ala Phe Gly Leu Thr Leu Tyr Gly Gln Tyr Ile Tyr Trp Thr
2595 2600 2605
Asp Leu Tyr Thr Gln Arg Ile Tyr Arg Ala Asn Lys Tyr Asp Gly Ser
2610 2615 2620
Gly Gln Ile Ala Met Thr Thr Asn Leu Leu Ser Gln Pro Arg Gly Ile
2625 2630 2635 2640
2 5 Asn Thr Val Val Lys Asn Gln Lys Gln Gln Cys Asn Asn Pro Cys Glu
2645 2650 2655
Gln Phe Asn Gly Gly Cys Ser His Ile Cys Ala Pro Gly Pro Asn Gly
2660 2665 2670
Ala Glu Cys Gln Cys Pro His Glu Gly Asn Trp Tyr Leu Ala Asn Asn
2675 2680 2685
Arg Lys His Cys Ile Val Asp Asn Gly Glu Arg Cys Gly Ala Ser Ser
2690 2695 2700
Phe Thr Cys Ser Asn Gly Arg Cys Ile Ser Glu Glu Trp Lys Cys Asp
2705 2710 2715 2720
Asn Asp Asn Asp Cys Gly Asp Gly Ser Asp Glu Met Glu Ser Val Cys
2725 2730 2735
Ala Leu His Thr Cys Ser Pro Thr Ala Phe Thr Cys Ala Asn Gly Arg
2740 2745 2750
Cys Val Gln Tyr Ser Tyr Arg Cys Asp Tyr Tyr Asn Asp Cys Gly Asp
2755 2760 2765
Gly Ser Asp Glu Ala Gly Cys Leu Phe Arg Asp Cys Asn Ala Thr Thr
2770 2775 2780
Glu Phe Met Cys Asn Asn Arg Arg Cys Ile Pro Arg Glu Phe Ile Cys
2785 2790 2795 2800
55 Asn Gly Val Asp Asn Cys His Asp Asn Asn Thr Ser Asp Glu Lys Asn
2805 2810 2815
Cys Pro Asp Arg Thr Cys Gln Ser Gly Tyr Thr Lys Cys His Asn Ser
2820 2825 2830
Asn Ile Cys Ile Pro Arg Val Tyr Leu Cys Asp Gly Asp Asn Asp Cys
2835 2840 2845
Gly Asp Asn Ser Asp Glu Asn Pro Thr Tyr Cys Thr Thr His Thr Cys
CA 0220S648 1997-OS-20
W O96/15801 PCT~US95/15203
~a
2850 2855 2860
Ser Ser Ser Glu Phe Gln Cys Ala Ser Gly Arg Cys Ile Pro Gln His
2865 2870 2875 2880
Trp Tyr Cys Asp Gln Glu Thr Asp Cys Phe Asp Ala Ser Asp Glu Pro
2885 2890 2895
Ala Ser Cys Gly His Ser Glu Arg Thr Cys Leu Ala Asp Glu Phe Lys
0 2900 2905 2910
Cys Asp Gly Gly Arg Cys Ile Pro Ser Glu Trp Ile Cys Asp Gly Asp
2915 2920 2925
Asn Asp Cys Gly Asp Met Ser Asp Glu Asp Lys Arg His Gln Cys Gln
2930 2935 2940
Asn Gln Asn Cys Ser Asp Ser Glu Phe Leu Cys Val Asn Asp Arg Pro
2945 2950 2955 2960
Pro Asp Arg Arg Cys Ile Pro Gln Ser Trp Val Cys Asp Gly Asp Val
2965 2970 2975
Asp Cys Thr Asp Gly Tyr Asp Glu Asn Gln Asn Cys Thr Arg Arg Thr
2g80 2985 2990
Cys Ser Glu Asn Glu Phe Thr Cys Gly Tyr Gly Leu Cys Ile Pro Lys
2995 3D00 3005
3 0 Ile Phe Arg Cys Asp Arg His Asn Asp Cys Gly Asp Tyr Ser Asp Glu
3010 3015 3020
Arg Gly Cys Leu Tyr Gln Thr Cys Gln Gln Asn Gln Phe Thr Cys Gln
3025 3030 3035 3040
Asn Gly Arg Cys Ile Ser Lys Thr Phe Val Cys Asp Glu Asp Asn Asp
3045 3050 3055
Cys Gly Asp Gly Ser Asp Glu Leu Met His Leu Cys His Thr Pro Glu
3060 3065 3070
Pro Thr Cys Pro Pro His Glu Phe Lys Cys Asp Asn Gly Arg Cys Ile
3075 3080 3085
Glu Met Met Lys Leu Cys Asn His Leu Asp Asp Cys Leu Asp Asn Ser
3090 3095 3100
Asp Glu Lys Gly Cys Gly Ile Asn Glu Cys His Asp Pro Ser Ile Ser
3105 3110 3115 312D
Gly Cys Asp His Asn Cys Thr Asp Thr Leu Thr Ser Phe Tyr Cys Ser
3125 3130 3135
Cys Arg Pro Gly Tyr Lys Leu Met Ser Asp Lys Arg Thr Cys Val Asp
3140 3145 3150
Ile Asp Glu Cys Thr Glu Met Pro Phe Val Cys Ser Gln Lys Cys Glu
3155 3160 3165
60 Asn Val Ile Gly Ser Tyr I le Cys Lys Cys Ala Pro Gly Tyr Leu Arg
3170 3175 3180
Glu Pro Asp Gly Lys Thr Cys Arg Gln Asn Ser Asn Ile Glu Pro Tyr
3185 3190 3195 3200
CA 0220~648 l997-0~-20
WO 9611~;801 PCTlUS95tl5203
/7~
Leu Ile Phe Ser Asn Arg Tyr Tyr Leu Arg Asn Leu Thr Ile Asp Gly
3205 3210 3215
5 Tyr Phe Tyr Ser Leu Ile Leu Glu Gly Leu Asp Asn Val Val Ala Leu
3220 3225 3230
Asp Phe Asp Arg Val Glu Lys Arg Leu Tyr Trp Ile Asp Thr Gln Arg
3235 3240 3245
' ,
Gln V~1 Ile Glu Arg Met Phe Leu Asn Lys Thr Asn Lys Glu 'rhr Ile
3250 3255 3260 -
Ile Asn His Arg Leu Pro Ala Ala Glu Ser Leu Ala Val Asp Trp Val
3265 3270 3275 3280
Ser Arg Lys Leu Tyr Trp Leu Asp Ala Arg Leu Asp Gly Leu Phe Val
3285 3290 3295
Ser Asp Leu Asn Gly Gly His Arg Arg Met Leu Ala Gln His Cys Val
3300 3305 3310
Asp Ala Asn Asn Thr Phe Cys Phe Asp Asn Pro Arg Gly l~eu Ala ~eu
3315 3320 3325
His Pro Gln Tyr Gly Tyr Leu Tyr Trp Ala Asp Trp Gly His Arg Ala
3330 3335 3340
Tyr Ile Gly Arg Val Gly Met Asp Gly Thr Asn Lys Ser Val Ile Ile
3345 3350 3355 3360
Ser Thr Lys Leu Glu Trp Pro Asn Gly Ile Thr Ile Asp Tyr Thr Asn
3365 3370 3375
3 5 Asp Leu Leu Tyr Trp Ala Asp Ala His Leu Gly Tyr Ile Glu Tyr Ser
3380 3385 3390
Asp Leu Glu Gly His His Arg His Thr Val Tyr Asp Gly Ala Leu Pro
3395 3400 3405
His Pro Phe Ala Ile Thr Ile Phe Glu Asp Thr Ile Tyr Trp Thr Asp
3410 3415 3420
Trp Asn Thr Arg Thr Val Glu Lys Gly Asn Lys Tyr Asp Gly Ser Asn
45 3425 3430 3435 3440
Arg Gln Thr Leu Val Asn Thr Thr His Arg Pro Phe Asp Ile His Val
3445 3450 3455
50 Tyr His Pro Tyr Arg Gln Pro Ile Val Ser Asn Pro Cys Gly Thr Asn
3460 3465 3470
Asn Gly Gly Cys Ser His Leu Cys Leu Ile Lys Pro Gly Gly Lys Gly
3475 3480 3485
" 55
Phe Thr Cys Glu Cys Pro Asp Asp Phe Arg Thr Leu Gln Leu Ser Gly
3490 3495 3500
Ser Thr Tyr Cys Met Pro Met Cys Ser Ser Thr Gln Phe Leu Cys Ala
60 3505 351Q 3515 3520
Asn Asn Glu Lys Cys Ile Pro Ile Trp Trp Lys Cys Asp Gly Gln Lys
3525 3530 3535
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
/7 ~
Asp Cys Ser Asp Gly Ser Asp Glu Leu Ala Leu Cys Pro Gln Arg Phe
3540 3545 3550
Cys Arg Leu Gly Gln Phe Gln Cys Ser Asp Gly Asn Cys Thr Ser Pro
3555 3560 3565
Gln Thr Leu Cys Asn Ala His Gln Asn Cys Pro Asp Gly Ser Asp Glu
3570 3575 3580
0 Asp Arg Leu Leu Cys Glu Asn His His Cys Asp Ser Asn Glu Trp Gln
3585 3590 3595 3600
Cys Ala Asn Lys Arg Cys Ile Pro Glu Ser Trp Gln Cys Asp Thr Phe
3605 3610 3615
Asn Asp Cys Glu Asp Asn Ser Asp Glu Asp Ser Ser His Cys Ala Ser
3620 3625 3630
Arg Thr Cys Arg Pro Gly Gln Phe Arg Cys Ala Asn Gly Arg Cys Ile
3635 3640 3645
Pro Gln Ala Trp Lys Cys Asp Val Asp Asn Asp Cys Gly Asp His Ser
3650 3655 3660
Asp Glu Pro Ile Glu Glu Cys Met Ser Ser Ala His Leu Cys Asp Asn
3665 3670 3675 3680
Phe Thr Glu Phe Ser Cys Lys Thr Asn Tyr Arg Cys Ile Pro Lys Trp
3685 3690 3695
Ala Val Cys Asn Gly Val Asp Asp Cys Arg Asp Asn Ser Asp Glu Gln
3700 3705 3710
Gly Cys Glu Glu Arg Thr Cys His Pro Val Gly Asp Phe Arg Cys Lys
3715 3720 3725
Asn His His Cys Ile Pro Leu Arg Trp Gln Cys Asp Gly Gln Asn Asp
3730 3735 3740
Cys Gly Asp Asn Ser Asp Glu Glu Asn Cys Ala Pro Arg Glu Cys Thr
3745 3750 3755 3760
Glu Ser Glu Phe Arg Cys Val Asn Gln Gln Cys Ile Pro Ser Arg Trp
3765 3770 3775
Ile Cys Asp His Tyr Asn Asp Cys Gly Asp Asn Ser Asp Glu Arg Asp
3780 3785 3790
Cys Glu Met Arg Thr Cys His Pro Glu Tyr Phe Gln Cys Thr Ser Gly
3795 3800 3805
His Cys Val Hi,s Ser Glu Leu Lys Cys Asp Gly Ser Ala Asp Cys Leu "
3810 3815 3820
Asp Ala Ser Asp Glu Ala Asp Cys Pro Thr Arg Phe Pro Asp Gly Ala
3825 3830 3835 3840 ~,
Tyr Cys Gln Ala Thr Met Phe Glu Cys Lys Asn His Val Cys Ile Pro
3845 3850 3855
Pro Tyr Trp Lys Cys Asp Gly Asp Asp Asp Cys Gly Asp Gly Ser Asp
3860 3865 3870
Glu Glu Leu His Leu Cys Leu Asp Val Pro Cys Asn Ser Pro Asn Arg
CA 0220~648 l997-0~-20
WO 96115801 PCT/US95/15203
/7~
3875 3880 3885
Phe Arg Cys Asp Asn Asn Arg Cys Ile Tyr Ser His Glu Val Cys Asn
3890 3895 3900
Gly Val Asp Asp Cys Gly Asp Gly Thr Asp Glu Thr Glu Glu His Cys
3905 3910 391S 3920
Arg Lys Pro Thr Pro Lys Pro Cys Thr Glu Tyr Glu Tyr Lys Cys Gly
0 3925 3930 3935
Asn Gly His Cys Ile Pro His Asp Asn Val Cys Asp Asp Ala Asp Asp . .
3940 3945 3950
Cys Gly Asp Trp Ser Asp Glu Leu Gly Cys Asn Lys Gly Lys Glu Arg
3955 3960 3965
Thr Cys Ala Glu Asn Ile Cys Glu Gln Asn Cys Thr Gln Leu Asn Glu
3970 3975 3980
Gly Gly Phe Ile Cys Ser Cys Thr Ala Gly Phe Glu Thr Asn Val Phe
3985 3990 3995 4000
Asp Arg Thr Ser Cys Leu Asp Ile Asn Glu Cys Glu Gln Phe Gly Thr
4005 4010 4015
Cys Pro Gln His Cys Arg Asn Thr Lys Gly Ser Tyr Glu Cys Val Cys
4020 4025 4030
3 0 Ala Asp Gly Phe Thr Ser Met Ser Asp Arg Pro Gly Lys Arg Cys Ala
4035 4040 4045
Ala Glu Gly Ser Ser Pro Leu Leu Leu Leu Pro Asp Asn Val Arg Ile
4050 4055 4060
Arg Lys Tyr Asn Leu Ser Ser Glu Arg Phe Ser Glu Tyr Leu Gln Asp
4065 4070 4075 4080
Glu Glu Tyr Ile Gln Ala Val Asp Tyr Asp Trp Asp Pro Glu Asp Ile
4085 4090 4095
Gly Leu Ser Val Val Tyr Tyr Thr Val Arg Gly Glu Gly Ser Arg Phe
4100 4105 411Q
Gly Ala Ile Lys Arg Ala Tyr Ile Pro Asn Phe Glu Ser Gly Arg Asn
4115 4120 4125
Asn Leu Val Gln Glu Val Asp Leu Lys Leu Lys Tyr Val Met Gln Pro
4130 4135 414Q
Asp Gly Ile Ala Val Asp Trp Val Gly Arg His Ile Tyr Trp Ser Asp
4145 4150 4155 4160
Val Lys Asn Lys Arg Ile Glu Val Ala Lys Leu Asp Gly Arg Tyr Arg
4165 4170 4175
Lys Trp Leu Ile Ser Thr Asp Leu Asp Gln Pro Ala Ala Ile Ala Val
4180 4185 4190
60 Asn Pro Lys Leu Gly Leu Met Phe Trp Thr Asp Trp Gly Lys Glu Pro
4195 4200 4205
Lys Xaa Glu Ser Ala Trp Met Asn Gly Glu Asp Arg Asn Ile Leu Val
4210 4215 4220
CA 0220~648 l997-0~-20
WO 96/lS801 PCTIUS95/~5203
/75/
Phe Glu Asp Leu Gly Trp Pro Thr Gly Leu Ser Ile Asp Tyr Leu Asn
4225 4230 4235 4240
5 Asn Asp Arg Ile Tyr Trp Ser Asp Phe Lys Glu Asp Val Ile Glu Thr
4245 4250 4255
Ile Lys Tyr Asp Gly Thr Asp Arg Arg Val Ile Ala Lys Glu Ala Met
4260 4265 4270
Asn Pro Tyr Ser Leu Asp - Ile Phe Glu Asp Gln Leu Tyr Trp Ile Ser
4275 4280 4285
Lys Glu IJYS Gly Glu Val Trp Lys Gln Asn Lys Phe Gly Gln Gly Lys
4290 4295 .4300
Lys Glu Lys Thr Leu Val Val Asn Pro Trp Leu Thr Gln Val Arg Ile
4305 4310 4315 4320
Phe His Gln Leu Arg Tyr Asn Lys Ser Val Pro Asn Leu Cys Lys Gln
4325 4330 g335
Ile Cys Ser His Leu Cys Leu Leu Arg Pro Gly Gly Tyr Ser Cys Ala
4340 4345 4350
Cys Pro Gln Gly Ser Ser Phe Ile Glu Gly Ser Thr Thr Glu Cys Asp
4355 4360 4365
Ala Ala Ile Glu Leu Pro Ile Asn Leu Pro Pro Pro Cys Arg Cys Met
4370 4375 4380
His Gly Gly Asn Cys Tyr Phe Asp Glu Thr Asp Leu Pro Lys Cys Lys
4385 4390 4395 4400
3 5 Cys Pro Ser Gly Tyr Thr Gly Lys Tyr Cys Glu Met Ala Phe Ser Lys
4405 4410 4415
Gly Ile Ser Pro Gly Thr Thr Ala Val Ala Val Leu Leu Thr Ile Leu
4420 4425 4430
Leu Ile Val Val Ile Gly Ala Leu Ala Ile Ala Gly Phe Phe His Tyr
4435 4440 4445
Arg Arg Thr Gly Ser Leu Leu Pro Ala Leu Pro Lys Leu Pro Ser Leu
4450 4455 4460
Ser Ser Leu Val Lys Pro Ser Glu Asn Gly Asn Gly Val Thr Phe Arg
4465 4470 4475 4480
S0 Ser Gly Ala Asp Leu Asn Met Asp Ile Gly Val Ser Gly Phe Gly Pro
4485 4490 4495
Glu Thr Ala Ile Asp Arg Ser Met Ala Met Ser Glu Asp Phe Val Met
4500 4505 4510
Glu Met Gly Lys Gln Pro Ile Ile Phe Glu Asn Pro Met Tyr Ser Ala
4515 4520 4525
Arg Asp Ser Ala Val Lys Val Val Gln Pro Ile Gln Val Thr Val Ser
4530 4535 4540
Glu Asn Val Asp Asn Lys Asn Tyr Gly Ser Pro Ile Asn Pro Ser Glu
4545 4550 4555 4560
CA 0220~648 l997-0~-20
.
W O96/1~801 PCTrUS95115203
1~
Ile Val Pro Glu Thr Asn Pro Thr Ser Pro Ala Ala Asp Gly Thr Gln
4565 4570 4575
Val Thr Lys Trp Asn Leu Phe Lys Arg Lys Ser Lys Gln Thr Thr Asn
4580 4585 4590
Phe Glu Asn Pro Ile Tyr Ala Gln Met Glu Asn Glu Gln Lys Glu Ser
4595 4600 4605
Val Ala Ala Thr Pro Pro Pro Ser Pro Ser Leu Pro Ala Lys Pro Lys
4610 4615 4620
Pro Pro Ser Arg Arg Asp Pro Thr Pro Thr Tyr Ser Ala Thr Glu Asp
4625 4630 4635 4640
Thr Phe Lys Asp Thr Ala Asn Leu Val Lys Glu Asp Ser Glu Val *
4645 4650 4655
(2) INFORMATION FOR SEQ ID NO:89:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14044 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: cDNA
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(vi) ORIGINAL SOURCE:
(A) ORGANISM: Homo sapiens
(F) TISSUE TYPE: Parathyroid
(ix) FEATURE:
~A) NAME/KEY: CDS
(B) LOCATION: 65.. 14032
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:89:
45 TGCGGTGTGC TACGCGCGCC CACCTCCCGG GGAAGGAACG GCGAGGCCGG GGACCGTCGC 60
GGAG ATG GAT CGC GGG CCG GCA GCA GTG GCG TGC ACG CTG CTC CTG GCT 109
Met Asp Arg Gly Pro Ala Ala Val Ala Cys Thr Leu Leu Leu Ala
4660 4665 4670
CTC GTC GCC TGC CTA GCC CCG GCC AGT GGC CAA GAA TGT GAC AGT GCG 157
Leu Val Ala Cys Leu Ala Pro Ala Ser Gly Gln Glu Cys Asp Ser Ala
4675 4680 4685
55 CAT TTT CGC TGT GGA AGT GGG CAT TGC ATC CCT GCA GAC TGG AGG TGT 205
His Phe Arg Cys Gly Ser Gly His Cys Ile Pro Ala Asp Trp Arg Cys
4690 4695 4700
GAT GGG ACC AAA GAC TGT TCA GAT GAC GCG GAT GAA ATT GGC TGC GCT 253
60 Asp Gly Thr Lys Asp Cys Ser Asp Asp Ala Asp Glu Ile Gly Cys Ala
4705 4710 4715
GTT GTG ACC TGC CAG CAG GGC TAT TTC AAG TGC CAG AGT GAG GGA CAA 301
Val Val Thr Cys Gln Gln Gly Tyr Phe Lys Cys Gln Ser Glu Gly Gln
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US9~/15203
/~'6
4720 4725 4730 4735
TGC ATC CCC AGC TCC TGG GTG TGT GAC CAA GAT CAA GAC TGT GAT GAT 349
Cys Ile Pro Ser Ser Trp Val Cys Asp Gln Asp Gln Asp Cys Asp Asp
4740 4745 4750
GGC TCA GAT GAA CGT CAA GAT TGC TCA CAA AGT ACA TGC TCA AGT CAT 3 97
Gly Ser Asp Glu Arg Gln Asp Cys Ser Gln Ser Thr Cys Ser Ser His
4755 4760 4765
CAG ATA ACA TGC TCC AAT GGT CAG TGT ATC CCA AGT GAA TAC AGG TGC 445
Gln Ile Thr Cys Ser Asn Gly Gln Cys Ile Pro Ser Glu Tyr Arg Cys
4770 4775 4780
GAC CAC GTC AGA GAC TGC CCC GAT GGA GCT GAT GAG AAT GAC TGC CAG 493
Asp His Val Arg Asp Cys Pro Asp Gly Ala Asp Glu Asn Asp Cys Gln
4785 4790 4795
TAC CCA ACA TGT GAG CAG CTT ACT TGT GAC AAT GGG GCC TGC TAT AAC 541
2 0 Tyr Pro Thr Cys Glu Gln I~eu Thr Cys Asp Asn Gly Ala Cys Tyr Asn
4800 4805 4810 4815
ACC AGT CAG AAG TGT GAT TGG AAA GTT GAT TGC AGG GAC TCC TCA GAT 589
Thr Ser Gln Lys Cys Asp Trp Lys Val Asp Cys Arg Asp Ser Ser Asp
4820 4825 4830
GAA ATC AAC TGC ACT GAG ATA TGC TTG CAC AAT GAG TTT TCA TGT GGC 637
Glu Ile Asn Cys Thr Glu Ile Cys Leu His Asn Glu Phe Ser Cys Gly
4835 4840 4845
AAT GGA GAG TGT ATC CCT CGT GCT TAT GTC TGT GAC CAT GAC AAT GAT 685
Asn Gly Glu Cys Ile Pro Arg Ala Tyr Val Cys Asp His Asp Asn Asp
4850 4855 4860
3 5 TGC CAA GAC GGC AGT GAC GAA CAT GCT TGC AAC TAT CCG ACC TGC GGT 733
Cys Gln Asp Gly Ser Asp Glu His Ala Cys Asn Tyr Pro Thr Cys Gly
4865 4870 4875
GGT TAC CAG TTC ACT TGC CCC AGT GGC CGA TGC ATT TAT CAA AAC TGG 781
Gly Tyr Gln Phe Thr Cys Pro Ser Gly Arg Cys Ile Tyr Gln Asn Trp
4880 4885 4890 4895
GTT TGT GAT GGA GAA GAT GAC TGT AAA GAT AAT GGA GAT GAA GAT GGA 829
Val Cys Asp Gly Glu Asp Asp Cys Lys Asp Asn Gly Asp Glu Asp Gly
4900 4905 4910
TGT GAA AGC GGT CCT CAT GAT GTT CAT AAA TGT TCC CCA AGA GAA TGG 877
Cys Glu Ser Gly Pro His Asp Val His Lys Cys Ser Pro Arg Glu Trp
4915 4920 4925
TCT TGC CCA GAG TCG GGA CGA TGC ATC TCC ATT TAT AAA GTT TGT GAT 925
Ser Cys Pro Glu Ser Gly Arg Cys Ile Ser Ile Tyr Lys Val Cys Asp
4930 4935 4940
5 5 GGG ATT TTA GAT TGC CCA GGA AGA GAA GAT GAA AAC AAC ACT AGT ACC 973
Gly Ile Leu Asp Cys Pro Gly Arg Glu Asp Glu Asn Asn Thr Ser Thr
4945 4g50 4955
GGA AAA TAC TGT AGT ATG ACT CTG TGC TCT GCC TTG AAC TGC CAG TAC 1021
Gly Lys Tyr Cys Ser Met Thr Leu Cys Ser Ala I~eu Asn Cys Gln Tyr
4960 4965 4970 4975
CAG TGC CAT GAG ACG CCG TAT GGA GGA GCG - TGT TTT TGT CCC CCA GGT 1069
Gln Cys His Glu Thr Pro Tyr Gly Gly Ala Cys Phe Cys Pro Pro Gly
CA 0220S648 1997-0~-20
W O96/1~801 PCT~US9S/15203
4980 4985 4990
' TAT ATC ATC AAC CAC AAT GAC AGC CGT ACC TGT GTT GAG TTT GAT GAT 1117
Tyr Ile Ile Asn His Asn Asp Ser Arg Thr Cys Val Glu Phe Asp Asp
4995 5000 5005
TGC CAG ATA TGG GGA ATT TGT GAC CAG AAG TGT GAA AGC CGA CCT GGC 1165
Cys Gln Ile Trp Gly Ile Cys Asp Gln Lys Cys Glu Ser Arg Pro Gly
5010 5015 5020
CGT CAC CTG TGC CAC TGT GAA GAA GGG TAT ATC TTG GAG CGT GGA CAG 1213
Arg His Leu Cys His Cys Glu Glu Gly Tyr Ile Leu Glu Arg Gly Gln
5025 5030 5035
TAT TGC AAA GCT AAT GAT TCC TTT GGC GAG GCC TCC ATT ATC TTC TCC 1261
Tyr Cys Lys Ala Asn Asp Ser Phe Gly GlU Als Ser Ile Ile Phe Ser
5040 5045 5050 5055
AAT GGT CGG GAT TTG TTA ATT GGT GAT ATT CAT GGA AGG AGC TTC CGG 1309
Asn Gly Arg Asp Leu Leu Ile Gly Asp Ile His Gly Arg Ser Phe Arg
5060 5065 5070
ATC CTA GTG GAG TCT CAG AAT CGT GGA GTG GCC GTG GGT GTG GCT TTC 1357
Ile Leu Val Glu Ser Gln Asn Arg Gly Val Ala Val Gly Val Ala Phe
5075 5080 5085
CAC TAT CAC CTG CAA AGA GTT TTT TGG ACA GAC ACC GTG CAA AAT AAG 1405
His Tyr His Leu Gln Arg Val Phe Trp Thr Asp Thr Val Gln Asn Lys
5090 5095 5100
GTT TTT TCA GTT GAC ATT AAT GGT TTA AAT ATC CAA GAG GTT CTC AAT 1453
Val Phe Ser Val Asp Ile Asn Gly Leu Asn Ile Gln Glu Val Leu Asn
5105 5110 5115
3 5 GTT TCT GTT GAA ACC CCA GAG AAC CTG GCT GTG GAC TGG GTT AAT AAT 1501
Val Ser Val Glu Thr Pro Glu Asn Leu Ala Val Asp Trp Val Asn Asn
5120 5125 5130 5135
AAA ATC TAT CTA GTG GAA ACC AAG GTC AAC CGC ATA GAT ATG GTA AAT 1549
Lys Ile Tyr Leu Val Glu Thr Lys Val Asn Arg Ile Asp Met Val Asn
5140 5145 5150
TTG GAT GGA AGC TAT CGG GTT ACC CTT ATA ACT GAA AAC TTG GGG CAT 1597
Leu Asp Gly Ser Tyr Arg Val Thr Leu Ile Thr Glu Asn Leu Gly ~lis
5155 5160 5165
CCT AGA GGA ATT GCC GTG GAC CCA ACT GTT GGT TAT TTA TTT TTC TCA 1645
Pro Arg Gly Ile Ala Val Asp Pro Thr Val Gly Tyr Leu Phe Phe Ser
5170 5175 5180
GAT TGG GAG AGC CTT TCT GGG GAA CCT AAG CTG GAA AGG GCA TTC ATG 1693
Asp Trp Glu Ser Leu Ser Gly Glu Pro Lys Leu Glu Arg Ala Phe Met
5185 5190 5195
"5 5 GAT GGC AGC AAC CGT AAA GAC TTG GTG AAA ACA AAG CTG GGA TGG CCT 1741
Asp Gly Ser Asn Arg Lys Asp Leu Val Lys Thr Lys Leu Gly Trp Pro
5200 5Z05 5210 5215
GCT GGG GTA ACT CTG GAT ATG ATA TCG AAG CGT GTT TAC TGG GTT GAC 1789
Ala Gly Val Thr Leu Asp Met Ile Ser Lys Arg Val Tyr Trp Val Asp
5220 5225 5230
TCT CGG TTT GAT TAC ATT GAA ACT GTA ACT TAT GAT GGA ATT CAA AGG 1837
Ser Arg Phe Asp Tyr Ile Glu Thr Val Thr Tyr Asp Gly Ile Gln Arg
_
CA 0220~648 l997-0~-20
W O96/15801 PCTrUS9~/15203
/7~
5235 5240 5245
AAG ACT GTA GTT CAT GGA GGC TCC CTC ATT CCT CAT CCC TTT GGA GTA 1885
Lys Thr Val Val His Gly Gly Ser Leu Ile Pro His Pro Phe Gly Val
5250 5255 5260
AGC TTA TTT GAA GGT CAG GTG TTC TTT ACA GAT TGG ACA AAG ATG GCC 1933
Ser Leu Phe Glu Gly Gln Val Phe Phe Thr Asp Trp Thr Lys Met Ala
5265 5270 5275
GTG CTG AAG GCA AAC AAG TTC ACA GAG ACC AAC CCA CAA GTG TAC TAC 1981
Val Leu Lys Ala Asn Lys Phe Thr Glu Thr Asn Pro Gln Val Tyr Tyr
5280 5285 5290 5295
15 CAG GCT TCC CTG AGG CCC TAT GGA GTG ACT GTT TAC CAT TCC CTC AGA 2029
Gln Ala Ser Leu Arg Pro Tyr Gly Val Thr Val Tyr His Ser Leu Arg
5300 5305 5310
CAG CCC TAT GCT ACC AAT CCG TGT AAA GAT AAC AAT GGG GGC TGT GAG 2077
20 Gln Pro Tyr Ala Thr Asn Pro Cys Lys Asp Asn Asn Gly Gly Cys Glu
5315 5320 5325
CAG GTC TGT GTY CTC AGC CAC AGA ACA GAT AAT GAT GGT TTG GGT TTC 2125
Gln Val Cys Val Leu Ser His Arg Thr Asp Asn Asp Gly Leu Gly Phe
5330 5335 5340
CGT TGC AAG TGC ACA TTC GGC TTC CAA CTG GAT ACA GAT GAG CGC CAC 2173
Arg Cys Lys Cys Thr Phe Gly Phe Gln Leu Asp Thr Asp Glu Arg His
5345 5350 5355
TGC ATT GCT GTT CAG AAT TTC CTC ATT TTT TCA TCC CAA GTT GCT ATT 2221
Cys Ile Ala Val Gln Asn Phe Leu Ile Phe Ser Ser Gln Val Ala Ile
5360 5365 5370 5375
35 CGT GGG ATC CCG TTC ACC TTG TCT ACC CAG GAA GAT GTC ATG GTT CCA 2269
Arg Gly Ile Pro Phe Thr Leu Ser Thr Gln Glu Asp Val Met Val Pro
5380 5385 5390
GTT TCG GGG AAT CCT TCT TTC TTT GTC GGG ATT GAT TTT GAC GCC CAG 2317
40 Val Ser Gly Asn Pro Ser Phe Phe Val Gly Ile Asp Phe Asp Ala Gln
5395 5400 5405
GAC AGC ACT ATC TTT TTT TCA GAT ATG TCA AAA CAC ATG ATT TTT AAG 2365
Asp Ser Thr Ile Phe Phe Ser Asp Met Ser Lys His Met Ile Phe Lys
5410 5415 5420
CAA AAG ATT GAT GGC ACA GGA AGA GAA ATT CTC GCA GCT AAC AGG GTG 2413
Gln Lys Ile Asp Gly Thr Gly Arg Glu Ile Leu Ala Ala Asn Arg Val
5425 5430 5435
GAA AAT GTT GAA AGT TTG GCT TTT GAT TGG ATT TCA AAG AAT CTC TAT 2461
Glu Asn Val Glu Ser Leu Ala Phe Asp Trp Ile Ser Lys Asn Leu Tyr
5440 5445 5450 5455
55 TGG ACA GAC TCT CAT TAC AAG AGT ATC AGT GTC ATG AGG CTA GCT GAT 2509
Trp Thr Asp Ser His Tyr Lys Ser Ile Ser Val Met Arg Leu Ala Asp
5460 5465 5470
AAA ACG AGA CGC ACG GTA GTT CAG TAT TTA AAT AAC CCA CGG TCG GTG 2557
60 Lys Thr Arg Arg Thr Val Val Gln Tyr Leu Asn Asn Pro Arg Ser Val
5475 5480 5485
GTA GTT CAT CCT TTT GCC GGG TAT CTA TTC TTC ACT GAT TGG TTC CGT 2605
Val Val His Pro Phe Ala Gly Tyr Leu Pne Phe Thr Asp Trp Phe Arg
_
CA 0220~648 1997-OS-20
W O 96/15801 PCT~US95/1S203
l7~
5490 5495 5500
CCT GCT AAA ATT ATG AGA GCA TGG AGT GAC GGA TCT CAC CTC TTG CCT 2653
Pro Ala Lys Ile Met Arg Ala Trp Ser Asp Gly Ser His Leu I,eu Pro
5505 5510 5515
y
GTA ATA AAC ACT ACT CTT GGA TGG CCC AAT GGC TTG GCC ATC GAT TGG 2701
Val Ile Asn Thr Thr Leu Gly Trp Pro Asn Gly Leu Ala I1Q ASP Trp
5520 5525 5530 5535
GCT GCT TCA CGA TTG TAC TGG GTA GAT GCC TAT TTT GAT AAA ATT GAG 2749
Ala Ala Ser Arg Leu Tyr Trp Val Asp Ala Tyr Phe Asp Lys Ile Glu
5540 5545 5550
CAC AGC ACC TTT GAT GGT TTA GAC AGA AGA AGA CTG GGC CAT ATA GAG 2797
His Ser Thr Phe Asp Gly Leu Asp Arg Arg Arg Leu Gly His Ile Glu
5555 5560 5565
CAG ATG ACA CAT CCG TTT GGA CTT GCC ATC TTT GGA GAG CAT TTA TTT 2845
Gln Met Thr His Pro Phe Gly Leu Ala Ile Phe Gly Glu His Leu Phe
5570 5575 5580
TTT ACT GAC TGG AGA CTG GGT GCC ATT ATT CGA GTC AGG AAA GCA GAT 2893
Phe Thr Asp Trp Arg Leu Gly Ala Ile Ile Arg Val Arg Lys Ala Asp
5585 5590 5595
GGT GGA GAA ATG ACA GTT ATC CGA AGT GGC ATT GCT TAC ATA CTG CAT 2941
Gly Gly Glu Met Thr Val Ile Arg Ser Gly Ile Ala Tyr Ile Leu His
5600 5605 5610 5615
TTG AAA TCG TAT GAT GTC AAC ATC CAG ACT GGT TCT AAC GCC TGT AAT 2989
Leu Lys Ser Tyr Asp Val Asn Ile Gln Thr Gly Ser Asn Ala Cys Asn
5620 5625 5630
CAA CCC ACG CAT CCT AAC GGT GAC TGC AGC CAC TTC TGC TTC CCG GTG 3037
Gln Pro Thr His Pro Asn Gly Asp Cys Ser His Phe Cys Phe Pro Val
5635 5640 5645
CCA AAT TTC CAG CGA GTG TGT GGG TGC CCT TAT GGA ATG AGG CTG GCT 3085
Pro Asn Phe Gln Arg Val Cys Gly Cys Pro Tyr Gly Met Arg Leu Ala
5650 5655 5660
TCC AAT CAC TTG ACA TGC GAG GGG GAC CCA ACM AAT GAA CCA CCC ACG 313 3
Ser Asn His Leu Thr Cys Glu Gly Asp Pro Thr Asn Glu Pro Pro Thr
5665 5670 5675
GAG CAG TGT GGC TTA TTT TCC TTC CCC TGT AAA AAT GGC AGA TGT GTG 3181
Glu Gln Cys Gly Leu Phe Ser Phe Pro Cys Lys Asn Gly Arg Cys Val
5680 5685 5690 5695
CCC AAT TAC TAT CTC TGT GAT GGA GTC GAT GAT TGT CAT GAT AAC AGT 3 2 2 9
Pro Asn Tyr Tyr Leu Cys Asp Gly Val Asp Asp Cys His Asp Asn Ser
5700 5705 5710
7 55 GAT GAG CAA CTA TGT GGC ACA CTT AAT AAT ACC TGT TCA TCT TCG GCG 3277
Asp Glu Gln Leu Cys Gly Thr Leu Asn Asn Thr Cys Ser Ser Ser Ala
5715 5720 5725
TTC ACC TGT GGC CAT GGG GAG TGC ATT CCT GCA CAC TGG CGC TGT GAC 3325
Phe Thr Cys Ely His Gly Glu Cys Ile Pro Ala llis Trp Arg Cys Asp
5730 5735 5740
AAA CGC AAC GAC TCT GTG GAT GGC AGT GAT GAG CAC AAC TGC CCC ACC 3373
Lys Arg Asn Asp Cys Val Asp Gly Ser Asp Glu His Asn Cys Pro Thr
CA 0220S648 l997-0~-20
W O96/15801 PCTrUS95/15203
/&
5745 5750 5755
CAC GCA CCT GCT TCC TGC CTT GAC ACC CAA TAC ACC TGT GAT AAT CAC 3421
His Ala Pro Ala Ser Cys Leu Asp Thr Gln Tyr Thr Cys Asp Asn His
5760 5765 5770 5775
CAG TGT ATC TCA AAG AAC TGG GTC TGT GAC ACA GAC AAT GAT TGT GGG 3469
Gln Cys Ile Ser Lys Asn Trp Val Cys Asp Thr Asp Asn Asp Cys Gly
. 5780 5785 5790
GAT GGA TCT GAT GAA AAG AAC TGC AAT TCG ACA GAG ACA TGC CAA CCT 3517
Asp Gly Ser Asp Glu Lys Asn Cys Asn Ser Thr Glu Thr Cys Gln Pro
5795 5800 5805
AGT CAG TTT AAT TGC CCC AAT CAT CGA TGT ATT GAC CTA TCG TTT GTC 3565
Ser Gln Phe Asn Cys Pro Asn His Arg Cys Ile Asp Leu Ser Phe Val
5810 5815 5820
TGT GAT GGT GAC AAG GAT TGT GTT GAT GGA. TCT GAT GAG GTT GGT TGT 3613
2 0 Cys Asp Gly Asp Lys Asp Cys Val Asp Gly Ser Asp Glu Val Gly Cys
5825 5830 5835
GTA TTA AAC TGT ACT GCT TCT CAA TTC AAG TGT GCC AGT GGG GAT AAA 3 6 61
Val Leu Asn Cys Thr Ala Ser Gln Phe Lys Cys Ala Ser Gly Asp Lys
5840 5845 5850 5855
TGT ATT GGC GTC ACA AAT CGT TGT GAT GGT GTT TTT GAT TGC AGT GAC 3709
Cys Ile Gly Val Thr Asn Arg Cys Asp Gly Val Phe Asp Cys Ser Asp
5860 5865 5870
AAC TCG GAT GAA GCG GGC TGT CCA ACC AGG CCT CCT GGT ATG TGC CAC 3757
Asn Ser Asp Glu Ala Gly Cys Pro Thr Arg Pro Pro Gly Met Cys His
5875 5880 5885
3 5 TCA GAT GAA TTT CAG TGC CAA GAA GAT GGT ATC TGC ATC CCG AAC TTC 3805
Ser Asp Glu Phe Gln Cys Gln Glu Asp Gly Ile Cys Ile Pro Asn Phe
5890 5895 5900
TGG GAA TGT GAT GGG CAT CCA GAC TGC CTC TAT GGA TCT GAT GAG CAC 3 853
Trp Glu Cys Asp Gly His Pro Asp Cys Leu Tyr Gly Ser Asp Glu His
5905 5910 5915
AAT GCC TGT GTC CCC AAG ACT TGC CCT TCA TCA TAT TTC CAC TGT GAC 3901
Asn Ala Cys Val Pro Lys Thr Cys Pro Ser Ser Tyr Phe His Cys Asp
5920 5925 5930 5935
AAC GGA AAC TGC ATC CAC AGG GCA TGG CTC TGT GAT CGG GAC AAT GAC 3 94 9
Asn Gly Asn Cys Ile His Arg Ala Trp Leu Cys Asp Arg Asp Asn Asp
5940 5945 5950
TGC GGG GAT ATG AGT GAT GAG AAG GAC TGC CCT ACT CAG CCC TTT CGC 3 9 9 7
Cys Gly Asp Met Ser Asp Glu ~ys Asp Cys Pro Thr Gln Pro Phe Arg
5955 5960 5965 -'
5 5 TGT CCT AGT TGG CAA TGG CAG TGT CTT GGC CAT AAC ATC TGT GTG AAT 4 0 4 5
Cys Pro Ser Trp Gln Trp Gln Cys Leu Gly His Asn Ile Cys Val Asn
5970 5975 5980
CTG AGT GTA GTG TGT GAT GGC ATC TTT GAC TGC CCC AAT GGG ACA GAT 4 0 9 3
Leu Ser Val Val Cys Asp Gly Ile Phe Asp Cys Pro Asn Gly Thr Asp
5985 5990 5995
GAG TCC CCA CTT TGC AAT GGG AAC AGC TGC TCA GAT TTC AAT GGT GGT 4141
Glu Ser Pro ~eu Cys Asn Gly Asn Ser Cys Ser Asp Phe Asn Gly Gly
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US9!i11~i203
1~1
6000 6005 6010 6015
TGT ACT CAC GAG TGT GTT CAA GAG CCC TTT GGG GCT AAA TGC CTA TGT ~ 189
Cys Thr His Glu Cys Val Gln Glu Pro Phe Gly Ala Lys Cys Leu Cys
6020 6025 6030
CCA TTG GGA TTC TTA CTT GCC AAT GAT TCT AAG ACC TGT GAA GAC ATA .4237
Pro Leu Gly Phe Leu Leu Ala Asn Asp Ser Lys Thr Cys Glu Asp Ile
6035 6040 6045
' ,
GAT GAA TGT GAT ATT Cl'A GGC TCT TGT AGC CAG CAC TGT TAC AAT ATG 4285
Asp Glu Cys Asp Ile Leu Gly Ser Cys Ser Gln His Cys Tyr Asn Met
- 6050 6055 6060
AGA GGT TCT TTC CGG TGC TCG TGT GAT ACA GGC TAC ATG TTA GAA AGT 4333
Arg Gly Ser Phe Arg Cys Ser Cys Asp Thr Gly Tyr Met Leu Glu Ser
6065 6070 6075
GAT GGG AGG ACT TGC AAA GTT ACA GCA TCT GAG AGT CTG CTG TTA CTT 4381
Asp Gly Arg Thr Cys Lys Val Thr Ala Ser Glu Ser Leu Leu Leu Leu
6080 608S 6090 6095
GTG GCA AGT CAG AAC AAA ATT ATT GCC GAC AGT GTC ACC TCC CAG GTC 4429
Val Ala Ser Gln Asn Lys Ile Ile Ala Asp Ser Val Thr Ser Gln Val
6100 6105 6110
CAC AAT ATC TAT TCA TTG GTC GAG AAT GGT TCT TAC ATT GTA GCT GTT 4477
His Asn Ile Tyr Ser Leu Val Glu Asn Gly Ser Tyr Ile Val Ala Val
6115 6120 6125
GAT TTT GAT TCA ATT AGT GGT CGT ATC TTT TGG TCT GAT GCA ACT CAG 4525
Asp Phe Asp Ser Ile Ser Gly Arg Ile Phe Trp Ser Asp Ala Thr Gln
6130 6135 6140
3 5 GGT AAA ACC TGG AGT GCG TTT CAA AAT GGA ACG GAC AGA AGA GTG GTA 4573
Gly Lys Thr Trp Ser Ala Phe Gln Asn Gly Thr Asp Arg Arg Val Val
6145 6150 6155
TTT GAC AGT AGC ATC ATC TTG ACT GAA ACT ATT GCA ATA GAT TGG GTA 4621 .
Phe Asp Ser Ser Ile Ile Leu Thr Glu Thr Ile Ala Ile Asp Trp Val
6160 6165 6170 6175
GGT CGT AAT CTT TAC TGG ACA GAC TAT GCT CTG GAA ACA ATT GAA GTC 4669
Gly Arg Asn Leu Tyr Trp Thr Asp Tyr Ala Leu Glu Thr Ile Glu Val
6180 6185 6190
TCC AAA ATT GAT GGG AGC CAC AGG ACT GTG CTG ATT AGT AAA AAC CTA 4717
Ser Lys Ile Asp Gly Ser His Arg Thr Val Leu Ile Ser Lys Asn Leu
6195 6200 6205
ACA AAT CCA AGA GGA CTA GCA TTA GAT CCC AGA ATG AAT GAG CAT CTA 4765
Thr Asn Pro Arg Gly Leu Ala Leu Asp Pro Arg Met Asn Glu His Leu
6210 6215 6220
.~ 55 CTG TTC TGG TCT GAC TGG GGC CAC CAC CCT CGC ATC GAG CGA GCC AGC 4813
Leu Phe Trp Ser Asp Trp Gly His His Pro Arg Ile Glu Arg Ala Ser
6225 6230 6235
ATG GAC GGC AGC ATG CGC ACT GTC ATT GTC CAG GAC AAG ATC TTC TGG 4861
Met Asp Gly Ser Met Arg Thr Val Ile Val Gln Asp Lys Ile Phe Trp
6240 6245 6250 6255
CCC TGC GGC TTA ACT ATT GAC TAC CCC AAC AGA CTG CTC TAC TTC ATG 4909
Pro Cys Gly Leu Thr Ile Asp Tyr Pro Asn Arg Leu Leu Tyr Phe Met
CA 0220~648 l997-0~-20
WO 96/15801 PCTrUS95/15203
/~
6260 6265 6270
GAC TCC TAT CTT GAT TAC ATG GAC TTT TGT GAT TAT AAT GGA CAC CAT 4957
Asp Ser Tyr Leu Asp Tyr Met Asp Phe Cys Asp Tyr Asn Gly His His
6275 6280 6285
CGG AGA CAG GTG ATA GCC AGT GAT TTG ATT ATA CGG CAC CCC TAT GCC 5005
Arg Arg Gln Val Ile Ala Ser Asp Leu Ile Ile Arg His Pro Tyr Ala
6290 6295 6300
CTA ACT CTC TTT GAA GAC TCT GTG TAC TGG ACT GAC CGT GCT ACT CGT 5053
Leu Thr Leu Phe Glu Asp Ser Val Tyr Trp Thr Asp Arg Ala Thr Arg
6305 6310 6315
15 CGG GTT ATG CGA GCC AAC AAG TGG CAT GGA GGG AAC CAG TCA GTT GTA 5101
Arg Val Met Arg Ala Asn Lys Trp His Gly Gly Asn Gln Ser Val Val
6320 6325 6330 6335
ATG TAT AAT ATT CAA TGG CCC CTT GGG ATT GTT GCG GTT CAT CCT TCG 5149
20 Met Tyr Asn Ile Gln Trp Pro Leu Gly Ile Val Ala Val His Pro Ser
6340 6345 6350
AAA CAA CCA AAT TCC GTG AAT CCA TGT GCC TTT TCC CGC TGC AGC CAT 5197
Lys Gln Pro Asn Ser Val Asn Pro Cys Ala Phe Ser Arg Cys Ser His
6355 6360 6365
CTC TGC CTG CTT TCC TCA CAG GGG CCT CAT TTT TAC TCC TGT GTT TGT 5245
Leu Cys Leu Leu Ser Ser Gln Gly Pro His Phe Tyr Ser Cys Val Cys
6370 6375 6380
CCT TCA GGA TGG AGT CTG TCT CCT GAT CTC CTG AAT TGC TTG AGA GAT 5293
Pro Ser Gly Trp Ser Leu Ser Pro Asp Leu Leu Asn Cys Leu Arg Asp
6385 6390 6395
35 GAT CAA CCT TTC TTA ATA ACT GTA AGG CAA CAT ATA ATT TTT GGA ATC 5341
Asp Gln Pro Phe Leu Ile Thr Val Arg Gln His Ile Ile Phe Gly Ile
6400 6405 6410 6415
TCC CTT AAT CCT GAG GTG AAG AGC AAT GAT GCT ATG GTC CCC ATA GCA 5389
40 Ser Leu Asn Pro Glu Val Lys Ser Asn Asp Ala Met Val Pro Ile Ala
6420 6425 6430
GGG ATA CAG AAT GGT TTA GAT GTT GAA TTT GAT GAT GCT GAG CAA TAC 5437
Gly Ile Gln Asn Gly Leu Asp Val Glu Phe Asp Asp Ala Glu Gln Tyr
6435 6440 6445
ATC TAT TGG GTT GAA AAT CCA GGT GAA ATT CAC AGA GTG AAG ACA GAT 5485
Ile Tyr Trp Val Glu Asn Pro Gly Glu Ile His Arg Val Lys Thr Asp
6450 6455 6460
GGC ACC AAC AGG ACA GTA TTT GCT TCT ATA TCT ATG GTG GGG CCT TCT 5533
Gly Thr Asn Arg Thr Val Phe Ala Ser Ile Ser Met Val Gly Pro Ser
6465 6470 6475
55 ATG AAC CTG GCC TTA GAT TGG ATT TCA AGA AAC CTT TAT TCT ACC AAT 5581
Met Asn Leu Ala Leu Asp Trp Ile Ser Arg Asn Leu Tyr Ser Thr Asn
6480 6485 6490 6495
CCT AGA ACT CAG TCA ATC GAG GTT TTG ACA CTC CAC GGA GAT ATC AGA 5629
60 Pro Arg Thr Gln Ser Ile Glu Val Leu Thr Leu His Gly Asp Ile Arg
6500 6505 6510
TAC AGA AAA ACA TTG ATT GCC AAT GAT GGG ACA GCT CTT GGA GTT GGC 5677
Tyr Arg Lys Thr Leu Ile Ala Asn Asp Gly Thr Ala Leu Gly Val Gly
CA 0220~648 l997-0~-20
WO 96/15801 PCTrUS95/15203
l~3
6515 - 6S20 6525
TTT CCA ATT GGC ATA ACT GTT GAT CCT GCT CGT GGG AAG CTG TAC TGG 5725
" Phe Pro Ile Gly Ile Thr Val Asp Pro Ala Arg Gly Lys Leu Tyr Trp
6530 6535 6540
TCA GAC CAA GGA ACT GAC AGT GGG GTT CCT GCC AAG ATC GCC AGT GCT 5773
Ser Asp Gln Gly Thr Asp Ser Gly Val Pro Ala Lys Ile Ala Ser Ala
6545 6550 6555
AAC ATG GAT GGC ACA TCT GTG AAA ACT CTC TTT ACT GGG AAC CTC GAA 5821
Asn Met Asp Gly Thr Ser Val Lys Thr Leu Phe Thr Gly Asn Leu G1U
6560 6565 6570 6575
CAC CTG GAG TGT GTC ACT CTT GAC ATC GAA GAG CAG AAA CTC TAC TGG 5869
His Leu Glu Cys Val Thr Leu Asp Ile Glu Glu Gln Lys Leu Tyr Trp
6580 6585 6590
GCA GTC ACT GGA AGA GGA GTG ATT GAA AGA GGA AAC GTG GAT GGA ACA 5917
Ala Val Thr Gly Arg Gly Val Ile Glu Arg Gly Asn Val Asp Gly Thr
6595 6600 6605
GAT CGA ATG ATC CTG GTA CAC CAG CTT TCC CAC CCC TGG GGA ATT GCA 5965
Asp Arg Met Ile Leu Val His Gln Leu Ser HiS Pro Trp Gly Ile Ala
6610 6615 6620
GTC CAT GAT TCT TTC CTT TAT TAT ACT GAT GAA CAG TAT GAG GTC ATT 6013
Val His Asp Ser Phe Leu Tyr Tyr Thr Asp Glu Gln Tyr Glu Val Ile
6625 6630 6635
GAA AGA GTT GAT AAG GCC ACT GGG GCC AAC AAA ATA GTC TTG AGA GAT 6061
Glu Arg Val Asp Lys Ala Thr Gly Ala Asn Lys Ile Val Leu Arg Asp
6640 6645 6650 6655
AAT GTT CCA AAT CTG AGG GGT CTT CAA GTT TAT CAC AGA CGC AAT GCC 6109
Asn Val Pro Asn Leu Arg Gly Leu Gln Val Tyr His Arg Arg Asn Ala
6660 6665 6670
GCC GAA TCC TCA AAT GGC TGT AGC AAC AAC ATG AAT GCC TGT CAG CAG 6157
Ala Glu Ser Ser Asn Gly Cys Ser Asn Asn Met Asn Ala Cys Gln Gln
6675 6680 6685
ATT TGC CTG CCT GTA CCA GGA GGA TTG TTT TCC TGC GCC TGT GCC ACT 6205
Ile Cys Leu Pro Val Pro Gly Gly Leu Phe Ser Cys Ala Cys Ala Thr
6690 6695 6700
GGA TTT AAA CTC AAT CCT GAT AAT CGG TCC TGC TCT CCA TAT AAC TCT 6253
Gly Phe Lys Leu Asn Pro Asp Asn Arg Ser Cys Ser Pro Tyr Asn Ser
6705 6710 6715
TTC ATT GTT GTT TCA ATG CTG TCT GCA ATC AGA GGC TTT AGC TTG GAA 6301
Phe Ile Val Val Ser Met Leu Ser Ala Ile Arg Gly Phe Ser Leu Glu
6720 6725 6730 6735
r 55 TTG TCA GAT CAT TCA GAA ACC ATG GTG CCG GTG GCA GGC CAA GGA CGA 6349
Leu Ser Asp His Ser Glu Thr Met Val Pro Val Ala Gly Gln Gly Arg
6740 6745 6750
AAC GCA CTG CAT GTG GAT GTG GAT GTG TCC TCT GGC TTT ATT TAT TGG 6397
Asn Ala Leu His Val Asp Val Asp Val Ser Ser Gly Phe Ile Tyr Trp
6755 6760 6765
TGT GAT TTT AGC AGC TCA GTG GCA TCT GAT ~AT GCG ATC CGT AGA ATT 6445
Cys Asp Phe Ser Ser Ser Val Ala Ser Asp Asn Ala Ile Arg Arg Ile
-
CA 0220S648 1997-OS-20
W O 96/15801 PCTrUS95115203
6770 6775 6780
AAA CCA GAT GGA TCT TCT CTG ATG AAC ATT GTG ACA CAT GGA ATA GGA 6493
Lys Pro Asp Gly Ser Ser Leu Met Asn Ile Val Thr His Gly Ile Gly
6785 6790 6795
GAA AAT GGA GTC CGG GGT ATT GCA GTG GAT TGG GTA GCA GGA AAT CTT 6541 "
Glu Asn Gly Val Arg Gly Ile Ala Val Asp Trp Val Ala Gly Asn Leu
6800 6805 6810 6815
TAT TTC ACC AAT GCC TTT GTT TCT GAA ACA CTG ATA GAA GTT CTG CGG 6589
Tyr Phe Thr Asn Ala Phe Val Ser Glu Thr Leu Ile Glu Val Leu Arg
6820 6825 6830
ATC AAT ACT ACT TAC CGC CGT GTT CTT CTT AAA GTC ACA GTG GAC ATG 6637
Ile Asn Thr Thr Tyr Arg Arg Val Leu Leu Lys Val Thr Val Asp Met
6835 6840 6845
CCT AGG CAT ATT GTT GTA GAT CCC AAG AAC AGA TAC CTC TTC TGG GCT 6685
Pro Arg His Ile Val Val Asp Pro Lys Asn Arg Tyr Leu Phe Trp Ala
6850 6855 6860
GAC TAT GGG CAG AGA CCA AAG ATT GAG CGT TCT TTC CTT GAC TGT ACC 6733
Asp Tyr Gly Gln Arg Pro Lys Ile Glu Ary Ser Phe Leu Asp Cys Thr
6865 6870 6875
AAT CGA ACA GTG CTT GTG TCA GAG GGC ATT GTC ACA CCA CGG GGC TTG 6781
Asn Arg Thr Val Leu Val Ser Glu Gly Ile Val Thr Pro Arg Gly Leu
6880 6885 6890 6895
GCA GTG GAC CGA AGT GAT GGC TAC GTT TAT TGG GTT GAT GAT TCT TTA 6829
Ala Val Asp Arg Ser Asp Gly Tyr Val Tyr Trp Val Asp Asp Ser Leu
6900 6905 6910
3 5 GAT ATA ATT GCA AGG ATT CGT ATC AAT GGA GAG AAC TCT GAA GTG ATT 6877
Asp Ile Ile Ala Arg Ile Arg Ile Asn Gly Glu Asn Ser Glu Val Ile
6915 6920 6925
CGT TAT GGC AGT CGT TAC CCA ACT CCT TAT GGC ATC ACT GTT TTT GAA 6925
Arg Tyr Gly Ser Arg Tyr Pro Thr Pro Tyr Gly Ile Thr Val Phe Glu
6930 6935 6940
AAT TCT ATC ATA TGG GTA GAT AGG AAT TTG AAA AAG ATC TTC CAA GCC 6973
Asn Ser Ile Ile Trp Val Asp Arg Asn Leu Lys Lys Ile Phe Gln Ala
6945 6950 6955
AGC AAG GAA CCA GAG AAC ACA GAG CCA CCC ACA GTG ATA AGA GAC AAT 7021
Ser Lys Glu Pro Glu Asn Thr Glu Pro Pro Thr Val Ile Arg Asp Asn
6960 6965 6970 . 6975
ATC AAC TGG CTA AGA GAT GTG ACC ATC TTT GAC AAG CAA GTC CAG CCC 7069
Ile Asn Trp Leu Arg Asp Val Thr Ile Phe Asp Lys Gln Val Gln Pro
6980 6985 6990
5 5 CGG TCA CCA GCA GAG GTC AAC AAC AAC CCT TGC TTG GAA AAC AAT GGT 7117
Arg Ser Pro Ala Glu Val Asn Asn Asn Pro Cys Leu Glu Asn Asn Gly
6995 7000 7005
GGG TGC TCT CAT CTC TGC TTT GCT CTG CCT GGA TTG CAC ACC CCA AAA 7165
Gly Cys Ser His Leu Cys Phe Ala Leu Pro Gly Leu His Thr Pro Lys
7010 7015 . 7020
TGT GAC TGT GC. TTT GGG ACC CTG CAA AGT GAT GGC AAG AAT TGT GCC 7213
Cys Asp Cys Ala Phe Gly Thr Leu Gin Ser Asp Gly Lys Asn Cys Ala
CA 0220~648 1997-05-20
W O 96/15801 PCT~US9S11~203
7025 7030 7035
ATT TCA ACA GAA AAT TTC CTC ATC TTT GCC TTG TCT AAT TCC TTG AGA 7261
Ile Ser Thr Glu Asn Phe Leu Ile Phe Ala Leu Ser Asn Ser Leu Arg
7040 7045 7050 7055
.. .AGC TTA CAC TTG GAC CCT GAA AAC CAT AGC CCA CCT TTC CAA ACA ATA 7309
Ser Leu His Leu Asp Pro Glu Asn His Ser Pro Pro Phe Gln Thr Ile
7060 7065 7070
AAT GTG GAA AGA ACT GTC ATG TCT CTA GAC TAT GAC AGT GTA AGT GAT 7357
Asn Val Glu Arg Thr Val Met Ser Leu Asp Tyr Asp Ser Val Ser Asp
7075 7080 7085
AGA ATC .TAC TTC ACA CAA AAT TTA GCC TCT GGA GTT GGA CAG ATT TCC 7405
Arg Ile Tyr Phe Thr Gln Asn Leu Ala Ser Gly Val Gly Gln Ile Ser
7090 7095 7100
TAT GCC ACC CTG TCT TCA GGG ATC CAT ACT CCA ACT GTC ATT GCT TCA 7453
Tyr Ala Thr Leu Ser Ser Gly Ile His Thr Pro Thr Val Ile Ala Ser
7105 7110 7115
GGT ATA GGG ACT GCT GAT GGC ATT GCC TTT GAC TGG ATT ACT AGA AGA 7501
Gly Ile Gly Thr Ala Asp Gly Ile Ala Phe Asp Trp Ile Thr Arg Arg
7120 7125 7130 7135
ATT TAT TAC AGT GAC TAC CTC AAC CAG ATG ATT AAT TCC ATG GCT GAA 7549
Ile Tyr Tyr Ser Asp Tyr Leu Asn Gln Met Ile Asn Ser Met Ala Glu
7140 7145 7150
GAT GGG TCT AAC CGC ACT GTG ATA GCC CGC GTT CCA AAA CCA AGA GCA 7597
Asp Gly Ser Asn Arg Thr Val Ile Ala Arg Val Pro Lys Pro Arg Ala
7155 7160 7165
ATT GTG TTA GAT CCC TGC CAA GGG TAC CTG TAC TGG GCT GAC TGG GAT 7645
Ile Val Leu Asp Pro Cys Gln Gly Tyr Leu Tyr Trp Ala Asp Trp Asp
7170 7175 7180
ACA CAT GCC AAA ATC GAG AGA GCC ACA TTG GGA GGA AAC TTC CGC GTA 7693
Thr His Ala Lys Ile Glu Arg Ala Thr Leu Gly Gly Asn Phe Arg Val
7185 7190 7195
CCC ATT GTG AAC AGC AGT CTG GTC ATG CCC AGT GGG CTG ACT CTG GAC 7741
Pro Ile Val Asn Ser Ser Leu Val Met Pro Ser Gly Leu Thr Leu Asp
4S 7200 7205 7210 7215
TAT GAA GAG GAC CTT CTC TAC TGG GTG GAT GCT AGT CTG CAG AGG ATT 7789.
Tyr Glu Glu Asp Leu Leu Tyr Trp Val Asp Ala Ser Leu Gln Arg Ile
7220 7225 7230
GAA CGC AGC ACT CTG ACG GGC GTG GAT CGT GAA GTC ATT GTC AAT GCA 7837
Glu Arg Ser Thr Leu Thr Gly Val Asp Arg Glu Val Ile Val Asn Ala
7235 7240 7245
GCC GTT CAT GCT TTT GGC TTG ACT CTC TAT GGC CAG TAT ATT TAC TGG 7885
Ala Val His Ala Phe Gly Leu Thr Leu Tyr Gly Gln Tyr Ile Tyr Trp
7250 7255 7260
ACT GAC TTG TAC ACA CAA AGA ATT TAC CGA GCT AAC AAA TAT GAC GGG 7933
Thr Asp Leu Tyr Thr Gln Arg Ile Tyr Arg Ala Asn Lys Tyr Asp Gly
7265 7270 7275
TCA GGT CAG ATT GCA ATG ACC ArA AAT TTG CTC TCC CAG CCC AGG GGA 7981
Ser Gly Gln Ile Ala Met Thr Thr Asn Leu Leu Ser Gln Pro Arg Gly
CA 02205648 1997-OS-20
W O 96/158ol PCTrUS95/15203
7280 7285 7290 7295
ATC AAC ACT GTT GTG AAG AAC CAG AAA CAA CAG TGT AAC AAT CCT TGT 8029
Ile Asn Thr Val Val Lys Asn Gln Lys Gln Gln Cys Asn Asn Pro Cys
7300 7305 7310
GAA CAG TTT AAT GGG GGC TGC AGC CAT ATC TGT GCA CCA GGT CCA AAT 8077
Glu Gln Phe Asn Gly Gly Cys Ser His Ile Cys Ala Pro Gly Pro Asn
7315 7320 7325
GGT GCC GAG TGC CAG TGT CCA CAT GAG GGC AAC TGG TAT TTG GCC AAC 8125
Gly Ala Glu Cys Gln Cys Pro His Glu Gly Asn Trp Tyr Leu Ala Asn
7330 7335 7340
AAC AGG AAG CAC TGC ATT GTG GAC AAT GGT GAA CGA TGT GGT GCA TCT 8173
Asn Arg Lys His Cys Ile Val Asp Asn Gly Glu Arg Cys Gly Ala Ser
7345 7350 7355
TCC TTC ACC TGC TCC AAT GGG CGC TGC ATC TCG GAA GAG TGG AAG TGT 8221
Ser Phe Thr Cys Ser Asn Gly Arg Cys Ile Ser Glu Glu Trp Lys Cys
7360 7365 7370 7375
GAT AAT GAC AAC GAC TGT GGG GAT GGC AGT GAT GAG ATG GAA AGT GTC 8269
Asp Asn Asp Asn Asp Cys Gly Asp Gly Ser Asp Glu Met Glu Ser Val
7380 7385 7390
TGT GCA CTT CAC ACC TGC TCA CCG ACA GCC TTC ACC TGT GCC AAT GGG 8317
Cys Ala Leu His Thr Cys Ser Pro Thr Ala Phe Thr Cys Ala Asn Gly
7395 7400 7405
CGA TGT GTC CAA TAC TCT TAC CGC TGT GAT TAC TAC AAT GAC TGT GGT 8365
Arg Cys Val Gln Tyr Ser Tyr Arg Cys Asp Tyr Tyr Asn Asp Cys Gly
7410 7415 7420
3 5 GAT GGC AGT GAT GAG GCA GGG TGC CTG TTC AGG GAC TGC AAT GCC ACC 8413
Asp Gly Ser Asp Glu Ala Gly Cys Leu Phe Arg Asp Cys Asn Ala Thr
7425 7430 7435
ACG GAG TTT ATG TGC AAT AAC AGA AGG TGC ATA CCT CGT GAG TTT ATC 8461
Thr Glu Phe Met Cys Asn Asn Arg Arg Cys Ile Pro Arg Glu Phe Ile
7440 7445 7450 ` 7455
TGC AAT GGT GTA GAC AAC TGC CAT GAT AAT AAC ACT TCA GAT GAG AAA 8509
Cys Asn Gly Val Asp Asn Cys His Asp Asn Asn Thr Ser Asp Glu Lys
7460 7465 7470
AAT TGC CCT GAT CGC ACT TGC CAG TCT GGA TAC ACA AAA TGT CAT AAT 8557
Asn Cys Pro Asp Arg Thr Cys Gln Ser Gly Tyr Thr Lys Cys His Asn
7475 7480 7485
TCA AAT ATT TGT ATT CCT CGC GTT TAT TTG TGT GAC GGA GAC AAT GAC 8605
Ser Asn Ile Cys Ile Pro Arg Val Tyr Leu Cys Asp Gly Asp Asn Asp
7490 7495 7500
TGT GGA GAT AAC AGT GAT GAA AAC CCT ACT TAT TGC ACC ACT CAC ACG 8653
Cys Gly Asp Asn Ser Asp Glu Asn Pro Thr Tyr Cys Thr Thr His Thr
7505 7510 7515
TGC AGC AGC AGT GAG TTC CAA TGC GCA TCT GGG CGC TGT ATT CCT CAA 8701
Cys Ser Ser Ser Glu Phe Gln Cys Ala Ser Gly Arg Cys Ile Pro Gln
7520 7525 7530 7535
CAT TGG TAT TGT GAT CAA GAA ACA GAT TGT TTT GAT GCC TCT GAT GAA 8749
His Trp Tyr Cys Asp Gln Glu Thr Asp Cys Phe Asp Ala Ser Asp Glu
CA 0220~648 l997-0~-20
WO 96/15801 PCTtUS95115203
Ig~ .
7540 7545 7550
CCT GCC TCT TGT GGT CAC TCT GAG CGA ACA TGC CTA GCT GAT GAG TTC 8797
Pro Ala Ser Cys Gly His Ser Glu Arg Thr Cys Leu Ala Asp Glu Phe
7555 7560 7565
AAG TGT GAT GGT GGG AGG TGC ATC CCA AGC GAA TGG ATC TGT GAC GGT 8845
Lys Cys Asp Gly Gly Arg Cys Ile Pro Ser Glu Trp Ile Cys Asp Gly
7570 7575 7580
GAT AAT GAC TGT GGG GAT ATG AGT GAC GAG GAT AAA AGG CAC CAG TGT 8893.
Asp Asn Asp Cys Gly Asp Met Ser Asp Glu Asp Lys Arg His Gln Cys
7585 7590 7595
CAG AAT CAA AAC TGC TCG GAT TCC GAG TTT CTC TGT GTA AAT GAC AGA 8941
Gln Asn Gln Asn Cys Ser Asp Ser Glu Phe Leu Cys Val Asn Asp Arg
7600 7605 7610 7615
CCT CCG GAC AGG AGG TGC ATT CCC CAG TCT TGG GTC TGT GAT GGC GAT 8989
Pro Pro Asp Arg Arg Cys Ile Pro Gln Ser Trp Val Cys Asp Gly Asp
7620 7625 7630
GTG GAT TGT ACT GAC GGC TAC GAT GAG AAT CAG AAT TGC ACC AGG AGA 9037
Val Asp Cys Thr Asp Gly Tyr Asp Glu Asn Gln Asn Cys Thr Arg Arg
7635 7640 7645
ACT TGC TCT GAA AAT GAA TTC ACC TGT GGT TAC GGA CTG TGT ATC CCA 9085
Thr Cys Ser Glu Asn Glu Phe Thr Cys Gly Tyr Gly Leu Cys Ile Pro
7650 7655 7660
AAG ATA TTC AGG TGT GAC CGG CAC AAT GAC TGT GGT GAC TAT AGC GAC 9133
Lys Ile Phe Arg Cys Asp Arg His Asn Asp Cys Gly Asp Tyr Ser Asp
7665 7670 7675
3 5 GAG AGG GGC TGC TTA TAC CAG ACT TGC CAA CAG AAT CAG TTT ACC TGT 9181
Glu Arg Gly Cys Leu Tyr Gln Thr Cys Gln Gln Asn Gln Phe Thr Cys
7680 7685 7690 7695
CAG AAC GGG CGC TGC ATT AGT AAA ACC TTC GTC TGT GAT GAG GAT AAT 9229
Gln Asn Gly Arg Cys Ile Ser Lys Thr Phe Val Cys Asp Glu Asp Asn
7700 7705 7710
GAC TGT GGA GAC GGA TCT GAT GAG CTG ATG CAC CTG TGC CAC ACC CCA 9277
Asp Cys Gly Asp Gly Ser Asp Glu Leu Met His Leu Cys His Thr Pro
7715 7720 7725
GAA CCC ACG TGT CCA CCT CAC GAG TTC AAG TGT GAC AAT GGG CGC TGC 9325
Glu Pro Thr Cys Pro Pro His Glu Phe Lys Cys Asp Asn Gly Arg Cys
7730 7735 7740
ATC GAG ATG ATG AAA CTC TGC AAC CAC CTA GAT GAC TGT TTG GAC AAC 9373
Ile Glu Met Met Lys Leu Cys Asn His Leu Asp Asp Cys Leu Asp Asn
7745 7750 7755
AGC GAT GAG AAA GGC TGT GGC ATT AAT GAA TGC CAT GAC CCT TCA ATC 9421
Ser Asp Glu Lys Gly Cys Gly Ile Asn Glu Cys His Asp Pro Ser Ile
7760 7765 7770 7775
AGT GGC TGC GAT CAC AAC TGC ACA GAC ACC TTA ACC AGT TTC TAT TGT 946 g
Ser Gly Cys Asp His Asn Cys Thr Asp Thr Leu Thr Ser Phe Tyr Cys
7780 7785 7790
TCC TGT CGT CCT GGT TAC AAG CTC ATG TCT GAC AAG CGG ACT TGT GTT 9517
Ser Cys Arg Pro Gly Tyr Lys Leu Met Ser Asp Lys Arg Thr Cys Val
-
CA 0220~648 1997-05-20
W O96/1~801 PCTrUS95/15203
1~
7795 7800 7805
GAT ATT GAT GAA TGC ACA GAG ATG CCT TTT GTC TGT AGC CAG AAG TÇT 9565
Asp Ile Asp Glu Cys Thr Glu Met Pro Phe Val Cys Ser Gln Lys Cys
7810 7815 7820
GAG AAT GTA ATA GGC TCC TAC ATC TGT AAG TGT GCC CCA GGC TAC CTC 9613
Glu Asn Val Ile Gly Ser Tyr Ile Cys Lys Cys Ala Pro Gly Tyr Leu
7825 7830 7835
CGA GAA CCA GAT GGA AAG ACC TGC CGG CAA AAC AGT AAC ATC GAA CCC 9661
Arg Glu Pro Asp Gly Lys Thr Cys Arg Gln Asn Ser Asn Ile Glu Pro
7840 7845 7850 7855
TAT CTC ATT TTT AGC AAC CGT TAC TAT TTG AGA AAT TTA ACT ATA GAT 9709
Tyr Leu Ile Phe Ser Asn Arg Tyr Tyr Leu Arg Asn Leu Thr Ile Asp
7860 7865 7870
GGC TAT TTT TAC TCC CTC ATC TTG GAA GGA CTG GAC AAT GTT GTG GCA 9757
Gly Tyr Phe Tyr Ser Leu Ile Leu Glu Gly Leu Asp Asn Val Val Ala
7875 7880 7885
TTA GAT TTT GAC CGA GTA GAG AAG AGA TTG TAT TGG ATT GAT ACA CAG 9805
Leu Asp Phe Asp Arg Val Glu Lys Arg Leu Tyr Trp Ile Asp Thr Gln
7890 7895 7900
AGG CAA GTC ATT GAG AGA ATG TTT CTG AAT AAG ACA AAC AAG GAG ACA 9853
Arg Gln Val Ile Glu Arg Met Phe Leu Asn Lys Thr Asn Lys Glu Thr
7905 7910 7915
ATC ATA AAC CAC AGA CTA CCA GCT GCA GAA AGT CTG GCT GTA GAC TGG 9901
Ile Ile Asn His Arg Leu Pro Ala Ala Glu Ser Leu Ala Val Asp Trp
7920 7925 7930 7935
3 5 GTT TCC AGA AAG CTC TAC TGG TTG GAT GCC CGC CTG GAT GGC CTC TTT . 9949
Val Ser Arg Lys Leu Tyr Trp Leu Asp Ala Arg Leu Asp Gly Leu Phe
7940 7945 7950
GTC TCT GAC CTC AAT GGT GGA CAC CGC CGC ATG CTG GCC CAG CAC TGT 9997
Val Ser Asp Leu Asn Gly Gly His Arg Arg Met Leu Ala Gln His Cys
7955 7960 7965
GTÇ GAT GCC AAC AAC ACC TTC TGC TTT GAT AAT CCC AGA GGA CTT GCC 10045
Val Asp Ala Asn Asn Thr Phe Cys Phe Asp Asn Pro Arg Gly Leu Ala
7970 7975 7980
CTT CAC CCT CAA TAT GGG TAC CTC TAC TGG GCA GAC TGG GGT CAC CGC 10093
Leu His Pro Gln Tyr Gly Tyr Leu Tyr Trp Ala Asp Trp Gly His Arg
7985 7990 7995
GCA TAC ATT GGG AGA GTA GGC ATG ÇAT GGA ACC AAC AAG TCT GTG ATA 10141
Ala Tyr Ile Gly Arg Val Gly Met Asp Gly Thr Asn Lys Ser Val Ile A
8000 8005 8010 8015
5 5 ATC TCC ACC AAG TTA GAG TGG CCT AAT GGC ATC ACC ATT GAT TAC ACC 10189
Ile Ser Thr Lys Leu Glu Trp Pro Asn Gly Ile Thr Ile Asp Tyr Thr
8020 8025 8030
AAT GAT CTA CTC TAC TGG GCA GAT GCC CAC CTG GGT TAC ATA GAG TAC 10237
Asn Asp Leu Leu Tyr Trp Ala Asp Ala His Leu Gly Tyr Ile Glu Tyr
8035 8040 8045
TCT GAT TTG GAG GGC CAC CAT CGA CAC ACG GTG TAT GAT GGG GCA CTG 10285
Ser Asp Leu Glu Gly His His Arg His Thr Val Tyr Asp Gly Ala Leu
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
l~q
8050 8055 8060
CCT CAC CCT TTC GCT ATT ACC ATT TTT GAA GAC ACT ATT TAT TGG ACA 10333
Pro His Pro Phe Ala Ile Thr Ile Phe GlU Asp Thr Ile Tyr Trp Thr
8065 8070 8075
GAT TGG AAT ACA AGG ACA GTG GAA AAG GGA AAC AAA TAT GAT GGA TCA 10381
Asp Trp Asn Thr Arg Thr Val Glu Lys Gly Asn Lys Tyr Asp Gly Ser
8080 8085 8090 8095
AAT AGA CAG ACA CTG GTG AAC ACA ACA CAC AGA CCA TTT GAC ATC CAT 10429
Asn Arg Gln Thr Leu Val Asn Thr Thr His Arg Pro Phe Asp Ile His
8100 8105 8110
GTG TAC CAT CCA TAT AGG CAG CCC ATT GTG AGC AAT CCC TGT GGT ACC 10477
Val Tyr His Pro Tyr Arg Gln Pro Ile Val Ser Asn Pro Cys Gly Thr
8115 8120 8125
AAC AAT GGT GGC TGT TCT CAT CTC TGC CTC ATC AAG CCA GGA GGA AAA 10525
Asn Asn Gly Gly Cys Ser His Leu Cys Leu Ile Lys Pro Gly Gly Lys
8130 8135 8140
GGG TTC ACT TGC GAG TGT CCA GAT GAC TTC CGC ACC CTT CAA CTG AGT 10573
Gly Phe Thr Cys Glu Cys Pro Asp Asp Phe Arg Thr Leu Gln Leu Ser
8145 8150 8155
GGC AGC ACC TAC TGC ATG CCC ATG TGC TCC AGC ACC CAG TTC CTG TGC 10621
Gly Ser Thr Tyr Cys Met Pro Met Cys Ser Ser Thr Gln Phe Leu Cys
8160 8165 8170 8175
GCT AAC AAT GAA AAG TGC ATT CCT ATC TGG TGG AAA TGT GAT GGA CAG 10669
Ala Asn Asn Glu Lys Cys Ile Pro Ile Trp Trp Lys Cys Asp Gly Gln
8180 8185 8190
AAA GAC TGC TCA GAT GGC TCT GAT GAA CTG GCC CTT TGC CCG CAG CGC 10717
Lys Asp Cys Ser Asp Gly Ser Asp Glù Leu Ala Leu Cys Pro Gln Arg
8195 8200 8205
TTC TGC CGA CTG GGA CAG TTC CAG TGC AGT GAC GGC AAC TGC ACC AGC 10765
Phe Cys Arg Leu Gly Gln Phe Gln Cys Ser Asp Gly Asn Cys Thr Ser
8210 8215 8220
CCG CAG ACT TTA TGC AAT GCT CAC CAA AAT TGC CCT GAT GGG TCT GAT 10813
Pro Gln Thr Leu Cys Asn Ala His Gln Asn Cys Pro Asp Gly Ser Asp
8225 8230 8235
GAA GAC CGT CTT CTT TGT GAG AAT CAC CAC TGT GAC TCC AAT GAA TGG 10861
Glu Asp Arg Leu Leu Cys Glu Asn His His Cys Asp Ser Asn Glu Trp
8240 8245 8250 8255
CAG TGC GCC AAC AAA CGT TGC ATC CCA GAA TCC TGG CAG TGT GAC ACA 10909
Gln Cys Ala Asn Lys Arg Cys Ile Pro Glu Ser Trp Gln Cys Asp Thr
8260 8265 8270
,55 TTT AAC GAC TGT GAG GAT. AAC TCA GAT GAA GAC AGT TCC CAC TGT GCC 10957
Phe Asn Asp Cys Glu Asp Asn Ser Asp Glu Asp Ser Ser His Cys Ala
8275 8280 8285
AGC AGG ACC TGC CGG CCG GGC CAG TTT CGG TGT GCT AAT GGC CGC TGC 11005
Ser Arg Thr Cys Arg Pro Gly Gln Phe Arg Cys Ala Asn Gly Arg Cys
8290 8295 8300
ATC CCG CAG GCC TGG AA(~ TGT GAT GTG GAT ~AT GAT TC,T GGA GAC CAC 110~3
Ile Pro Gln Ala Trp Lys Cys Asp Val Asp Asn Asp Cys Gly Asp His
CA 0220~648 l997-0~-20
WO 96115801 PCT/US95115203
8305 8310 8315
TCG GAT GAG CCC ATT GAA GAA TGC ATG AGC TCT GCC CAT CTC TGT GAC 11101
Ser Asp Glu Pro Ile Glu Glu Cys Met Ser Ser Ala His Leu Cys Asp
8320 8325 8330 8335
AAC TTC ACA GAA TTC AGC TGC AAA ACA AAT TAC CGC TGC ATC CCA AAG 11149
Asn Phe Thr Glu Phe Ser Cys Lys Thr Asn Tyr Arg Cys Ile Pro Lys
8340 8345 . 8350
TGG GCC GTG TGC AAT GGT GTA GAT GAC TGC AGG GAC AAC AGT GAT GAG 111 g 7
Trp Ala Val Cys Asn Gly Val Asp Asp Cys Arg Asp Asn Ser Asp Glu
8355 8360 8365
CAA GGC TGT GAG GAG AGG ACA TGC CAT CCT GTG GGG GAT TTC CGC TGT 11245
Gln Gly Cys Glu Glu Arg Thr Cys His Pro Val Gly Asp Phe Arg Cys
8370 8375 8380
AAA AAT CAC CAC TGC ATC CCT CTT CGT TGG CAG TGT GAT GGG CAA AAT 11293
Lys Asn His His Cys Ile Pro Leu Arg Trp Gln Cys Asp Gly Gln Asn
8385 8390 8395
GAC TGT GGA GAT AAC TCA GAT GAG GAA AAC TGT GCT CCC CGG GAG TGC 11341
Asp Cys Gly Asp Asn Ser Asp Glu Glu Asn Cys Ala Pro Arg Glu Cys
8400 8405 8410 8415
ACA GAG AGC GAG TTT CGA TGT GTC AAT CAG CAG TGC ATT CCC TCG CGA 11389
Thr Glu Ser Glu Phe Arg Cys Val Asn Gln Gln Cys Ile Pro Ser Arg
8420 8425 8430
TGG ATC TGT GAC CAT TAC AAC GAC TGT GGG GAC AAC TCA GAT GAA CGG 11437
Trp Ile Cys Asp His Tyr Asn Asp Cys Gly Asp Asn Ser Asp Glu Arg
8435 8440 8g45
3 5 GAC TGT GAG ATG AGG ACC TGC CAT CCT GAA TAT TTT CAG TGT ACA AGT 11485
Asp Cys Glu Met Arg Thr Cys His Pro Glu Tyr Phe Gln Cys Thr Ser
8450 8455 8460
GGA CAT TGT GTA CAC AGT GAA CTG AAA TGC GAT GGA TCC GCT GAC TGT 11533
Gly His Cys Val His Ser Glu Leu Lys Cys Asp Gly Ser Ala Asp Cys
8465 8470 8475
TTG GAT GCG TCT GAT GAA GCT GAT TGT CCC ACA CGC TTT CCT GAT GGT 11581
Leu Asp Ala Ser Asp Glu Ala Asp Cys Pro Thr Arg Phe Pro Asp Gly
8480 8485 8490 8495
GCA TAC TGC CAG GCT ACT ATG TTC GAA TGC AAA AAC CAT GTT TGT ATC 11629
Ala Tyr Cys Gln Ala Thr Met Phe Glu Cys Lys Asn His Val Cys Ile
8500 8505 8510
CCG CCA TAT TGG AAA TGT GAT GGC GAT GAT GAC TGT GGC GAT GGT TCA 11677
Pro Pro Tyr Trp Lys Cys Asp Gly Asp Asp Asp Cys Gly Asp Gly Ser
8515 8520 8525
5 5 GAT GAA GAA CTT CAC CTG TGC TTG GAT GTT CCC TGT AAT TCA CCA AAC 11725
Asp Glu Glu Leu His Leu Cys Leu Asp Val Pro Cys Asn Ser Pro Asn
8530 8535 8540
CGT TTC CGG TGT GAC AAC AAT CGC TGC ATT TAT AGT CAT GAG GTG TGC 11773
Arg Phe Arg Cys Asp Asn Asn Arg Cys Ile Tyr Ser His Glu Val Cys
8545 8550 8555
AAT GGT GTG GAT GAC TGT GGA GAT GGA ACT GAT GAG ACA GAG GAG CAC 11821
Asn Gly Val Asp Asp Cys Gly Asp Gly Thr Asp Glu Thr Glu Glu His
CA 0220~648 l997-OS-20
W O 96/15801 PCTrUS95/15203
~4
8560 8565 8570 8575
TGT AGA AAA CCG ACC CCT AAA CCT TGT ACA GAA TAT GAA TAT AAG TGT 11869
Cys Arg Lys Pro Thr Pro Lys Pro Cys Thr Glu Tyr Glu Tyr Lys Cys
8580 8585 8590
GGC AAT GGG CAT TGC ATT CCA CAT GAC AAT GTG TGT GAT GAT GCC GAT 11917
Gly Asn Gly His Cys Ile Pro His Asp Asn Val Cys Asp Asp Ala Asp
8595 8600 8605
GAC TGT GGT GAC TGG TCC GAT GAA CTG GGT TGC AAT AAA GGA AAA GAA 119 65
Asp Cys Gly Asp Trp Ser Asp Glu Leu Gly Cys Asn Lys Gly Lys Glu
8610 8615 8620
AGA ACA TGT GCT GAA AAT ATA TGC GAG CAA AAT TGT ACC CAA TTA AAT 12013
Arg Thr Cys Ala Glu Asn Ile Cys Glu Gln Asn Cys Thr Gln Leu Asn
8625 8630 8635
GAA GGA GGA TTT ATC TGC TCC TGT ACA GCT GGG TTC GAA ACC AAT GTT 12061
Glu Gly Gly Phe Ile Cys Ser Cys Thr Ala Gly Phe Glu Thr Asn Val
8640 8645 8650 8655
TTT GAC AGA ACC TCC TGT CTA GAT ATC AAT GAA TGT GAA CAA TTT GGG 12109
Phe Asp Arg Thr Ser Cys Leu Asp Ile Asn Glu Cys Glu Gln Phe Gly
8660 8665 8670
ACT TGT CCC CAG CAC TGC AGA AAT ACC AAA GGA AGT TAT GAG TGT GTC 12157
Thr Cys Pro Gln His Cys Arg Asn Thr Lys Gly Ser Tyr Glu Cys Val
8675 8680 8685
TGT GCT GAT GGC TTC ACG TCT ATG AGT GAC CGC CCT GGA AAA CGA TGT 12205
Cys Ala Asp Gly Phe Thr Ser Met Ser Asp Arg Pro Gly Lys Arg Cys
8690 8695 8700
GCA GCT GAG GGT AGC TCT CCT TTG TTG CTA CTG CCT GAC AAT GTC CGA 12253
Ala Ala Glu Gly Ser Ser Pro Leu Leu Leu Leu Pro Asp Asn Val Arg
8705 8710 8715
ATT CGA AAA TAT AAT CTC TCA TCT GAG AGG TTC TCA GAG TAT CTT CAA 12301
Ile Arg Lys Tyr Asn Leu Ser Ser Glu Arg Phe Ser Glu Tyr Leu Gln
8720 8725 8730 8735
GAT GAG GAA TAT ATC CAA GCT GTT GAT TAT GAT TGG GAT CCC GAG GAC 1234g
Asp Glu Glu Tyr Ile Gln Ala Val Asp Tyr Asp Trp Asp Pro Glu Asp
8740 8745 8750
ATA GGC CTC AGT GTT GTG TAT TAC ACT GTG CGA GGG GAG GGC TCT AGG 12397
Ile Gly Leu Ser Val Val Tyr Tyr Thr Val Arg Gly Glu Gly Ser Arg
8755 8760 8765
" TTT GGT GCT ATC AAA CGT GCC TAC ATC CCC AAC TTT GAA TCC GGC CGC 12445
Phe Gly Ala Ile Lys Arg Ala Tyr Ile Pro Asn Phe Glu Ser Gly Arg
8770 8775 8780
f 55 AAT AAT CTT GTG CAG GAA GTT GAC CTG AAA CTG AAA TAC GTA ATG CAG 12493
Asn Asn Leu Val Gln Glu Val Asp Leu Lys Leu Lys Tyr Val Met Gln
8785 8790 8795
CCA GAT GGA ATA GCA GTG GAC TGG GTT GGA AGG CAT ATT TAC TGG TCA 12 541
Pro Asp Gly Ile Ala Val Asp Trp Val Gly Arg His Ile Tyr Trp Ser
8800 8805 8810 8815
GAT GTC AAG AAT AAA CGC ATT GAG &T& &CT AAA CTT GAT GGA AGG TAC 12589
Asp Val Lys Asn Lys Arg Ile Glu Val Ala Lys Leu Asp Gly Arg Tyr
CA 0220~648 l997-0~-20
W O96/15801 PCTrUS95/15203
/q~
8820 8825 8830
AGA AAG TGG CTG ATT TCC ACT GAC CTG GAC CAA CCA GCT GCT ATT GCT 12637
Arg Lys Trp Leu Ile Ser Thr Asp Leu Asp Gln Pro Ala Ala Ile Ala
8835 8840 8845
GTG AAT CCC AAA CTA GGG CTT ATG TTC TGG ACT GAC TGG GGA AAG GAA 12685
Val Asn Pro Lys Leu Gly Leu Met Phe Trp Thr Asp Trp Gly Lys Glu
8850 8855 8860
CCT AAA CTC GAG TCT GCC TGG ATG AAT GGA GAG GAC CGC AAC ATC CTG 12733
Pro Lys Leu Glu Ser Ala Trp Met Asn Gly Glu Asp Arg Asn Ile ~eu
8865 8870 8875
GTT TTC GAG GAC CTT GGT TGG CCA ACT GGC CTT TCT ATC GAT TAT TTG 12781
Val Phe Glu Asp Leu Gly Trp Pro Thr Gly Leu Ser Ile Asp Tyr Leu
8880 8885 8890 8895
AAC AAT GAC CGA ATC TAC TGG AGT GAC TTC AAG GAG GAC GTT ATT GAA 12829
Asn Asn Asp Arg Ile Tyr Trp Ser Asp Phe Lys Glu Asp Val Ile Glu
8900 8905 8910
ACC ATA AAA TAT GAT GGG ACT GAT AGG AGA GTC ATT GCA AAG GAA GCA 12877
Thr Ile Lys Tyr Asp Gly Thr Asp Arg Arg Val Ile Ala Lys Glu Ala
8915 8920 8925
ATG AAC CCT TAC AGC CTG GAC ATC TTT GAA GAC CAG TTA TAC TGG ATA 12925
Met Asn Pro Tyr Ser Leu Asp Ile Phe Glu Asp Gln Leu Tyr Trp Ile
8930 8935 8940
TCT AAG GAA AAG GGA GAA GTA TGG AAA CAA AAT AAA TTT GGG CAA GGA 12973
Ser Lys Glu Lys Gly Glu Val Trp Lys Gln Asn Lys Phe Gly Gln Gly
8945 8950 8955
AAG AAA GAG AAA ACG CTG GTA GTG AAC CCT TGG CTC ACT CAA GTT CGA 13021
Lys Lys Glu Lys Thr Leu Val Val Asn Pro Trp Leu Thr Gln Val Arg
8960 8965 8970 8975
ATC TTT CAT CAA CTC AGA TAC AAT AAG TCA GTG CCC AAC CTT TGC AAA 13069.
Ile Phe His Gln Leu Arg Tyr Asn Lys Ser Val Pro Asn Leu Cys Lys
8980 8985 8990
CAG ATC TGC AGC CAC CTC TGC CTT CTG AGA CCT GGA GGA TAC AGC TGT 13117
Gln Ile Cys Ser His Leu Cys Leu Leu Arg Pro Gly Gly Tyr Ser Cys
8995 9000 9005
GCC TGT CCC CAA GGC TCC AGC TTT ATA GAG GGG AGC ACC ACT GAG TGT 13165
Ala Cys Pro Gln Gly Ser Ser Phe Ile Glu Gly Ser Thr Thr Glu Cys
9010 9015 9020
GAT GCA GCC ATT GAA CTG CCT ATC AAC CTG CCC CCC CCA TGC AGG TGC 13213
Asp Ala Ala Ile Glu Leu Pro Ile Asn Leu Pro Pro Pro Cys Arg Cys
9025 9030 9035
ATG CAC GGA GGA AAT TGC TAT TTT GAT GAG ACT GAC CTC CCC AAA TGC 13261
~et His Gly Gly Asn Cys Tyr Phe Asp Glu Thr Asp Leu Pro Lys Cys
9040 9045 9050 9055
AAG TGT CCT AGC GGC TAC ACC GGA AAA TAT TGT GAA ATG GCG TTT TCA 13309
Lys Cys Pro Ser Gly Tyr Thr Gly Lys Tyr Cys Glu Met Ala Phe Ser
9060 9065 9070
AAA GGC ATC TCT CCA GGA ACA ACC GCA GTA GCT GTG CTG TTG ACA ATC 13357
Lys Gly Ile Ser Pro Gly Thr Tnr Ala Val Ala Val Leu Leu Thr Ile
CA 0220~648 l997-0~-20
W O96/15801 PCT~US95/15203
/~3
9075 9080 9085
CTC TTG ATC GTC GTA ATT GGA GCT CTG GCA ATT GCA GGA TTC TTC CAC 13405
Leu Leu Ile Val Val Ile Gly Ala Leu Ala Ile Ala Gly Phe Phe His
gogo 9095 9100
TAT AGA AGG ACC GGC TCC CTT TTG CCT GCT CTG CCC AAG CTG CCA AGC 13453
Tyr Arg Arg Thr Gly Ser Leu Leu Pro Ala Leu Pro Lys Leu Pro Ser
9105 9110 gll5
TTA AGC AGT CTC GTC AAG CCC TCT GAA AAT GGG AAT GGG GTG ACC TTC 13501
Leu Ser Ser Leu Val Lys Pro Ser Glu Asn Gly Asn Gly Val Thr Phe
9120 9125 9130 9135
AGA TCA GGG GCA GAT CTT AAC ATG GAT ATT GGA GTG TCT GGT TTT GGA 13549
Arg Ser Gly Ala Asp Leu Asn Met Asp Ile Gly Val Ser Gly Phe Gly
9140 9145 9150
CCT GAG ACT GCT ATT GAC AGG TCA ATG GCA ATG AGT GAA GAC TTT GTC 13597
Pro Glu Thr Ala Ile Asp Arg Ser Met Ala Met Ser Glu Asp Phe Val
9155 9160 9165
ATG GAA ATG GGG AAG CAG CCC ATA ATA TTT GAA AAC CCA ATG TAC TCA 13645
Met Glu Met Gly Lys Gln Pro Ile Ile Phe Glu Asn Pro Met Tyr Ser
9170 9175 9180
GCC AGA GAC AGT GCT GTC AAA GTG GTT CAG CCA ATC CAG GTG ACT GTA 13693
Ala Arg Asp Ser Ala Val Lys Val Val Gln Pro Ile Gln Val Thr Val
9185 9190 9195
TCT GAA AAT GTG GAT AAT AAG AAT TAT GGA AGT CCC ATA AAC CCT TCT 13741 .
Ser Glu Asn Val Asp Asn Lys Asn Tyr Gly Ser Pro Ile Asn Pro Ser
9200 9205 9210 9215
GAG ATA GTT CCA GAG ACA AAC CCA ACT TCA CCA GCT GCT GAT GGA ACT 13789
Glu Ile Val Pro Glu Thr Asn Pro Thr Ser Pro Ala Ala Asp Gly Thr
9220 9225 9230
CAG GTG ACA AAA TGG AAT CTC TTC AAA CGA AAA TCT AAA CAA ACT ACC 13837
Gln Val Thr Lys Trp Asn Leu Phe Lys Arg Lys Ser Lys Gln Thr Thr
9235 9240 9245
AAC TTT GAA AAT CCA ATC TAT GCA CAG ATG GAG AAC GAG CAA AAG GAA 13885
Asn Phe Glu Asn Pro Ile Tyr Ala Gln Met Glu Asn Glu Gln Lys Glu
9250 9255 9260
AGT GTT GCT GCG ACA CCA CCT CCA TCA CCT TCG CTC CCT GCT AAG CCT 13933
Ser Val Ala Ala Thr Pro Pro Pro Ser Pro Ser Leu Pro Ala Lys Pro
9265 9270 9275
AAG CCT CCT TCG AGA AGA GAC CCA ACT CCA ACC TAT TCT GCA ACA GAA 13981
Lys Pro Pro Ser Arg Arg Asp Pro Thr Pro Thr Tyr Ser Ala Thr Glu
9280 9285 9290 9295
GAC ACT TTT AAA GAC ACC GCA AAT CTT GTT AAA GAA GAC TCT GAA GTA 14029
Asp Thr Phe Lys Asp Thr Ala Asn Leu Val Lys Glu Asp Ser Glu Val
9300 9305 9310
TAG CTATACCAGC TA 14044
~2) INFORMATION FOR SEQ ID NO:90:
CA 0220~648 l997-0~-20
WO 96/15801 PCTIUS95/15203
~qs~
( i ) SEQUENCE CHARACTERISTICS:
( A ) LENGTH: 4656 amino ac ids
(B) TYPE: amino acid
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:90:
Met Asp Arg Gly Pro Ala Ala Val Ala Cys Thr Leu Leu Leu Ala Leu
Val Ala Cys Leu Ala Pro Ala Ser Gly Gln Glu Cys Asp Ser Ala His
20 25 30
Phe Arg Cys Gly Ser Gly His Cys Ile Pro Ala Asp Trp Arg Cys Asp
0 Gly Thr Lys Asp Cys Ser Asp Asp Ala Asp Glu Ile Gly Cys Ala Val
Val Thr Cys Gln Gln Gly Tyr Phe Lys Cys Gln Ser Glu Gly Gln Cys
65 70 75 80
Ile Pro Ser Ser Trp Val Cys Asp Gln Asp Gln Asp Cys Asp Asp Gly
85 90 95
Ser Asp Glu Arg Gln Asp Cys Ser Gln Ser Thr Cys Ser Ser His Gln
. 100 105 110
Ile Thr Cys Ser Asn Gly Gln Cys Ile Pro Ser Glu Tyr Arg Cys Asp
115 120 125
3 5 His Val Arg Asp Cys Pro Asp Gly Ala Asp Glu Asn Asp Cys Gln Tyr
130 135 140
Pro Thr Cys Glu Gln Leu Thr Cys Asp Asn Gly Ala Cys Tyr Asn Thr
145 150 155 160
Ser Gln Lys Cys Asp Trp Lys Val Asp Cys Arg Asp Ser Ser Asp Glu
165 170 175
Ile Asn Cys Thr Glu Ile Cys Leu His Asn Glu Phe Ser Cys Gly Asn
180 185 190
Gly Glu Cys Ile Pro Arg Ala Tyr Val Cys Asp His Asp Asn Asp Cys
195 200 205
Gln Asp Gly Ser Asp Glu His Ala Cys Asn Tyr Pro Thr Cys Gly Gly
210 215 220
Tyr Gln Phe Thr Cys Pro Ser Gly Arg Cys Ile Tyr Gln Asn Trp Val
225 230 235 240
Cys Asp Gly Glu Asp Asp Cys Lys Asp Asn Gly Asp Glu Asp Gly Cys
245 250 255
Glu Ser Gly Pro His Asp Val His Lys Cys Ser Pro Arg Glu Trp Ser
260 265 270
Cys Pro Glu Ser Gly Arg Cys Ile Ser Ile Tyr Lys Val Cys Asp Gly
275 280 285
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
5,
Ile Leu Asp Cys Pro Gly Arg Glu Asp Glu Asn Asn Thr Ser Thr Gly
290 295 300
Lys Tyr Cys Ser Met Thr Leu Cys Ser Ala Leu Asn Cys Gln Tyr Gln
305 310 315 320
Cys His Glu Thr Pro Tyr Gly Gly Ala Cys Phe Cys Pro Pro Gly Tyr
325 330 335
Ile Ile Asn His Asn Asp Ser Arg Thr Cys Val Glu Phe Asp Asp Cys
340 345 350
Gln Ile Trp Gly Ile Cys Asp Gln Lys Cys Glu Ser Arg Pro Gly Arg
355 360 365
His Leu Cys His Cys Glu Glu Gly Tyr Ile Leu Glu Arg Gly Gln Tyr
370 375 380
Cys Lys Ala Asn Asp Ser Phe Gly Glu Ala Ser Ile Ile Phe Ser Asn
385 390 3g5 400
Gly Arg Asp Leu Leu Ile Gly Asp Ile His Gly Arg Ser Phe Arg Ile
405 410 415
2 5 Leu Val Glu Ser Gln Asn Arg Gly Val Ala Val Gly Val Ala Phe His
420 425 430
Tyr His Leu Gln Arg Val Phe Trp Thr Asp Thr Val Gln Asn Lys Val
435 440 445
Phe Ser Val Asp Ile Asn Gly Leu Asn Ile Gln Glu Val Leu Asn Val
450 455 460
Ser Val Glu Thr Pro Glu Asn Leu Ala Val Asp Trp Val Asn Asn Lys
465 470 475 480
Ile Tyr Leu Val Glu Thr Lys Val Asn Arg Ile Asp Met Val Asn Leu
485 490 495
Asp Gly Ser Tyr Arg Val Thr Leu Ile Thr Glu Asn Leu Gly His Pro
500 505 510
Arg Gly Ile Ala Val Asp Pro Thr Val Gly Tyr Leu Phe Phe Ser Asp
515 520 525
Trp Glu Ser Leu Ser Gly Glu Pro Lys Leu Glu Arg Ala Phe Met Asp
530 535 540
Gly Ser Asn Arg Lys Asp Leu Val Lys Thr Lys Leu Gly Trp Pro Ala
545 550 555 560
Gly ~Tal Thr Leu Asp Met Ile Ser Lys Arg Val Tyr Trp Val Asp Ser
565 570 575
5 Arg Phe Asp Tyr Ile Glu Thr Val Thr Tyr Asp Gly Ile Gln Arg Lys
580 585 590
Thr Val Val His Gly Gly Ser Leu Ile Pro His Pro Phe Gly Val Ser
595 600 605
Leu Phe Glu Gly Gln Val Phe Phe Thr Asp Trp Thr Lys Met Ala Val
610 615 620
Leu Lys Ala Asn Lys Phe Thr Glu Thr Asn Pro Gln Val Tyr Tyr Gln
CA 0220S648 l997-0~-20
W O 96/15801 PCTrUS9~tlS203
I~G
625 630 635 640
Ala Ser Leu Arg Pro Tyr Gly Val Thr Val Tyr His Ser Leu Arg Gln
645 650 655
Pro Tyr Ala Thr Asn Pro Cys Lys Asp Asn Asn Gly Gly Cys Glu Gln
660 665 670
Val Cys Val Leu Ser His Arg Thr Asp Asn Asp Gly Leu Gly Phe Arg
0 675 680 685
Cys Lys Cys Thr Phe Gly Phe Gln Leu Asp Thr Asp Glu Arg His Cys
690 695 700
Ile Ala Val Gln Asn Phe Leu Ile Phe Ser Ser Gln Val Ala Ile Arg
705 710 715 720
Gly Ile Pro Phe Thr Leu Ser Thr Gln Glu Asp Val Met Val Pro Val
725 730 735
Ser Gly Asn Pro Ser Phe Phe Val Gly Ile Asp Phe Asp Ala Gln Asp
740 745 750
Ser Thr Ile Phe Phe Ser Asp Met Ser Lys His Met Ile Phe Lys Gln
755 760 765
Lys Ile Asp Gly Thr Gly Arg Glu Ile Leu Ala Ala Asn Arg Val Glu
770 775 780
Asn Val Glu Ser Leu Ala Phe Asp Trp Ile Ser Lys Asn Leu Tyr Trp
785 790 795 800
Thr Asp Ser His Tyr Lys Ser Ile Ser Val Met Arg Leu Ala Asp Lys
805 810 815
Thr Arg Arg Thr Val Val Gln Tyr Leu Asn Asn Pro Arg Ser Val Val
820 825 830
Val His Pro Phe Ala Gly Tyr Leu Phe Phe Thr Asp Trp Phe Arg Pro
835 840 845
Ala Lys Ile Met Arg Ala Trp Ser Asp Gly Ser His Leu Leu Pro Val
850 855 860
Ile Asn Thr Thr Leu Gly Trp Pro Asn Gly Leu Ala Ile Asp Trp Ala
865 870 875 880
Ala Ser Arg Leu Tyr Trp Val Asp Ala Tyr Phe Asp Lys Ile Glu His
885 890 895
Ser Thr Phe Asp Gly Leu Asp Arg Arg Arg Leu Gly His Ile Glu Gln
900 905 910
Met Thr His Pro Phe Gly Leu Ala Ile Phe Gly Glu His Leu Phe Phe
915 , 920 925
Thr Asp Trp Arg Leu Gly Ala Ile Ile Arg Val Arg Lys Ala Asp Gly
930 935 940
Gly Glu Met Thr Val Ile Arg Ser Gly Ile Ala Tyr Ile Leu His Leu
945 950 955 960
Lys Ser Tyr Asp Val Asn Ile Gln Thr Gly Ser Asn Ala Cys Asn Gln
965 970 975
CA 0220~648 l997-0~-20
WO 96/15801 PCTIUS95/15203
Pro Thr His Pro Asn Gly Asp Cys Ser~is Phe Cys Phe Pro Val Pro
980 985 990
Asn Phe Gln Arg Val Cys Gly Cys Pro Tyr Gly Met Arg Leu Ala Ser
995 1000 1005
Asn His Leu Thr Cys Glu Gly Asp Pro Thr Asn Glu Pro Pro Thr Glu
1010 1015 1020
Gln Cys Gly Leu Phe Ser Phe Pro Cys Lys Asn Gly Arg Cys Val Pro
1025 1030 1035 1040
Asn Tyr Tyr Leu Cys Asp Gly Val Asp Asp Cys His Asp Asn Ser Asp
10a~5 1050 1055
Glu Gln Leu Cys Gly Thr Leu Asn Asn Thr Cys Ser Ser Ser Ala Phe
1060 1065 1070
20 Thr Cys Gly His Gly Glu Cys Ile Pro Ala His Trp Arg Cys Asp Lys
1075 1080 1085
Arg Asn Asp Cys Val Asp Gly Ser Asp Glu His Asn Cys Pro Thr His
lOgO 1095 1100
Ala Pro Ala Ser Cys Leu Asp Thr Gln Tyr Thr Cys Asp Asn His Gln
1105 1110 1115 1120
Cys Ile Ser Lys Asn Trp Val Cys Asp Thr Asp Asn Asp Cys Gly Asp
1125 1130 1135
Gly Ser Asp Glu Lys Asn Cys Asn Ser Thr Glu Thr Cys Gln Pro Ser
1140 1145 1150
3 5 Gln Phe Asn Cys Pro Asn His Arg Cys Ile Asp Leu Ser Phe Val Cys
1155 1160 1165
Asp Gly Asp Lys Asp Cys Val Asp Gly Ser Asp Glu Val Gly Cys Val
1170 1175 1180
Leu Asn Cys Thr Ala Ser Gln Phe Lys Cys Ala Ser Gly Asp Lys Cys
1185 1190 1195 1200
Ile Gly Val Thr Asn Arg Cys Asp Gly Val Phe Asp Cys Ser Asp Asn
1205 1210 1215
Ser Asp Glu Ala Gly Cys Pro Thr Arg Pro Pro Gly Met Cys His Ser
1220 1225 1230
Asp Glu Phe Gln Cys Gln Glu Asp Gly Ile Cys Ile Pro Asn Phe Trp
1235 1240 1245
Glu Cys Asp Gly His Pro Asp Cys Leu Tyr Gly Ser Asp Glu His Asn
1250 1255 1260
Ala Cys Val Pro Lys Thr Cys Pro Ser Ser Tyr Phe His Cys Asp Asn
1265 1270 1275 1280
Gly Asn Cys Ile His Arg Ala Trp Leu Cys Asp Arg Asp Asn Asp Cys
1285 1290 1295
Gly Asp Met Ser Asp Glu Lys Asp Cys Pro Thr Gln Pro Phe Arg Cys
1300 1305 1310
CA 02205648 1997-OS-20
W 096/15801 PCTrUS9S/15203
/~
Pro Ser Trp Gln Trp Gln Cys Leu Gly His Asn Ile Cys Val Asn Leu
1315 1320 1325
Ser Val Val Cys Asp Gly Ile Phe Asp Cys Pro Asn Gly Thr Asp Glu
1330 1335 1340
Ser Pro Leu Cys Asn Gly Asn Ser Cys Ser Asp Phe Asn Gly Gly Cys
1345 1350 1355 1360
0 Thr His Glu Cys Val Gln Glu Pro Phe Gly Ala Lys Cys Leu Cys Pro
1365 1370 1375
Leu Gly Phe Leu Leu Ala Asn Asp Ser Lys Thr Cys Glu Asp Ile Asp
1380 1385 1390
Glu Cys Asp Ile Leu Gly Ser Cys Ser Gln His Cys Tyr Asn Met Arg
1395 1400 14Q5
Gly Ser Phe Arg Cys Ser Cys Asp Thr Gly Tyr Met Leu Glu Ser Asp
1410 1415 1420
Gly Arg Thr Cys Lys Val Thr Ala Ser Glu Ser Leu Leu Leu Leu Val
1425 1430 1435 1440
Ala Ser Gln Asn Lys Ile Ile Ala Asp Ser Val Thr Ser Gln Val His
1445 1450 1455
Asn Ile Tyr Ser Leu Val Glu Asn Gly Ser Tyr Ile Val Ala Val Asp
1460 1465 1470
Phe Asp Ser Ile Ser Gly Arg Ile Phe Trp Ser Asp Ala Thr Gln Gly
1475 1480 1485
Lys Thr Trp Ser Ala Phe Gln Asn Gly Thr Asp Arg Arg Val Val Phe
1490 1495 1500
Asp Ser Ser Ile Ile Leu Thr Glu Thr Ile Ala Ile Asp Trp Val G~y
lS05 1510 1515 1520
Arg Asn Leu Tyr Trp Thr Asp Tyr Ala Leu Glu Thr Ile Glu Val Ser
1525 1530 1535
Lys Ile Asp Gly Ser His Arg Thr Val Leu Ile Ser Lys Asn Leu Thr
1540 1545 1550
Asn Pro Arg Gly Leu Ala Leu Asp Pro Arg Met Asn Glu His Leu Leu
1555 1560 1565
Phe Trp Ser Asp Trp Gly His His Pro Arg Ile Glu Arg Ala Ser Met
1570 1575 1580
Asp Gly Ser Met Arg Thr Val Ile Val Gln Asp l.ys Ile Phe Trp Pro
1585 1590 1595 1600
Cys Gly Leu Thr Ile Asp Tyr Pro Asn Arg Leu Leu Tyr Phe Met Asp
1605 1610 1615
Ser Tyr Leu Asp Tyr Met Asp Phe Cys Asp Tyr Asn Gly His His Arg
1620 1625 1630
Arg Gln Val Ile Ala Ser Asp Leu Ile Ile Arg His Pro Tyr Ala Leu
- 1635 1640 1645
Thr Leu Phe Glu Asp Ser Val Tyr Trp Thr Asp Arg Ala Thr Arg Arg
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US9S/lS203
1650 1655 1660
Val Met Arg Ala Asn Lys Trp His Gly Gly Asn Gln Ser Val Val Met
1665 1670 1675 1680
~- Tyr Asn Ile Gln Trp Pro Leu Gly Ile Val Ala Val His Pro Ser Lys
1685 1690 169S
Gln Pro Asn Ser Val Asn Pro Cys Ala Phe Ser Arg Cys Ser His Leu
0 1700 1705 1710
Cys Leu Leu Ser Ser Gln Gly Pro His Phe Tyr Ser Cys Val Cys Pro
1715 1720 1725
15 Ser Gly Trp Ser Leu Ser Pro Asp Leu Leu Asn Cys Leu Arg Asp Asp
1730 1735 1740
Gln Pro Phe Leu Ile Thr Val Arg Gln His Ile Ile Phe Gly Ile Ser
1745 1750 1755 1760
Leu Asn Pro Glu Val Lys Ser Asn Asp Ala Met Val Pro Ile Ala Gly
1765 1770 1775
Ile Gln Asn Gly Leu Asp Val Glu Phe Asp Asp Ala Glu Gln Tyr Ile
1780 1785 1790
Tyr Trp Val Glu Asn Pro Gly Glu Ile His Arg Val Lys Thr Asp Gly
1795 1800 1805
3 0 Thr Asn Arg Thr Val Phe Ala Ser Ile Ser Met Val Gly Pro Ser Met
1810 1815 1820
Asn Leu Ala Leu Asp Trp Ile Ser Arg Asn Leu Tyr Ser Thr Asn Pro
1825 1830 1835 1840
Arg Thr Gln Ser Ile Glu Val Leu Thr Leu His Gly Asp Ile Arg Tyr
184S 1850 18S5
Arg Lys Thr Leu Ile Ala Asn Asp Gly Thr Ala Leu Gly Val Gly Phe
1860 1865 1870
Pro Ile Gly Ile Thr Val Asp Pro Ala Arg Gly Lys Leu Tyr Trp Ser
1875 1880 1885
45 Asp Gln Gly Thr Asp Ser Gly Val Pro Ala Lys Ile Ala Ser Ala Asn
1890 1895 1900
Met Asp Gly Thr Ser Val Lys Thr Leu Phe Thr Gly Asn Leu Glu His
1905 1910 1915 1920
Leu Glu Cys Val Thr Leu Asp Ile Glu Glu Gln Lys Leu Tyr Trp Ala
1925 1930 1935
Val Thr Gly Arg Gly Val Ile Glu Arg Gly Asn Val Asp Gly Thr Asp
1940 1945 1950
Arg Met Ile Leu Val His Gln Leu Ser His Pro Trp Gly Ile Ala Val
1955 1960 1965
60 His Asp Ser Phe ~eu Tyr Tyr Thr Asp Glu Gln Tyr Glu Val Ile Glu
1970 1975 198Q
Arg Val Asp Lys Ala Thr Gly Ala Asn Lys Ile Val Leu Arg Asp Asn
1985 1990 1995 2000
.
CA b2205648 1997-OS-20
W 096/15801 PCT~US95115203
~ G6
Val Pro Asn Leu Arg Gly Leu Gln Val Tyr His Arg Arg Asn Ala Ala
2005 2010 2015
5 Glu Ser Ser Asn Gly Cys Ser Asn Asn ~qet Asn Ala Cys Gln Gln Ile
2020 2025 2030
Cys ~eu Pro Val Pro Gly Gly Leu Phe Ser Cys Ala Cys Ala Thr Gly
2035 2040 2045
10 '
Phe Lys Leu Asn Pro Asp Asn Arg Ser Cys Ser Pro Tyr Asn Ser Phe
2050 2055 2060
Ile Val Val Ser Met Leu Ser Ala Ile Arg Gly Phe Ser Leu Glu Leu
2065 2070 2075 2080
Ser Asp His Ser Glu Thr Met Val Pro Val Ala Gly Gln Gly Arg Asn
2085 2090 2095
Ala Leu His Val Asp Val Asp Val Ser Ser Gly Phe Ile Tyr Trp Cys
2100 2105 2110
Asp Phe Ser Ser Ser Val Ala Ser Asp Asn Ala Ile Arg Arg Ile Lys
2115 2120 2125
Pro Asp Gly Ser Ser Leu Met Asn Ile Val Thr His Gly Ile Gly Glu
2130 2135 2140
Asn Gly Val Arg Gly Ile Ala Val Asp Trp Val Ala Gly Asn Leu Tyr
2145 2150 2155 2160
Phe Thr Asn Ala Phe Val Ser Glu Thr Leu Ile Glu Val Leu Arg Ile
2165 2170 2175
3 5 Asn Thr Thr Tyr Arg Arg Val Leu Leu Lys Val Thr Val Asp Met Pro
2180 2185 2190
Arg His Ile Val Val Asp Pro Lys Asn Arg Tyr Leu Phe Trp Ala Asp
2195 2200 2205
Tyr Gly Gln Arg Pro Lys Ile Glu Arg Ser Phe Leu Asp Cys Thr Asn
2210 2215 2220
Arg Thr Val Leu Val Ser Glu Gly Ile Val Thr Pro Arg Gly Leu Ala
2225 2230 2235 2240
Val Asp Arg Ser Asp Gly Tyr Val Tyr Trp Val Asp Asp Ser Leu Asp
2245 2250 2255
Ile Ile Ala Arg Ile Arg Ile Asn Gly Glu Asn Ser Glu Val Ile Arg
2260 2265 2270
Tyr Gly Ser Arg Tyr Pro Thr Pro Tyr Gly Ile Thr Val Phe Glu Asn
2275 2280 ~ 2285
Ser Ile Ile Trp Val Asp Arg Asn Leu Lys Lys Ile Phe Gln Ala Ser
2290 2295 2300
Lys Glu Pro Glu Asn Thr Glu Pro Pro Thr Val Ile Arg Asp Asn Ile
2305 2310 2315 2320
Asn Trp Leu Arg Asp Val Thr Ile Phe Asp Lys Gln Val Gln Pro Arg
2325 2330 2335
CA 0220~648 1997-05-20
W O96/15801 PCTrUS95/15203
Ser Pro Ala Glu Val Asn Asn Asn Pro Cys Leu Glu Asn Asn Gly Gly
2340 2345 2350
Cys Ser His Leu Cys Phe Ala Leu Pro Gly Leu His Thr Pro Lys Cys
2355 2360 2365
Asp Cys Ala Phe Gly Thr Leu Gln Ser Asp Gly Lys Asn Cys Ala Ile
2370 2375 2380
0 Ser Thr Glu Asn Phe Leu Ile Phe Ala Leu Ser Asn Ser ~eu Arg Ser
2385 2390 2395 2400
Leu His Leu Asp Pro Glu Asn His Ser Pro Pro Phe Gln Thr Ile Asn
2405 2410 2415
Val Glu Arg Thr Val Met Ser Leu Asp Tyr Asp Ser Val Ser Asp Arg
2420 2425 2430
Ile Tyr Phe Thr Gln Asn Leu Ala Ser Gly Val Gly Gln Ile Ser Tyr
2435 2440 2445
Ala Thr Leu Ser Ser Gly Ile His Thr Pro Thr Val Ile Ala Ser Gly
2450 2455 2460
Ile Gly Thr Ala Asp Gly Ile Ala Phe Asp Trp Ile Thr Arg Arg Ile
2465 2470 2475 2480
Tyr Tyr Ser Asp Tyr Leu Asn Gln Met Ile Asn Ser Met Ala Glu Asp
2485 2490 2495
Gly Ser Asn Arg Thr Val Ile Ala Arç7 Val Pro Lys Pro Arg Ala Ile
2500 2505 2510
Val Leu Asp Pro Cys Gln Gly Tyr Leu Tyr Trp Ala Asp Trp Asp Thr
2515 2520 2525
His Ala Lys Ile Glu Arg Ala Thr Leu Gly Gly Asn Phe Arg Val Pro
2530 2535 2540
Ile Val Asn Ser Ser Leu Val Met Pro Ser Gly Leu Thr Leu Asp Tyr
2545 2550 2555 2560
Glu Glu Asp Leu Leu Tyr Trp Val Asp Ala Ser Leu Gln Arg I le Glu
2565 2570 2575
Arg Ser Thr Leu Thr Gly Val Asp Arg Glu Val Ile Val Asn Ala Ala
2580 2585 2590
Val His Ala Phe Gly Leu Thr Leu Tyr Gly Gln Tyr Ile Tyr Trp Thr
2595 2600 2605
Asp Leu Tyr Thr Gln Arg Ile Tyr Arg Ala Asn Lys Tyr Asp Gly Ser
2610 2615 2620
55 Gly Gln Ile Ala Met Thr Thr Asn Leu Leu Ser Gln Pro Arg Gly Ile
2625 2630 2635 2640
Asn Thr Val Val Lys Asn Gln Lys Gln Gln Cys Asn Asn Pro Cys Glu
2645 2650 2655
Gln Phe Asn Gly Gly Cys Ser His Ile Cys Ala Pro Gly Pro Asn Gly
2660 2665 2670
Ala Glu Cys Gln Cys Pro His Glu Gly Asn Trp Tyr Leu Ala Asn Asn
CA 0220~648 l997-0~-20
WO 96/15801 PCTIUS95/15203
~ Z
2675 2680 2685
Arg Lys His Cys Ile Val Asp Asn Gly Glu Arg Cys Gly Ala Ser Ser
2690 2695 2700
Phe Thr Cys Ser Asn Gly Arg Cys Ile Ser Glu Glu Trp Lys Cys Asp
2705 2710 2715 2720 ~,
Asn Asp Asn Asp Cys Gly Asp Gly Ser Asp Glu Met Glu Ser Val Cys
0 2725 2730 2735
,
Ala ~eu His Thr Cys Ser Pro Thr Ala Phe Thr Cys Ala Asn Gly Arg
2740 2745 2750 .
Cys Val Gln Tyr Ser Tyr Arg Cys Asp Tyr Tyr Asn Asp Cys Gly Asp
2755 2760 2765
Gly Ser Asp Glu Ala Gly Cys Leu Phe Arg Asp Cys Asn Ala Thr Thr
2770 2775 2780
Glu Phe Met Cys Asn Asn Arg Arg Cys Ile Pro Arg Glu Phe Ile Cys
2785 2790 2795 2800
Asn Gly Val Asp Asn Cys His Asp Asn Asn Thr Ser Asp Glu Lys Asn
2805 2810 2815
Cys Pro Asp Arg Thr Cys Gln Ser Gly Tyr Thr Lys Cys His Asn Ser
2820 2825 2830
Asn Ile Cys Ile Pro Arg Val Tyr I.eu Cys Asp Gly Asp Asn Asp Cys
2835 2840 2845
Gly Asp Asn Ser Asp Glu Asn Pro Thr Tyr Cys Thr Thr His Thr Cys
2850 2855 2860
Ser Ser Ser Glu Phe Gln Cys Ala Ser Gly Arg Cys Ile Pro Gln His
2865 2870 2875 2880
Trp Tyr Cys Asp Gln Glu Thr Asp Cys Phe Asp Ala Ser Asp Glu Pro
2885 2890 2895
Ala Ser Cys Gly His Ser Glu Arg Thr Cys Leu Ala Asp Glu Phe Lys
2900 2905 2910
Cys Asp Gly Gly Arg Cys Ile Pro Ser Glu Trp Ile Cys Asp Gly Asp
2915 2920 2925
Asn Asp Cys Gly Asp Met Ser Asp Glu Asp Lys Arg His Gln Cys Gln
2930 2935 29~0
Asn Gln Asn Cys Ser Asp Ser Glu Phe Leu Cys Val Asn Asp Arg Pro
2945 2950 2955 2960 A
Pro Asp Arg Arg Cys Ile Pro Gln Ser Trp Val Cys Asp Gly Asp Val
2965 2970 2975
Asp Cys Thr Asp Gly Tyr Asp Glu Asn Gln Asn Cys Thr Arg Arg Thr
2980 2985 2990
60 Cys Ser Glu Asn Glu Phe Thr Cys Gly Tyr Gly Leu Cys Ile Pro Lys
2995 3000 3005
Ile Phe Arg Cys Asp Arg His Asn Asp Cys Gly Asp Tyr Ser Asp Glu
3010 3015 3020
CA 0220~648 l997-0~-20
WO 9~/15801 PCTIUS9~115203
~53
Arg Gly Cys Leu Tyr Gln Thr Cys Gln Gln Asn Gln Phe Thr Cys Gln
3025 3030 3035 3040
Asn Gly Arg Cys Ile Ser Lys Thr Phe Val Cys Asp Glu Asp Asn Asp
r 3045 3050 3055
Cys Gly Asp Gly Ser Asp Glu Leu Met His Leu Cys His Thr Pro Glu
3060 3065 3070
.10
Pro Thr Cys Pro Pro His Glu Phe Lys Cys Asp Asn Gly Arg Cys Ile
3075 3080 3085
Glu Met Met Lys Leu Cys Asn His Leu Asp Asp Cys Leu Asp Asn Ser
3090 3095 3100
Asp Glu Lys Gly Cys Gly Ile Asn Glu Cys His Asp Pro Ser Ile Ser
3105 3110 3115 3120
2 0 Gly Cys Asp His Asn Cys Thr Asp Thr Leu Thr Ser Phe Tyr Cys Ser
3125 3130 3135
Cys Arg Pro Gly Tyr Lys Leu Met Ser Asp Lys Arg Thr Cys Val Asp
3140 3145 3150
Ile Asp Glu Cys Thr Glu Met Pro Phe Val Cys Ser Gln Lys Cys Glu
3155 3160 3165
Asn Val Ile Gly Ser Tyr Ile Cys Lys Cys Ala Pro Gly Tyr Leu Arg
3170 3175 3180
Glu Pro Asp Gly Lys Thr Cys Arg Gln Asn Ser Asn Ile Glu Pro Tyr
3185 3190 3195 3200
3 5 Leu Ile Phe Ser Asn Arg Tyr Tyr Leu Arg Asn Leu Thr Ile Asp Gly
3205 3210 3215
Tyr Phe Tyr Ser Leu Ile Leu Glu Gly Leu Asp Asn Val Val Ala Leu
3220 3225 3230
Asp Phe Asp Arg Val Glu Lys Arg Leu Tyr Trp Ile Asp Thr Gln Arg
3235 3240 3245
Gln Val Ile Glu Arg Met Phe Leu Asn Lys Thr Asn Lys Glu Thr Ile
3250 3255 3260
Ile Asn His Arg Leu Pro Ala Ala Glu Ser Leu Ala Val Asp Trp Val
3265 3270 3275 3280
Ser Arg Lys Leu Tyr Trp Leu Asp Ala Arg Leu Asp Gly Leu Phe Val
3285 3290 3295
Ser Asp Leu Asn Gly Gly His Arg Arg Met Leu Ala Gln His Cys Val
3300 3305 3310
Asp Ala Asn Asn Thr Phe Cys Phe Asp Asn Pro Arg Gly Leu Ala Leu
3315 3320 3325
His Pro Gln Tyr Gly Tyr Leu Tyr Trp Ala Asp Trp Gly His Arg Ala
3330 3335 334G
Tyr Ile Gly Arg Val Gly Met Asp Gly Thr Asn Lys Ser Val Ile Ile
3345 335C 3355 3360
CA 02205648 1997-0~-20
W O96/15801 PCT~US95115203
,~0~
Ser Thr Lys Leu Glu Trp Pro Asn Gly Ile Thr Ile Asp Tyr Thr Asn
3365 3370 3375
Asp Leu Leu Tyr Trp Ala Asp Ala His Leu Gly Tyr Ile Glu Tyr Ser
3380 3385 3390
Asp Leu Glu Gly His His Arg His Thr Val Tyr Asp Gly Ala Leu Pro
3395 3400 3405
0 His Pro Phe Ala Ile Thr Ile Phe Glu Asp Thr Ile Tyr Trp Thr Asp
3410 3415 3420
Trp Asn Thr Arg Thr Val Glu Lys Gly Asn Lys Tyr Asp Gly Ser Asn
3425 3430 3435 3440
Arg Gln Thr Leu Val Asn Thr Thr His Arg Pro Phe Asp Ile His Val
3445 3450 3455
Tyr His Pro Tyr Arg Gln Pro Ile Val Ser Asn Pro Cys Gly Thr Asn
3460 3465 3470
Asn Gly Gly Cys Ser His Leu Cys Leu Ile Lys Pro Gly Gly ~ys Gly
3475 3480 3485
Phe Thr Cys Glu Cys Pro Asp Asp Phe Arg Thr Leu Gln Leu Ser Gly
3490 3495 3500
Ser Thr Tyr Cys Met Pro Met Cys Ser Ser Thr Gln Phe Leu Cys Ala
3505 3510 3515 3520
Asn Asn Glu Lys Cys Ile Pro Ile Trp Trp Lys Cys Asp Gly Gln Lys
3525 3530 3535
Asp Cys Ser Asp Gly Ser Asp Glu Leu Ala Leu Cys Pro Gln Arg Phe
3540 3545 3550
Cys Arg Leu Gly Gln Phe Gln Cys Ser Asp Gly Asn Cys Thr Ser Pro
3555 3560 3565
Gln Thr Leu Cys Asn Ala His Gln Asn Cys Pro Asp Gly Ser Asp Glu
3570 3575 3580
Asp Arg Leu Leu Cys Glu Asn His His Cys Asp Ser Asn Glu Trp Gln
3585 3590 3595 3600
Cys Ala Asn Lys Arg Cys Ile Pro Glu Ser Trp Gln Cys Asp Thr Phe
3605 3610 3615
Asn Asp Cys Glu Asp Asn Ser Asp Glu Asp Ser Ser His Cys Ala Ser
3620 3625 3630
Arg Thr Cys Arg Pro Gly Gln Phe Arg Cys Ala Asn Gly Arg Cys Ile
3635 3640 3645
55 Pro Gln Ala Trp Lys Cys Asp Val Asp Asn Asp Cys Gly Asp His Ser
3650 3655 3660
Asp Glu Pro Ile Glu Glu Cys Met Ser Ser Ala His Leu Cys Asp Asn
3665 3670 3675 3680
Phe Thr Glu Phe Ser Cys Lys Thr Asn Tyr Arg Cys Ile Pro Lys Trp
3685 3690 36 g 5
Ala Val Cys Asn Gly Val Asp Asp Cys Arg Asp Asn Ser Asp Glu Gln
CA 0220~648 l997-0~-20
WO 96/15801 PCT/US95/15203
3700 3705 3710
Gly Cys Glu Glu Arg Thr Cys His Pro Val Gly Asp Phe Arg Cys Lys
3715 3720 3725
Asn His His Cys Ile Pro Leu Arg Trp Gln Cys Asp Gly Gln Asn Asp
3730 3735 3740
Cys Gly Asp Asn Ser Asp Glu Glu Asn Cys Ala Pro Arg Glu Cys Thr
0 3745 3750 3755 3760
Glu Ser Glu Phe Arg Cys Val Asn Gln Gln Cys Ile Pro Ser Arg Trp
3765 3770 3775
Ile Cys Asp His Tyr Asn Asp Cys Gly Asp Asn Ser Asp Glu Arg Asp
3780 3785 3790
Cys Glu Met Arg Thr Cys His Pro Glu Tyr Phe Gln Cys Thr Ser Gly
3795 3800 3805
His Cys Val His Ser Glu Leu Lys Cys Asp Gly Ser Ala Asp Cys Leu
3810 3815 3820
Asp Ala Ser Asp Glu Ala Asp Cys Pro Thr Arg Phe Pro Asp Gly Ala
3825 3830 3835 3840
Tyr Cys Gln Ala Thr Met Phe Glu Cys Lys Asn His Val Cys Ile Pro
3845 3850 3855
Pro Tyr Trp Lys Cys Asp Gly Asp Asp Asp Cys Gly Asp Gly Ser Asp
3860 3865 3870
Glu Glu Leu His Leu Cys Leu Asp Val Pro Cys Asn Ser Pro Asn Arg
3875 3880 3885
Phe Arg Cys Asp Asn Asn Arg Cys Ile Tyr Ser His Glu Val Cys Asn
3890 3895 3900
Gly Val Asp Asp Cys Gly Asp Gly Thr Asp Glu Thr Glu Glu His Cys
3905 3910 3915 3920
Arg Lys Pro Thr Pro Lys Pro Cys Thr Glu Tyr Glu Tyr Lys Cys Gly
3925 3930 3935
Asn Gly His Cys Ile Pro His Asp Asn Val Cys Asp Asp Ala Asp Asp
3940 3945 3950
Cys Gly Asp Trp Ser Asp Glu Leu Gly Cys Asn Lys Gly Lys Glu Arg
3955 3g60 3965
~, Thr Cys Ala Glu Asn I le Cys Glu Gln Asn Cys Thr Gln Leu Asn Glu
3970 3975 3980
Gly Gly Phe Ile Cys Ser Cys Thr Ala Gly Phe Glu Thr Asn Val Phe
3985 3990 3995 4000
Asp Arg Thr Ser Cys Leu Asp Ile Asn Glu Cys Glu Gln Phe Gly Thr
4005 4010 4015
60 Cys Pro Gln His Cys Arg Asn Thr Lys Gly Ser Tyr Glu Cys Val Cys
4020 4025 4030
Ala Asp Gly Phe Thr Ser Met Ser Asp Arg Pro Gly ~ys Arg Cys Ala
4035 4040 4045
CA 0220~648 1997-05-20
W O96/1~801 PCTrUS95/15203
Ala Glu Gly Ser Ser Pro Leu Leu Leu Leu Pro Asp Asn Val Arg Ile
4050 4055 4060
Arg Lys Tyr Asn Leu Ser Ser Glu Arg Phe Ser Glu Tyr Leu Gln Asp
4065 4070 . 4075 4080
Glu Glu Tyr Ile Gln Ala Val Asp Tyr Asp Trp Asp Pro Glu Asp Ile
4085 4090 4095
, 10
Gly Leu Ser Val Val Tyr Tyr Thr Val Arg Gly Glu Gly Ser Arg Phe
4100 4105 4110
Gly Ala Ile Lys Arg Ala Tyr Ile Pro Asn Phe Glu Ser Gly Arg Asn
4115 4120 4125
Asn heu Val Gln Glu Val Asp Leu Lys Leu Lys Tyr Val Met Gln Pro
4130 4135 4140
Asp Gly Ile Ala Val Asp Trp Val Gly Arg His Ile Tyr Trp Ser Asp
4145 4150 4155 4160
Val Lys Asn Lys Arg Ile Glu Val Ala Lys Leu Asp Gly Arg Tyr Arg
4165 4170 4175
Lys Trp Leu Ile Ser Thr Asp Leu Asp Gln Pro Ala Ala Ile Ala Val
4180 4185 4190
Asn Pro Lys Leu Gly Leu Met Phe Trp Thr Asp Trp Gly Lys Glu Pro
4195 4200 4205
Lys Leu Glu Ser Ala Trp Met Asn Gly Glu Asp Arg Asn Ile Leu Val
4210 4215 4220
Phe Glu Asp Leu Gly Trp Pro Thr Gly Leu Ser Ile Asp Tyr Leu Asn
4225 4230 4235 4240
Asn Asp Arg Ile Tyr Trp Ser Asp Phe Lys Glu Asp Val Ile Glu Thr
4245 4250 4255
Ile Lys Tyr Asp Gly Thr Asp Arg Arg Val Ile Ala Lys Glu Ala Met
4260 4265 4270
Asn Pro Tyr Ser Leu Asp Ile Phe Glu Asp Gln Leu Tyr Trp Ile Ser
4275 4280 4285
Lys Glu Lys Gly Glu Val Trp Lys Gln Asn Lys Phe Gly Gln Gly Lys
4290 4295 4300
Lys Glu Lys Thr Leu Val Val Asn Pro Trp Leu Thr Gln Val Arg Ile
4305 4310 4315 4320
Phe His Gln Leu Arg Tyr Asn Lys Ser Val Pro Asn Leu Cys Lys Gln
4325 4330 4335
Ile Cys Ser His Leu Cys Leu Leu Arg Pro Gly Gly Tyr Ser Cys Ala
4340 4345 4350
Cys Pro Gln Gly Ser Ser Phe I le Glu Gly Ser Thr Thr Glu Cys Asp
4355 4360 4365
Ala Ala Ile Glu Leu Pro Ile Asn Leu Pro Pro Pro Cys Arg Cys Met
4370 4375 4380
CA 0220~648 l997-0~-20
W O96/1~801 PCTAUS95/15203
~07
His Gly Gly Asn Cys Tyr Phe Asp Glu Thr Asp Leu Pro Lys Cys Lys
4385 4390 4395 4400
Cys Pro Ser Gly Tyr Thr Gly Lys Tyr Cys Glu Met Ala Phe Ser Lys
4405 4410 4415
Gly Ile Ser Pro Gly Thr Thr Ala Val Ala Val Leu Leu Thr Ile Leu
4420 4425 4430
Leu Ile Val Val Ile Gly Ala Leu Ala Ile Ala Gly Phe Phe His Tyr
4435 4440 4445
Arg Arg Thr Gly Ser Leu Leu Pro Ala Leu Pro Lys Leu Pro Ser Leu
4450 4455 4460
Ser Ser Leu Val Lys Pro Ser Glu Asn Gly Asn Gly Val Thr Phe Arg
4465 4470 4475 4480
Ser Gly Ala Asp Leu Asn Met Asp Ile Gly Val Ser Gly Phe Gly Pro
4485 4490 4495
Glu Thr Ala Ile Asp Arg Ser Met Ala Met Ser Glu Asp Phe Val Met
4500 4505 4510
Glu Met Gly Lys Gln Pro Ile Ile Phe G1U Asn Pro Met Tyr Ser Ala
4515 4520 4525
Ary Asp Ser Ala Val Lys Val Val Gln Pro Ile Gln Val Thr Val Ser
4530 4535 4540
Glu Asn Val Asp Asn Lys Asn Tyr Gly Ser Pro Ile Asn Pro Ser Glu
4545 4550 4555 4560
Ile Val Pro Glu Thr Asn Pro Thr Ser Pro Ala Ala Asp Gly Thr Gln
4565 4570 4575
Val Thr Lys Trp Asn Leu Phe Lys Arg Lys Ser Lys Gln Thr Thr Asn
4580 4585 4590
Phe Glu Asn Pro Ile Tyr Ala Gln Met Glu Asn Glu Gln Lys Glu Ser
4595 4600 4605
Val Ala Ala Thr Pro Pro Pro Ser Pro Ser Leu Pro Ala Lys Pro Lys
4610 4615 4620
Pro Pro Ser Arg Arg Asp Pro Thr Pro Thr Tyr Ser Ala Thr Glu Asp
4625 4630 4635 4640
Thr Phe Lys Asp Thr Ala Asn Leu Val Lys Glu Asp Ser Glu Val
4645 4650 4655
(2) INFORMATION FOR SEQ ID NO:91:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: other nucleic acid
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
CA 0220~648 1997-0~-20
W O96/15801 PCTrUS95/lS203
~a~
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:9l: t
GCAGACCTAA AGGAGCGTT l9
(2) INFORMATION FOR SEQ ID NO:92:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 20 base pairs
(B) TYPE: nucleic acid
(C) STRANv~vN~:SS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: other nucleic acid
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:92:
CCCGACCATT GGAGAAGATA 20
(2) INFORMATION FOR SEQ ID NO:93:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: l9 base pairs
(B) TYPE: nucleic acid
(C) STRANv~:vN~:SS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: other nucleic acid
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:93:
GCCAGTACCA GTGCCATGA l9
(2) INFORMATION FOR SEQ ID NO:94:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 base pairs
(B) TYPE: nucleic acid
(C) STRANvEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: other nucIeic acid
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
CA 02205648 1997-05-20
W O 96/15801 PCTrUS9S/15203
~?~q
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:94:
CCTCATGACA CTGATACTCT T 2l
(2) INFORMATION FOR SEQ ID NO:95:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY:-linear
(ii) MOLECULE TYPE: other nucleic acid
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:95:
GGCTGTGAGC AG~l~l~l . _ l8
(2) INFORMATION FOR SEQ ID NO:96:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 23 base pairs
(B) TYPE: nucleic ~cid
(C) STRAN~N~:SS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: other nucleic acid
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:96:
45 CGACCACTAA TTGAATCAAA ATC 23
(2) INFORMATION FOR SEQ ID NO:97:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: l9 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single;
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: other nucleic acid
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:97:
65 CGGTGCTCGT GTGATACAG l9
CA 0220S648 1997-05-20
W O96/15801 PCTrUS95/15203
~2/o
(2) INFORMATION FOR SEQ ID NO:98:
. (i) SEQUENCE CHARACTERISTICS:
tA) LENGTH: 18 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: other nucleic acid
(iii) HYPOTHETICAL: NO
(iv~ ANTI-SENSE: NO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:98:
20 ATCCACATCC ACATGCAG l8
(2) INFORMATION FOR SEQ ID NO:9g:
(i) SEQUENCE CHARACTERISTICS:
(A) LEN~TH: 22 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: other nucleic acid
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:99:
40 CCTCAAATGG CTGTAGCAAC AA 22
(2) INFORMATION FOR SEQ ID NO:l00:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 base pairs
(B) TYPE: nucleic ~cid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: other nucleic acid
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:l00:
60 CTGCTGCTGC ACGTGTGA l8
(2) INFORMATION FOR SEQ ID NO:l0l:
(i) SEQUENCE CHARACTERISTICS:
CA 02205648 l997-05-20
W O96/15801 PCT~US95/15203
~//
(A) LENGTH: 22 base pairs
(B) TYPE: nucleic acid
(C) STRA~N~SS: single
. (D) TOPOLOGY: linear
t (ii) MOLECULE TYPE: other nucleic acid
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:101:
CCAGTCTGGA TACACAAAAT GT 22
(2) INFORMATION FOR SEQ ID NO:102:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 base pairs
(B) TYPE: nucleic acid
(C) STR~ l)N~:ss single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: other nucleic acid
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:102:
GGCGCACTGC CATTC 15
(2) INFORMATION FOR SEQ ID NO:103:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 base pairs
(B) TYPE: nucleic acid
(C) sTRA~nFn~ss single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: other nucleic acid
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:103:
CTCAGATGGC TCTGATGAAC T 21
(2) INFORMATION FOR SEQ ID NO:104:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
CA 02205648 1997-OS-20
W O 96/15801 PCTrUS95/15203
~/~
(ii) MOLECULE TYPE: other nucleic acid
(iii) HYPOTHETICAL: NO
(iv) ANTI-SENSE: NO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:104:
GC~l"l"l"l~C~ C ~ C~l' T 2`1
(2) INFORMATION FOR SEQ ID NO:105:
, 15
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 22 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: other nucleic acid
(iii) HYPOTHETICAL: NO
2~
(iv) ANTI-SENSE: NO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:105:
GAGAGTCATT GCAAAGGAAG CA 22
(2) INFORMATION FOR SEQ ID NO:106:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 23 base pairs
(B) TYPE: nucleic acid
(C) STRANDEDNESS: single
~D) TOPOLOGY: linear
~ii) MOLECULE TYPE: other nucleic acid
(iii) HYPOTHETICAL: NO
~iv) ANTI-SENSE: NO
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:106:
AATATATGTG CAAAAGTGTG TT~ 23 .
