NOVEL NUCLEOTIDE AND AMINO ACID SEQUENCES, AND ASSAYS AND METHODS OF USE THEREOF FOR DIAGNOSIS OF LUNG CANCER

NOUVELLES SEQUENCES D'ACIDES AMINES ET DE NUCLEOTIDES, ET DOSAGES ET METHODES D'UTILISATION CONNEXES POUR LE DIAGNOSTIC DU CANCER DU POUMON

English Abstract

Novel markers for lung cancer that are both sensitive and accurate. These
markers are
overexpressed in lung cancer specifically, as opposed to normal lung tissue.
The measurement
of these markers, alone or in combination, in patient samples provides
information that the
diagnostician can correlate with a probable diagnosis of lung cancer. The
markers of the present
invention, alone or in combination, show a high degree of differential
detection between lung
cancer and non-cancerous states.

French Abstract

L'invention se rapporte à de nouveaux marqueurs sensibles et précis du cancer du poumon. Ces marqueurs sont particulièrement surexprimés dans le cancer du poumon, en comparaison au tissu pulmonaire normal. La mesure de ces marqueurs, seuls ou associés, dans des échantillons de patients, fournit des informations que le diagnosticien peut mettre en corrélation avec un diagnostic probable du cancer du poumon. Les marqueurs selon l'invention, seuls ou combinés, montrent un degré élevé de détection différentielle entre le cancer du poumon et des états non cancéreux.

Claims

1401


WHAT IS CLAIMED IS:

1. An isolated polynucleotide comprising a polynucleotide having a sequence of
R11723_PEA_1_T5.
2. The isolated polynucleotide of claim 1, comprising a node having a sequence
of:
R11723_PEA_1_node_13.
3. An isolated polypeptide comprising a polypeptide having a sequence of:
R11723_PEA_1_P13.
4. The isolated of claim 3, comprising a chimeric polypeptide encoding for
R11723_PEA_1_P13, comprising a first amino acid sequence being at least 95 %
homologous
to
MVWLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV
MEQSA corresponding to amino acids 1 - 63 of Q96AC2, which also corresponds to
amino
acids 1 - 63 of R11723_PEA_1_P13, and a second amino acid sequence being at
least about
95% homologous to a polypeptide having the sequence DTKRTNTLLFEMRHFAKQLTT
corresponding to amino acids 64 - 84 of R11723_PEA_1_P13, wherein said first
and second
amino acid sequences are contiguous and in a sequential order.
4. The isolated polypeptide of claim 4, comprising a tail of R11723_PEA_1_P13,
comprising a polypeptide being at least about 95% homologous to the sequence
DTKRTNTLLFEMRHFAKQLTT in R11723_PEA_1_P13.
5. The isolated oligonucleotide of claim 1, comprising an amplicon according
to
SEQ ID NO: 1684.
6. A primer pair, comprising a pair of isolated oligonucleotides capable of
amplifying said amplicon of claim 5.


1402


7. The primer pair of claim 6, comprising a pair of isolated oligonucleotides:
SEQ
NOs 1682 and 1683.
8. An antibody capable of specifically binding to an epitope of an amino acid
sequence of
claim 3.
9. The antibody of claim 8, wherein said amino acid sequence comprises said
tail of claim
4.
10. The antibody of claim 8, wherein said antibody is capable of
differentiating between
a splice variant having said epitope and a corresponding known protein PSEC.
11. A kit for detecting lung cancer, comprising a kit detecting overexpression
of a
splice variant according to claim 1.
12. The kit of claim 11, wherein said kit comprises a NAT-based technology.
13. The kit of claim 11, wherein said kit further comprises at least one
primer pair
capable of selectively hybridizing to a nucleic acid sequence according to
claim 1.
14. The kit of claim 11, wherein said kit further comprises at least one
oligonucleotide capable of selectively hybridizing to a nucleic acid sequence
according to claim
1.
12. A kit for detecting lung cancer, comprising a kit detecting overexpression
of a
splice variant according to claim 3, said kit comprising an antibody according
claim 8.
13. The kit of claim 12, wherein said kit further comprises at least one
reagent for
performing an ELISA or a Western blot.


1403


14. A method for detecting lung cancer, comprising detecting overexpression of
a
splice variant according to claim 1.
15. The method of claim 14, wherein said detecting overexpression is performed
with a NAT-based technology.
16. A method for detecting lung cancer, comprising detecting overexpression of
a
splice variant according to claim 3, wherein said detecting overexpression is
performed with an
immunoassay.
17. The method of claim 16, wherein said immunoassay comprises an antibody
according to claim 8.
18. A biomarker capable of detecting lung cancer, comprising a nucleic acid
sequence according to claim 1 or a fragment thereof, or an amino acid sequence
according to
claim 3 or a fragment thereof.
19. A method for screening for lung cancer, comprising detecting lung cancer
cells
with a biomarker according to claim 18.
20. A method for diagnosing lung cancer, comprising detecting lung cancer
cells
with a biomarker according to claim 18.
21. A method for monitoring disease progression and/or treatment efficacy
and/or
relapse of lung cancer, comprising detecting lung cancer cells with a
biomarker according to
claim 18.
22. A method of selecting a therapy for lung cancer, comprising detecting lung
cancer cells with a biomarker according to claim 18 and selecting a therapy
according to said
detection.

Description

DEMANDES OU BREVETS VOLUMINEUX
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Brevets.
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THAN ONE VOLUME.
THIS IS VOLUME 1 OF 5
NOTE: For additional volumes please contact the Canadian Patent Office.

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CA 02555509 2006-07-26
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NOVEL NUCLEOTIDE AND AMINO ACID SEQUENCES, AND ASSAYS AND
METHODS OF USE THEREOF FOR DIAGNOSIS OF LUNG CANCER
FIELD OF THE INVENTION
The present invention is related to novel nucleotide and protein sequences
that are
diagnostic markers for lung cancer, and assays and methods of use thereof.
BACKGROUND OF THE INVENTION
Lung cancer is the primary cause of cancer death among both men and women in
the U.
S., with an estimated 172,000 new cases being reported in 1994. The five-year
survival rate
among all lung cancer patients, regardless of the stage of disease at
diagnosis, is only 13%. This
contrasts with a five-year survival rate of 46% among cases detected while the
disease is still
localized. However, only 16% of lung cancers are discovered before the disease
has spread.
Lung cancers are broadly classified into small cell or non-small cell lung
cancers. Non-small
cell lung cancers are further divided into adenocarcinomas, bronchoalveolar-
alveolar, squamous
cell and large cell carcinomas. Approximately, 75-85 percent of lung cancers
are non-small cell
cancers and 15-25 percent are small cell cancers of the lung.
Early detection is difficult since clinical symptoms are often not seen until
the disease
has reached an advanced stage. Currently, diagnosis is aided by the use of
chest x-rays, analysis
of the type of cells contained in sputum and fiberoptic examination of the
bronchial passages.
Treatment regimens are determined by the type and stage of the cancer, and
include surgery,
radiation therapy and/or chemotherapy.
Early detection of primary, metastatic, and recurrent disease can
significantly impact the
prognosis of individuals suffering from lung cancer. Non-small cell lung
cancer diagnosed at an
early stage has a significantly better outcome than that diagnosed at more
advanced stages.
Similarly, early diagnosis of small cell lung cancer potentially has a better
prognosis.
Although current radiotherapeutic agents, chemotherapeutic agents and
biological toxins
are potent cytotoxins, they do not discriminate between normal and malignant
cells, producing
adverse effects and dose-limiting toxicities. There remains a need for lung
cancer specific
cancer markers. There remains a need for reagents and kits which can be used
to detect the
presence of lung cancer markers in samples from patients. There remains a need
for methods of

CA 02555509 2006-07-26
2
screening and diagnosing individuals who have lung cancer and methods of
monitoring response
to treatment, disease progression and disease recurrence in patients diagnosed
with lung cancer.
There remains a need for reagents, kits and methods for determining the type
of lung cancer that
an individual who has lung cancer has. There remains a need for compositions
which can
specifically target lung cancer cells. There remains a need for imaging agents
which can
specifically bind to lung cancer cells. There remains a need for improved
methods of imaging
lung cancer cells. There remains a need for therapeutic agents which can
specifically bind to
lung cancer cells. There remains a need for improved methods of treating
individuals who are
suspected of suffering from lung cancer.
SUMMARY OF THE INVENTION
The background art does not teach or suggest markers for lung cancer that are
sufficiently sensitive and/or accurate, alone or in combination.
The present invention overcomes these deficiencies of the background art by
providing
novel markers for lung cancer that are both sensitive and accurate.
Furthermore, these markers
are able to distinguish between different types of lung cancer, such as small
cell or non-small
cell lung cancer, and further between non-small cell lung cancer types, such
as
adenocarcinomas, squamous cell and large cell carcinomas. These markers are
overexpressed in
lung cancer specifically, as opposed to normal lung tissue. The measurement of
these markers,
alone or in combination, in patient (biological) samples provides information
that the
diagnostician can correlate with a probable diagnosis of lung cancer. The
markers of the present
invention, alone or in combination, show a high degree of differential
detection between lung
cancer and non-cancerous states.
According to preferred embodiments of the present invention, examples of
suitable
biological samples which may optionally be used with preferred embodiments of
the present
invention include but are not limited to blood, serum, plasma, blood cells,
urine, sputum, saliva,
stool, spinal fluid or CSF, lymph fluid, the external secretions of the skin,
respiratory, intestinal,
and genitourinary tracts, tears, milk, neuronal tissue, lung tissue, any human
organ or tissue,
including any tumor or normal tissue, any sample obtained by lavage (for
example of the
bronchial system or of the breast ductal system), and also samples of in vivo
cell culture
constituents. In a preferred embodiment, the biological sample comprises lung
tissue and/or

3
f
CA 02555509 2006-07-26
3
sputum and/or a serum sample and/or a urine sample and/or any other tissue or
liquid sample.
The sample can optionally be diluted with a suitable eluant before contacting
the sample to an
antibody and/or performing any other diagnostic assay.
Information given in the text with regard to cellular localization was
determined
according to four different software programs: (i) tmhmm (from Center for
Biological Sequence
Analysis, Technical University of Denmark DTU,
http://www.cbs.dtu.dk/services/TMHMM/TMHMM2.Ob.guide.php) or (ii) tmpred (from
EMBnet, maintained by the ISREC Bionformatics group and the LICR Information
Technology
Office, Ludwig Institute for Cancer Research, Swiss Institute of
Bioinformatics,
http://www.ch.embnet.org/software/TMPRED form.html for transmembrane region
prediction;
(iii) signalp_hmm or (iv) signalp nn (both from Center for Biological Sequence
Analysis,
Technical University of Denmark DTU,
http://www.cbs.dtu.dk/services/SignalP/background/prediction.php) for signal
peptide
prediction. The terms "signalp hmm" and "signalp nn" refer to two modes of
operation for the
program SignalP: hmm refers to Hidden Markov Model, while nn refers to neural
networks.
Localization was also determined through manual inspection of known protein
localization
and/or gene structure, and the use of heuristics by the individual inventor.
In some cases for the
manual inspection of cellular localization prediction inventors used the
ProLoc computational
platform [Einat Hazkani-Covo, Erez Levanon, Galit Rotman, Dan Graur and Amit
Novik;
(2004) "Evolution of multicellularity in metazoa: comparative analysis of the
subcellular
localization of proteins in Saccharomyces, Drosophila and Caenorhabditis."
Cell Biology
International 2004;28(3):171-8.], which predicts protein localization based on
various
parameters including, protein domains (e.g., prediction of trans-membranous
regions and
localization thereof within the protein), pI, protein length, amino acid
composition, homology to
pre-annotated proteins, recognition of sequence patterns which direct the
protein to a certain
organelle (such as, nuclear localization signal, NLS, mitochondria
localization signal), signal
peptide and anchor modeling and using unique domains from Pfam that are
specific to a single
compartment.

CA 02555509 2006-07-26
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Information is given in the text with regard to SNPs (single nucleotide
polymorphisms).
A description of the abbreviations is as follows. "T - > C", for example,
means that the SNP
results in a change at the position given in the table from T to C. Similarly,
"M - > Q", for
example, means that the SNP has caused a change in the corresponding amino
acid sequence,
from methionine (M) to glutamine (Q). If, in place of a letter at the right
hand side for the
nucleotide sequence SNP, there is a space, it indicates that a frameshift has
occurred. A
frameshift may also be indicated with a hyphen (-). A stop codon is indicated
with an asterisk at
the right hand side (*). As part of the description of an SNP, a comment may
be found in
parentheses after the above description of the SNP itself. This comment may
include an FTId,
which is an identifier to a SwissProt entry that was created with the
indicated SNP. An FTId is
a unique and stable feature identifier, which allows construction of links
directly from position-
specific annotation in the feature table to specialized protein-related
databases. The FTId is
always the last component of a feature in the description field, as follows:
FTId=XXX number,
in which XXX is the 3-letter code for the specific feature key, separated by
an underscore from
a 6-digit number. In the table of the amino acid mutations of the wild type
proteins of the
selected splice variants of the invention, the header of the first column is
"SNP positions) on
amino acid sequence", representing a position of a known mutation on amino
acid sequence.
SNPs may optionally be used as diagnostic markers according to the present
invention, alone or
in combination with one or more other SNPs and/or any other diagnostic marker.
Preferred
embodiments of the present invention comprise such SNPs, including but not
limited to novel
SNPs on the known (WT or wild type) protein sequences given below, as well as
novel nucleic
acid and/or amino acid sequences formed through such SNPs, and/or any SNP on a
variant
amino acid and/or nucleic acid sequence described herein.
Information given in the text with regard to the Homology to the known
proteins was
determined by Smith-Waterman version 5.1.2 using special (non default)
parameters as follows:
-model=sw.model
-GAPEXT=0
-GAPOP=100.0
-MATRIX=blosum100

CA 02555509 2006-07-26
Information is given with regard to overexpression of a cluster in cancer
based on ESTs.
A key to the p values with regard to the analysis of such overexpression is as
follows:
- library-based statistics: P-value without including the level of expression
in cell-
lines (P 1 )
5 - library based statistics: P-value including the level of expression in
cell-lines (P2)
- EST clone statistics: P-value without including the level of expression in
cell-lines
(SP1)
- EST clone statistics: predicted overexpression ratio without including the
level of
expression in cell-lines (R3)
- EST clone statistics: P-value including the level of expression in cell-
lines (SP2)
- EST clone statistics: predicted overexpression ratio including the level of
expression in cell-lines (R4)
Library-based statistics refer to statistics over an entire library, while EST
clone statistics
refer to expression only for ESTs from a particular tissue or cancer.
Information is given with regard to overexpression of a cluster in cancer
based on
microarrays. As a microarray reference, in the specific segment paragraphs,
the unabbreviated
tissue name was used as the reference to the type of chip for which expression
was measured.
There are two types of microarray results: those from microarrays prepared
according to a
design by the present inventors, for which the microarray fabrication
procedure is described in
detail in Materials and Experimental Procedures section herein; and those
results from
microarrays using Affymetrix technology. As a microarray reference, in the
specific segment
paragraphs, the unabbreviated tissue name was used as the reference to the
type of chip for
which expression was measured. For microarrays prepared according to a design
by the present
inventors, the probe name begins with the name of the cluster (gene), followed
by an identifying
number. Oligonucleotide microarray results taken from Affymetrix data were
from chips
available from Affymetrix Inc, Santa Clara, CA, USA (see for example data
regarding the
Human Genome U133 (HG-U133) Set at
www.affymetrix.com/products/arrays/specific/hgu133.affx; GeneChip Human Genome
U133A
2.0 Array at www.affymetrix.com/products/arrays/specific/hgu133av2.affx; and
Human
Genome U133 Plus 2.0 Array at

CA 02555509 2006-07-26
www.affymetrix.com/products/arrays/specific/hgu133plus.affx). The probe names
follow the
Affymetrix naming convention. The data is available from NCBI Gene Expression
Omnibus
(see www.ncbi.nlm.nih.gov/projects/geo/ and Edgar et al, Nucleic Acids
Research, 2002, Vol.
30, No. 1 207-210). The dataset (including results) is available from
S www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE1133 for the Series GSE1133
database
(published on March 2004); a reference to these results is as follows: Su et
al (Proc Natl Acad
Sci U S A. 2004 Apr 20;101(16):6062-7. Epub 2004 Apr 09). Probes designed by
the present
inventors are listed below.
>H61775 0 11 0
CCCCAGCTTTTATAGAGCGGCCCAAGGAAGAATATTTCCAAGAAGTAGGG
>M85491 0 0 25999
GACATCTTTGCATATCATGTCAGAGCTATAACATCATTGTGGAGAAGCTC
>M85491 0 14 0
GTCATGAAAATCAACACCGAGGTGCGGAGCTTCGGACCTGTGTCCCGCAG
>Z21368 0 0 61857
AGTTCATCCTTCTTCAGTGTGACCAGTAAATTCTTCCCATACTCTTGAAG
>HUMGRPSE 0 0 16630
GCTGATATGGAAGTTGGGGAATCTGAATTGCCAGAGAATCTTGGGAAGAG
>HUMGRPSE 0 2 0
TCTCATAGAAGCAAAGGAGAACAGAAACCACCAGCCACCTCAACCCAAGG
>D56406 0 5 0
TCTGACTTTTACGGACTTGGCTTGTTAGAAGGCTGAAAGATGATGGCAGG
>F05068 0 0 5744
ACGGGAGGGAAGGAAGGTGTGCGGGAGGAGTTCTCTGTCTCCACTCCCCT
>F05068 0 0 5754
CAAGGGGAACTGACCGTTGGTCCCGAAGGTCTAGAAGTGAATGGGAGCAG
>F05068 0 8 0
CTGGGCTTGGACTTCGGAGTTTTGCCATTGCCAGTGGGACGTCTGAGACT
>F05068 0 1 5751
TCTTAGCAGGTAGGTGCCGCAGACCCTGCGGGTTAAGAGGTGGGGTGGGG
>H38804 0 3 0

CA 02555509 2006-07-26
CGTAATTGCAGTGCATTTAGACAGGCATCTATTTGGACCTGTTTCTATCT
>HSENA78 0 1 0
TGAAGAGTGTGAGGAAAACCTATGTTTGCCGCTTAAGCTTTCAGCTCAGC
>R00299 0 8 0
CCAAGGCTCGTCTGCGCACCTTGTGTCTTGTAGGGTATGGTATGTGGGAC
>Z44808 0 8 0
AAAAGCATGAGTTTCTGACCAGCGTTCTGGACGCGCTGTCCACGGACATG
>Z44808 0 0 72347
ATGTTCTTAGGAGGCAAGCCAGGAGAAGCCGGGTCTGACTTTTCAGCTCA
>Z44808 0 0 72349
TCCTCCAGACCCAAAGCCACAACCCATCGCAAGTCAAGAACACTTTCCAG
>AA161187 0 0 433
ACCCTGGGTGGGCAAAA.ACGTGCTTTCCCGGACGGGGTTGAAGGGGAGAA
>AA161187 0 0 430
TGGAGACTGTTGCCCCACTCTGCAGATGCAGA.AACGGAGGCTTGGCTGCT
>R66178 0 7 0
CCAGTGTGGTATCCTGGGAAACTCGGTTAAAAGGTGAGGCAGAGTACCAG
>HLTMPHOSLIP 0 0 18458
AAGGAAGCAGGACCAGTGGATGTGAGGCGTGGTCGAAGAACAACAGAAAG
>HIJMPHOSLIP 0 0 18487
ACAGGGGCCAGATGGTGACCCATGACCCAGCCTAA.AAGGCAGCCAGAGGG
>AI076020 0 3 0
ATCAGCACTGCCACCTACACCACGGTGCCGCGCGTGGCCTTCTACGCCGG
>T23580 0 0 902
GTGAAACCCCATTGGCTTCATTGGCTCCTTGATTTAAACCACGCCCGGCT
>T23580 0 0 901
TGAGTCCGTGTTATATCATCTGGTCTCATTGATAGGCGGGATAGGGAGGG
>M79217 0 9 0
TTTGTGGAATAGCAACCCATGGTTATGGCGAGTGACCCGACGTGATCTGG
>M62096 0 0 20588
AAGGCTTAGGTGCAAAGCCATTGGATACCATACCTGAGACCACACAGCCA

CA 02555509 2006-07-26
>M62096 0 7 0
ACCAGAAGCAGCTGTCCAGACTCCGAGACGAAATTGAGGAGAAGCAGAAA
>M78076 0 7 0
GAGAAGATGAACCCGCTGGAACAGTATGAGCGAAAGGTGAATGCGTCTGT
>T99080 0 0 58896
AACTCACAGCAAGAGCTGTGTTCCAGTTAGCTTTGCTACCAGTTATGCAG
>T08446 0 9 0
CATTTCCACTACGAGAACGTTGACTTTGGCCACATTCAGCTCCTGCTGTC
>HLTMCA 1 XIA 0 0 14909
GCTGCAATCTAAGTTTCGGAATACTTATACCACTCCAGAAATAATCCTCG
>HLTMCA1XIA 0 18 0
TTCAGAACTGTTAACATCGCTGACGGGAAGTGGCATCGGGTAGCAATCAG
>T11628 0 9 0
ACAAGATCCCCGTGAAGTACCTGGAGTTCATCTCGGAATGCATCATCCAG
>T11628 0 0 45174
TAAACAATCAAAGAGCATGTTGGCCTGGTCCTTTGCTAGGTACTGTAGAG
>T11628 0 0 45161
TGCCTCGCCACAATGGCACCTGCCCTAAAATAGCTTCCCATGTGAGGGCT
>HLTMCEA 0 0 96
CAAGAGGGGTTTGGCTGAGACTTTAGGATTGTGATTCAGCTTAGAGGGAC
>HUMCEA 0 0 15183
CCTGGTGGGAGCCCATGAGAAGCGAGTTCTCTGTGCAACGGACTTAGTAA
>HUMCEA 0 0 15182
GCTCCCTGGAGCATCAGCATCATATTCTGGGGTGGAGTCTATCTGGTTCT
>HUMCEA 0 0 1 S 168
TCCTGCCTGTCACCTGAAGTTCTAGATCATTCCCTGGACTCCACTCTATC
>HUMCEA 0 0 15180
TTTAACACAGGATTGGGACAGGATTCAGAGGGACACTGTGGCCCTTCTAC
>R35137 0 5 0
TATGTGGAGGTGGTGAACATGGACGCTGCAGTGCAGCAGCAGATGCTGAA
>Z25299 0 3 0

CA 02555509 2006-07-26
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AACTCTGGCACCTTGGGCTGTGGAAGGCTCTGGAAAGTCCTTCAAAGCTG
>HSSTROL3 0 0 12518
ATGAGAGTAACCTCACCCGTGCACTAGTTTACAGAGCATTCACTGCCCCA
>HSSTROL3 0 0 12517
CAGAGATGAGAGCCTGGAGCATTGCAGATGCCAGGGACTTCACAAATGAA
>HSS100PCB 0 0 12280
CTCAAAATGAAACTCCCTCTCGCAGAGCACAATTCCAATTCGCTCTAAAA
>R20779 0 0 30670
CCGCGTTGCTTCTAGAGGCTGAATGCCTTTCAAATGGAGAAGGCTTCCAT
The following list of abbreviations for tissues was used in the TAA
histograms. The
term "TAA" stands for "Tumor Associated Antigen", and the TAA histograms,
given in the
text, represent the cancerous tissue expression pattern as predicted by the
biomarkers selection
engine, as described in detail in examples 1-5 below:
"BONE" for "bone";
"COL" for "colon";
"EPI" for "epithelial";
"GEN" for "general";
"LIVER" for "liver";
"LUN" for "lung";
"LYMPH" for "lymph nodes";
"MARROW" for "bone marrow";
"OVA" for "ovary";
"PANCREAS" for "pancreas";
"PRO" for "prostate";
"STOMACH" for "stomach";
"TCELL" for "T cells";
"THYROID" for "Thyroid";
"MAM" for "breast";
"BRAIN" for "brain";
"UTERUS" for "uterus";
"SKIN" for "skin";

CA 02555509 2006-07-26
"KIDNEY" for "kidney";
"MUSCLE" for "muscle";
"ADREN" for "adrenal";
"HEAD" for "head and neck";
"BLADDER" for "bladder";
It should be noted that the terms "segment", "seg" and "node" are used
interchangeably
in reference to nucleic acid sequences of the present invention; they refer to
portions of nucleic
acid sequences that were shown to have one or more properties as described
below. They are
10 also the building blocks that were used to construct complete nucleic acid
sequences as
described in greater detail below. Optionally and preferably, they are
examples of
oligonucleotides which are embodiments of the present invention, for example
as amplicons,
hybridization units and/or from which primers and/or complementary
oligonucleotides may
optionally be derived, and/or for any other use.
1 S As used herein the phrase "lung cancer" refers to cancers of the lung
including small cell
lung cancer and non-small cell lung cancer, including but not limited to lung
adenocarcinoma,
squamous cell carcinoma, and adenocarcinoma.
The term "marker" in the context of the present invention refers to a nucleic
acid
fragment, a peptide, or a polypeptide, which is differentially present in a
sample taken from
subjects (patients) having lung cancer (or one of the above indicative
conditions) as compared to
a comparable sample taken from subjects who do not have lung cancer (or one of
the above
indicative conditions).
The phrase "differentially present" refers to differences in the quantity of a
marker
present in a sample taken from patients having lung cancer (or one of the
above indicative
conditions) as compared to a comparable sample taken from patients who do not
have lung
cancer (or one of the above indicative conditions). For example, a nucleic
acid fragment may
optionally be differentially present between the two samples if the amount of
the nucleic acid
fragment in one sample is significantly different from the amount of the
nucleic acid fragment in
the other sample, for example as measured by hybridization and/or NAT-based
assays. A
polypeptide is differentially present between the two samples if the amount of
the polypeptide in
one sample is significantly different from the amount of the polypeptide in
the other sample. It

CA 02555509 2006-07-26
11
should be noted that if the marker is detectable in one sample and not
detectable in the other,
then such a marker can be considered to be differentially present.
As used herein the phrase "diagnostic" means identifying the presence or
nature of a
pathologic condition. Diagnostic methods differ in their sensitivity and
specificity. The
"sensitivity" of a diagnostic assay is the percentage of diseased individuals
who test positive
(percent of "true positives"). Diseased individuals not detected by the assay
are "false
negatives." Subjects who are not diseased and who test negative in the assay
are termed "true
negatives." The "specificity" of a diagnostic assay is 1 minus the false
positive rate, where the
"false positive" rate is defined as the proportion of those without the
disease who test positive.
While a particular diagnostic method may not provide a definitive diagnosis of
a condition, it
suffices if the method provides a positive indication that aids in diagnosis.
As used herein the phrase "diagnosing" refers to classifying a disease or a
symptom,
determining a severity of the disease, monitoring disease progression,
forecasting an outcome of
a disease and/or prospects of recovery. The term "detecting" may also
optionally encompass any
of the above.
Diagnosis of a disease according to the present invention can be effected by
determining
a level of a polynucleotide or a polypeptide of the present invention in a
biological sample
obtained from the subject, wherein the level determined can be correlated with
predisposition to,
or presence or absence of the disease. It should be noted that a "biological
sample obtained from
the subject" may also optionally comprise a sample that has not been
physically removed from
the subject, as described in greater detail below.
As used herein, the term "level" refers to expression levels of RNA and/or
protein or to
DNA copy number of a marker of the present invention.
Typically the level of the marker in a biological sample obtained from the
subject is
different (i.e., increased or decreased) from the level of the same variant in
a similar sample
obtained from a healthy individual (examples of biological samples are
described herein).
Numerous well known tissue or fluid collection methods can be utilized to
collect the
biological sample from the subject in order to determine the level of DNA, RNA
and/or
polypeptide of the variant of interest in the subject.
Examples include, but are not limited to, fine needle biopsy, needle biopsy,
core needle
biopsy and surgical biopsy (e.g., brain biopsy), and lavage. Regardless of the
procedure

CA 02555509 2006-07-26
12
employed, once a biopsy/sample is obtained the level of the variant can be
determined and a
diagnosis can thus be made.
Determining the level of the same variant in normal tissues of the same origin
is
preferably effected along-side to detect an elevated expression and/or
amplification and/or a
decreased expression, of the variant as opposed to the normal tissues.
A "test amount" of a marker refers to an amount of a marker in a subject's
sample that is
consistent with a diagnosis of lung cancer (or one of the above indicative
conditions). A test
amount can be either in absolute amount (e.g., microgram/ml) or a relative
amount (e.g., relative
intensity of signals).
A "control amount" of a marker can be any amount or a range of amounts to be
compared against a test amount of a marker. For example, a control amount of a
marker can be
the amount of a marker in a patient with lung cancer (or one of the above
indicative conditions)
or a person without lung cancer (or one of the above indicative conditions). A
control amount
can be either in absolute amount (e.g., microgram/ml) or a relative amount
(e.g., relative
intensity of signals).
"Detect" refers to identifying the presence, absence or amount of the object
to be
detected.
A "label" includes any moiety or item detectable by spectroscopic, photo
chemical,
biochemical, immunochemical, or chemical means. For example, useful labels
include 32P, 3sS,
fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in
an ELISA),
biotin-streptavadin, dioxigenin, haptens and proteins for which antisera or
monoclonal
antibodies are available, or nucleic acid molecules with a sequence
complementary to a target.
The label often generates a measurable signal, such as a radioactive,
chromogenic, or
fluorescent signal, that can be used to quantify the amount of bound label in
a sample. The label
can be incorporated in or attached to a primer or probe either covalently, or
through ionic, van
der Waals or hydrogen bonds, e.g., incorporation of radioactive nucleotides,
or biotinylated
nucleotides that are recognized by streptavadin. The label may be directly or
indirectly
detectable. Indirect detection can involve the binding of a second label to
the first label, directly
or indirectly. For example, the label can be the ligand of a binding partner,
such as biotin, which
is a binding partner for streptavadin, or a nucleotide sequence, which is the
binding partner for a
complementary sequence, to which it can specifically hybridize. The binding
partner may itself

CA 02555509 2006-07-26
13
be directly detectable, for example, an antibody may be itself labeled with a
fluorescent
molecule. The binding partner also may be indirectly detectable, for example,
a nucleic acid
having a complementary nucleotide sequence can be a part of a branched DNA
molecule that is
in turn detectable through hybridization with other labeled nucleic acid
molecules (see, e.g., P.
D. Fahrlander and A. Klausner, Bio/Technology 6:1165 (1988)). Quantitation of
the signal is
achieved by, e.g., scintillation counting, densitometry, or flow cytometry.
Exemplary detectable labels, optionally and preferably for use with
immunoassays,
include but are not limited to magnetic beads, fluorescent dyes, radiolabels,
enzymes (e.g., horse
radish peroxide, alkaline phosphatase and others commonly used in an ELISA),
and calorimetric
labels such as colloidal gold or colored glass or plastic beads.
Alternatively, the marker in the
sample can be detected using an indirect assay, wherein, for example, a
second, labeled antibody
is used to detect bound marker-specific antibody, and/or in a competition or
inhibition assay
wherein, for example, a monoclonal antibody which binds to a distinct epitope
of the marker are
incubated simultaneously with the mixture.
"Immunoassay" is an assay that uses an antibody to specifically bind an
antigen. The
immunoassay is characterized by the use of specific binding properties of a
particular antibody
to isolate, target, and/or quantify the antigen.
The phrase "specifically (or selectively) binds" to an antibody or
"specifically (or
selectively) immunoreactive with," when referring to a protein or peptide (or
other epitope),
refers to a binding reaction that is determinative of the presence of the
protein in a
heterogeneous population of proteins and other biologics. Thus, under
designated immunoassay
conditions, the specified antibodies bind to a particular protein at least two
times greater than the
background (non-specific signal) and do not substantially bind in a
significant amount to other
proteins present in the sample. Specific binding to an antibody under such
conditions may
require an antibody that is selected for its specificity for a particular
protein. For example,
polyclonal antibodies raised to seminal basic protein from specific species
such as rat, mouse, or
human can be selected to obtain only those polyclonal antibodies that are
specifically
immunoreactive with seminal basic protein and not with other proteins, except
for polymorphic
variants and alleles of seminal basic protein. This selection may be achieved
by subtracting out
antibodies that cross-react with seminal basic protein molecules from other
species. A variety of
immunoassay formats rnay be used to select antibodies specifically
immunoreactive with a

CA 02555509 2006-07-26
14
particular protein. For example, solid-phase ELISA immunoassays are routinely
used to select
antibodies specifically immunoreactive with a protein (see, e.g., Harlow &
Lane, Antibodies, A
Laboratory Manual (1988), for a description of immunoassay formats and
conditions that can be
used to determine specific immunoreactivity). Typically a specific or
selective reaction will be
at least twice background signal or noise and more typically more than 10 to
100 times
background.
According to preferred embodiments of the present invention, preferably any of
the
above nucleic acid and/or amino acid sequences further comprises any sequence
having at least
about 70%, preferably at least about 80%, more preferably at least about 90%,
most preferably
at least about 95% homology thereto.
Unless otherwise noted, all experimental data relates to variants of the
present invention,
named according to the segment being tested (as expression was tested through
RT-PCR as
described).
All nucleic acid sequences and/or amino acid sequences shown herein as
embodiments
of the present invention relate to their isolated form, as isolated
polynucleotides (including for
all transcripts), oligonucleotides (including for all segments, amplicons and
primers), peptides
(including for all tails, bridges, insertions or heads, optionally including
other antibody epitopes
as described herein) and/or polypeptides (including for all proteins). It
should be noted that
oligonucleotide and polynucleotide, or peptide and polypeptide, may optionally
be used
interchangeably.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ LD NOs: 1 and 2.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 1022, 1023, 1024, 1025, 1026
and 1027.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ ID NOs: 1281 and 1282.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 3 and 4.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 1028, 1029, 1030, 1031, 1032,
1033, 1034,
1035, 1036, 1037 and 1038.

CA 02555509 2006-07-26
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ m NOs: 1283 and 1284.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ 1D NOs: 5, 6, 7 and 8.
5 According to preferred embodiments of the present invention, there is
provided an
isolated polynucleotide comprising SEQ 1D NOs: 1039, 1040, 1041, 1042, 1043,
1044, 1045,
1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058,
1059, 1060,
1061, 1062, 1063, 1064, 1065 and 1066.
According to preferred embodiments of the present invention, there is provided
an
10 isolated polypeptide comprising SEQ >D NOs: 1285, 1286, 1287 and 1288.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ m NOs: 9, 10; 11, 12, 13, 14 and 15.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs: 1067, 1068, 1069, 1070, 1071,
1072, 1073,
15 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1082, 1083, 1084, 1085,
1086, 1087, 1088,
1089, 1090, 1091, 1092, 1093,.1094, 1095, 1096, 1097, 1098, 1099 and 1100.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ m NOs 1289, 1290, 1291, 1292, 1293 and
1294.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ m NOs: 20 and 21.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs: 1130, 1131, 1132, 1133 and
1134.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ >D NOs: 1299 and 1300.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs: 22, 23 and 24.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs: 1135, 1136, 1137, 1138, 1139,
1140, 1141,
1142, 1143 and 1144.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ m NOs 1301, 1302 and 1303.

CA 02555509 2006-07-26
16
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ >D NOs: 25, 26 and 27.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ >D NOs: 1145, 1146, 1147, 1148, 1149,
1150, 1151,
1152, 1153, 1154, 1155 and 1156.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ ID NOs 1304 and 1305.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ >D NOs: 28.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 1157, 1158, 1159, 1160, 1161,
1162, 1163,
1164, 1165, 1166, 1167, 1168, 1169, 1170 and 1171.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ >D NO: 1306.
1 S According to preferred embodiments of the present invention, there is
provided an
isolated polynucleotide comprising SEQ m NOs: 29 and 30.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ m NOs: 1172, 1173, 1174, 1175, 1176,
1177, 1178,
1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190 and
1191.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ ID NOs 1307 and 1308.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ 1D NOs: 31.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ m NOs: 1192, 1193, 1194, 1195, 1196,
1197 and
1198.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ ID NO: 1309.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ m NOs: 32.

CA 02555509 2006-07-26
17
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ >D NOs: 1199, 1200, 1201, 1202, 1203,
1204, 1205,
1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214 and 1215.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ >D NO. 1310.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 33.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs: 1216 and 1217, 1218, 1219,
1220, 1221,
1222, 1223, 1224, 1225, 1226 and 1227.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ >D NO: 1311.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ >D NOs: 34.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ >D NOs: 1228, 1229, 1230, 1231, 1232
and 1223.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ >D NO: 1312.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ m NOs: 35.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ >D NOs: 1234, 1235, 1236, 1237, 1238,
1239, 1240,
1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253
and 1254.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ ID NO: 1313.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ >D NOs: 36, 37, 38, 39 and 40.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ m NOs: 1255, 1256, 1257, 1258, 1259,
1260, 1261,
1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274
and 1275.

CA 02555509 2006-07-26
18
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ m NOs 1314, 1315, 1316 and 1317.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ >D NOs: 125, 126, 127, 128, 129 and
130.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ >D NOs: 887, 888, 889, 890, 891, 892,
893, 894, 895,
896, 897, 898, 899, 900, 901 and 902.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ ID NOs: 1394, 1395, 1396, 1397 and 1398.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising a transcript SEQ ID NOs: 131 and 132.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 903, 904, 905, 906, 907, 907,
908 and 909.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ >D NOs 1399 and 1400.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ >D NOs: 99, 100, 101 and 102.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 742, 743, 744, 745, 746, 747,
748, 749, 750,
751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765,
766, 767, 768, 769,
770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784,
785, 786, 787 and
788.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ m NOs 1372, 1373, 1374 and 1375.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ m NOs: 134.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs: 913, 914, 915, 916, 917, 918,
919, 920, 921,
922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935 and 936.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ m NO: 1402.

CA 02555509 2006-07-26
19
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ 1D NO: 133.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ >D NOs: 910, 911 and 912.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs: 141, 142 and 142.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 961, 962, 963, 964, 965, 966,
967, 968, 969,
970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984,
985, 986, 987, 988,
989 and 990.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising :
Protein Name
HUMOSTRO PEA 1 PEA 1 P21
HUMOSTRO PEA 1 PEA 1 P25
HUMOSTRO PEA 1 PEA 1 P30
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs: 51, 52, 53" 54, 55, 56 and 57.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 518, S 19, 520, 521, 522, 523,
524, 525, 526,
527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 54I,
542, 543, 544, 545,
546, 547,548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561,
562, 563" 564,
565, 566, 567, 568, 569 and 570.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ >D NOs 1327, 1328, 1329, 1330, 1331, 1332
and 1333.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 135, 136, 137, 138, 139 and
140.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs: 937, 938, 939, 940, 941, 942,
943, 944, 945,
946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959 and 960.

CA 02555509 2006-07-26
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ ID NOs 1403, 1404, 1405, 1406, 1407 and
1408.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ >D NOs: 41, 42, 43, 44, 45, 46 and 47..
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs: 482, 483, 484, 495, 486, 487,
488, 489, 490,
491, 492, 493, 494, 495, 496, 497, 498, 499, 500 and SO1.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ >D NOs: 1318, 1319, 1320, 1321, 1322 and
1323.
10 According to preferred embodiments of the present invention, there is
provided an
isolated polynucleotide comprising SEQ >D NOs: 121, 122, 123 and 124.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ >D NOs: 876, 877, 878, 879, 880, 881,
882, 883, 884,
885 and 886.
15 According to preferred embodiments of the present invention, there is
provided an
isolated polypeptide comprising SEQ ID NOs: 1390, 1391, 1392 and 1393.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ m NOs: 48, 49 and 50.
According to preferred embodiments of the present invention, there is provided
an
20 isolated polynucleotide comprising SEQ ID NOs: 502, 503, 504, SOS, 506,
507, 508, 509, 510,
511,512,513,514,515,516and517.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ m NOs: 1324, 1325 and 1326.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ >D NOs: 1464 and 1465.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising a SEQ m NOs: 1276, 1277, 1278, 1279 and
1280.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ >D NO: 1415.
Protein Name Corresponding Transcripts)
HSU33147 PEA 1 PS HSU33147 PEA 1 T1; HSU33147 PEA 1 T2

CA 02555509 2006-07-26
21
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NO: 58.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs: 571, 572, 573, 574, 575, 576,
577 and 578.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ m NO: 1334.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs: 74, 75, 76, 77, 78, 79, 80, 81
and 82.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs: 659, 660, 661, 662, 663, 664,
665, 666, 667,
668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682,
683, 684, 685, 686,
687, 688, 689, 690, 691, 692 and 693.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ )D NOs 1350, 1351, 1352, 1353, 1354, 1355,
1356 and
1357.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs:
Transcript Name
T23580 T10
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 579, 580, 581, 582 and 583.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ >D NOs 1335.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 59, 60, 61, 62, 63 and 64.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ >D NOs: 584, 585, 586, 587, 588, 589,
590, 591, 592,
593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607,
608, 609, 610, 611,
612, 613, 614 and 615.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ )D NOs: 1336, 1337, 1338,1339 and 1340.

CA 02555509 2006-07-26
22
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs: 65, 66, 67, 68, 69, 70, 71, 72
and 73.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 616, 617, 618, 619, 620, 621,
622, 623, 624,
625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639,
640, 641, 642, 643,
644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658 and
659.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ m NOs: 1341, 1342, 1343, 1344, 1345, 1346,
1347, 1348
and 1349.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 83, 84, 85, 86, 87, 88, 89, 90,
91, 92, 93, 94,
95 and 96.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs: 695, 696, 697, 698, 699, 700,
701, 702, 703,
704 and 705.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ B7 NOs 1358, 1359, 1360, 1361, 1362, 1363,
1364, 1365,
1366, 1367, 1368 and 1369.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 97 and 98.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ m NOs: 706, 707, 708, 709, 710, 711,
712, 713, 714,
715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729,
730, 731, 732, 733,
734, 735, 736, 737, 738, 739, 740 and 741.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ m NOs: 1370 and 1371.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs: 103, 104, 105, 106, 107 and
108.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ )D NOs: 789, 790, 791, 792, 793, 794,
795, 796, 797,
798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 8 09, 810, 811, 812 and
813.

CA 02555509 2006-07-26
23
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ m NOs: 1376, 1377, 1378 and 1379.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ m NOs: 114, 115, 116, 117, 118 and 119.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ m NOs: 856, 857, 858, 859, 860, 861,
862, 863, 864,
865, 866, 867, 868, 869, 870, 871, 872, 873, 874 and 875.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ ID NOs: 1385, 1386, 1387, 1388 and 1389.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 144, 145, 146, 147, 148 and
149.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ m NOs: 991, 992, 993, 994, 995, 996,
997, 998, 999,
1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012,
1013, 1014,
1015 and 1016.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ ID NOs: 1409, 1410, 1411, 1412 and 1413.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ m NO: 150.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ m NOs: 1017, 1018, 1019, 1020 and 1021.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ ID NO: 1414.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 109, 110, 111, 112 and 113.
According to preferred embodiments of the present invention, there is provided
an
isolated polynucleotide comprising SEQ ID NOs: 814, 815, 816, 817, 818, 819,
820, 821, 822,
823, 824, 825, 826, 827, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838,
839, 840, 841, 842,
843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854 and 855.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide comprising SEQ ID NOs 1380, 1381, 1382, 1383 and 1384.

CA 02555509 2006-07-26
24
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for.HSSTROL3 P4, comprising a first
amino acid
sequence being at least 90 % homologous to
MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS
PAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVLSGGRWEKTDLTYRILRFP
WQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW corresponding to
amino acids 1 - 163 of MM11 HUMAN, which also corresponds to amino acids 1 -
163 of
HSSTROL3 P4, a bridging amino acid H corresponding to amino acid 164 of
HSSTROL3 P4,
a second amino acid sequence being at least 90 % homologous to
GDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWTIGDDQGTDLLQVAAHEFGHVLG
LQHTTA.AKALMSAFYTFRYPLSLSPDDCRGVQHLYGQPWPTVTSRTPALGPQAGIDTN
EIAPLEPDAPPDACEASFDAVSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGL
PSPVDAAFEDAQGHIWFFQGAQYWVYDGEKPVLGPAPLTELGLVRFPVHAALVWGPE
KNKIYFFRGRDYWRFHPSTRRVDSPVPRRATDWRGVPSEIDAAFQDADG corresponding
to amino acids 165 - 445 of MM11 HUMAN, which also corresponds to amino acids
165 - 445
of HSSTROL3 P4, and a third amino acid sequence being at least 70%, optionally
at least 80%,
preferably at least 85%, more preferably at least 90% and most preferably at
least 95%
homologous to a polypeptide having the sequence
ALGVRQLVGGGHSSRFSHLWAGLPHACHRKSGSSSQVLCPEPSALLSVAG
corresponding to amino acids 446 - 496 of HSSTROL3 P4, wherein said first
amino acid
sequence, bridging amino acid, second amino acid sequence and third amino acid
sequence are
contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of HSSTROL3 P4, comprising a
polypeptide being at
least 70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least
about 90% and most preferably at least about 95% homologous to the sequence
ALGVRQLVGGGHSSRFSHLVVAGLPHACHRKSGSSSQVLCPEPSALLSVAG in
HSSTROL3 P4.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HSSTROL3 P5, comprising a first
amino acid
sequence being at least 90 % homologous to

CA 02555509 2006-07-26
MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS
PAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVLSGGRWEKTDLTYRILRFP
WQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW corresponding to
amino acids 1 - 163 of MM11 HUMAN, which also corresponds to amino acids 1 -
163 of
5 HSSTROL3 P5, a bridging amino acid H corresponding to amino acid 164 of
HSSTROL3 PS,
a second amino acid sequence being at least 90 % homologous to
GDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWTIGDDQGTDLLQVAAHEFGHVLG
LQHTTAAKALMSAFYTFRYPLSLSPDDCRGVQHLYGQPWPTVTSRTPALGPQAGIDTN
EIAPLEPDAPPDACEASFDAVSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGL
10 PSPVDAAFEDAQGHIWFFQ corresponding to amino acids 165 - 358 of MM11 HUMAN,
which also corresponds to amino acids 165 - 358 of HSSTROL3_P5, and a third
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
ELGFPSSTGRDESLEHCRCQGLHK corresponding to amino acids 359 - 382 of
15 HSSTROL3 P5, wherein said first amino acid sequence, bridging amino acid,
second amino
acid sequence and third amino acid sequence are contiguous and in a sequential
order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of HSSTROL3 P5, comprising a
polypeptide being at
least 70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least
20 about 90% and most preferably at least about 95% homologous to the sequence
ELGFPSSTGRDESLEHCRCQGLHK in HSSTROL3 P5.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HSSTROL3 P7, comprising a first
amino acid
sequence being at least 90 % homologous to
25 MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS
PAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVLSGGRWEKTDLTYRILRFP
WQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW corresponding to
amino acids 1 - 163 of MM11 HUMAN, which also corresponds to amino acids 1 -
163 of
HSSTROL3 P7, a bridging amino acid H corresponding to amino acid 164 of
HSSTROL3 P7,
a second amino acid sequence being at least 90 % homologous to
GDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWTIGDDQGTDLLQVAAHEFGHVLG

CA 02555509 2006-07-26
26
LQHTTAAKALMSAFYTFRYPLSLSPDDCRGVQHLYGQPWPTVTSRTPALGPQAGIDTN
EIAPLEPDAPPDACEASFDAV STIRGELFFFKAGFV WRLRGGQLQPGYPALASRHWQGL
PSPVDAAFEDAQGHIWFFQG corresponding to amino acids 165 - 359 of MM11 HUMAN,
which also corresponds to amino acids 165 - 359 of HSSTROL3_P7, and a third
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
TTGVSTPAPGV corresponding to amino acids 360 - 370 of HSSTROL3 P7, wherein
said first
amino acid sequence, bridging amino acid, second amino acid sequence and third
amino acid
sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of HSSTROL3_P7, comprising a
polypeptide being at
least 70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least
about 90% and most preferably at least about 95% homologous to the sequence
TTGVSTPAPGV in HSSTROL3 P7.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HSSTROL3 P8, comprising a first
amino acid
sequence being at least 90 % homologous to
MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS
PAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVLSGGRWEKTDLTYRILRFP
WQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW corresponding to
amino acids 1 - 163 of MM11 HUMAN, which also corresponds to amino acids 1 -
163 of
HSSTROL3 P8, a bridging amino acid H corresponding to amino acid 164 of
HSSTROL3 P8,
a second amino acid sequence being at least 90 % homologous to
GDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWTIGDDQGTDLLQVAAHEFGHVLG
LQHTTAAKALMSAFYTFRYPLSLSPDDCRGVQHLYGQPWPTVTSRTPALGPQAGIDTN
EIAPLE corresponding to amino acids 165 - 286 of MM11 HUMAN, which also
corresponds
to amino acids 165 - 286 of HSSTROL3 P8, and a third amino acid sequence being
at least
70%, optionally at least 80%, preferably at least 85%, more preferably at
least 90% and most
preferably at least 95% homologous to a polypeptide having the sequence
VRPCLPVPLLLCWPL corresponding to amino acids 287 - 301 of HSSTROL3_P8, wherein

CA 02555509 2006-07-26
27
said first amino acid sequence, bridging amino acid, second amino acid
sequence and third
amino acid sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of HSSTROL3_P8, comprising a
polypeptide being at
least 70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least
about 90% and most preferably at least about 95% homologous to the sequence
VRPCLPVPLLLCWPL in HSSTROL3 P8.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HSSTROL3 P9, comprising a first
amino acid
sequence being at least 90 % homologous to
MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS
PAPAPATQEAPRPASSLRPPRCGVPDPSDGLSARNRQK corresponding to amino acids 1 -
96 of MM11 HUMAN, which also corresponds to amino acids 1 - 96 of HSSTROL3_P9,
a
second amino acid sequence being at least 90 % homologous to
RILRFPWQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW
corresponding to amino acids 113 - 163 of MM 11 HUMAN, which also corresponds
to amino
acids 97 - 147 of HSSTROL3 P9, a bridging amino acid H corresponding to amino
acid 148 of
HSSTROL3 P9, a third amino acid sequence being at least 90 % homologous to
GDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWTIGDDQGTDLLQVAAHEFGHVLG
LQHTTAAKALMSAFYTFRYPLSLSPDDCRGVQHLYGQPWPTVTSRTPALGPQAGIDTN
EIAPLEPDAPPDACEASFDAVSTIRGELFFFKAGFVWRLRGGQLQPGYPALASRHWQGL
PSPVDAAFEDAQGHIWFFQG corresponding to amino acids 165 - 359 of MM11 HUMAN,
which also corresponds to amino acids 149 - 343 of HSSTROL3 P9, and a fourth
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
TTGVSTPAPGV corresponding to amino acids 344 - 354 of HSSTROL3 P9, wherein
said first
amino acid sequence, second amino acid sequence, bridging amino acid, third
amino acid
sequence and fourth amino acid sequence axe contiguous and in a sequential
order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of HSSTROL3 P9,
comprising a
polypeptide having a length "n", wherein n is at least about 10 amino acids in
length, optionally

CA 02555509 2006-07-26
28
at least about 20 amino acids in length, preferably at least about 30 amino
acids in length, more
preferably at least about 40 amino acids in length and most preferably at
least about 50 amino
acids in length, wherein at least two amino acids comprise KR, having a
structure as follows: a
sequence starting from any of amino acid numbers 96-x to 96; and ending at any
of amino acid
numbers 97+ ((n-2) - x), in which x varies from 0 to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of HSSTROL3 P9, comprising a
polypeptide being at
least 70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least
about 90% and most preferably at least about 95% homologous to the sequence
TTGVSTPAPGV in HSSTROL3 P9.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMCA1XIA P14, comprising a first
amino acid
sequence being at least 90 % homologous to
MEPWSSRWKTKRWLWDFTVTTLALTFLFQAREVRGAAPVDVLKALDFHNSPEGISKTT
GFCTNRKNSKGSDTAYRVSKQAQLSAPTKQLFPGGTFPEDFSILFTVKPKKGIQSFLLSIY
NEHGIQQIGVEVGRSPVFLFEDHTGKPAPEDYPLFRTVNIADGKWHRVAISVEKKTVTM
IVDCKKKTTKPLDRSERAIVDTNGITVFGTRILDEEVFEGDIQQFLITGDPKAAYDYCEH
YSPDCDSSAPKAAQAQEPQIDEYAPEDIIEYDYEYGEAEYKEAESVTEGPTVTEETIAQT
EANIVDDFQEYNYGTMESYQTEAPRHVSGTNEPNPVEEIFTEEYLTGEDYDSQRKNSED
TLYENKEIDGRDSDLLVDGDLGEYDFYEYKEYEDKPTSPPNEEFGPGVPAETDITETSIN
GHGAYGEKGQKGEPAVVEPGMLVEGPPGPAGPAGIMGPPGLQGPTGPPGDPGDRGPPG
RPGLPGADGLPGPPGTMLMLPFRYGGDGSKGPTISAQEAQAQAILQQARIALRGPPGPM
GLTGRPGPVGGPGSSGAKGESGDPGPQGPRGVQGPPGPTGKPGKRGRPGADGGRGMP
GEPGAKGDRGFDGLPGLPGDKGHRGERGPQGPPGPPGDDGMRGEDGEIGPRGLPGEAG
PRGLLGPRGTPGAPGQPGMAGVDGPPGPKGNMGPQGEPGPPGQQGNPGPQGLPGPQG
PIGPPGEKGPQGKPGLAGLPGADGPPGHPGKEGQSGEKGALGPPGPQGPIGYPGPRGVK
GADGVRGLKGSKGEKGEDGFPGFKGDMGLKGDRGEV GQIGPRGEDGPEGPKGRAGPT
GDPGPSGQAGEKGKLGVPGLPGYPGRQGPKGSTGFPGFPGANGEKGARGVAGKPGPR
GQRGPTGPRGSRGARGPTGKPGPKGTSGGDGPPGPPGERGPQGPQGPVGFPGPKGPPGP
PGKDGLPGHPGQRGETGFQGKTGPPGPGGVVGPQGPTGETGPIGERGHPGPPGPPGEQG
LPGAAGKEGAKGDPGPQGISGKDGPAGLRGFPGERGLPGAQGAPGLKGGEGPQGPPGP

CA 02555509 2006-07-26
29
V corresponding to amino acids 1 - 1056 of CA1B HUMAN VS, which also
corresponds to
amino acids 1 - 1056 of HUMCA1XIA P14, and a second amino acid sequence being
at least
70%, optionally at least 80%, preferably at least 85%, more preferably at
least 90% and most
preferably at least 95% homologous to a polypeptide having the sequence
VSMMIINSQTIMVVNYSSSFITLML corresponding to amino acids 1057 - 1081 of
HUMCA 1 XIA P 14, wherein said first amino acid sequence and second amino acid
sequence
are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of HUMCA1XIA P14, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
VSMMIINSQTIMVVNYSSSFITLML in HUMCA1XIA P14.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMCA1XIA P15, comprising a first
amino acid
sequence being at least 90 % homologous to
MEPWSSRWKTKRWLWDFTVTTLALTFLFQAREVRGAAPVDVLKALDFHNSPEGISKTT
GFCTNRKNSKGSDTAYRVSKQAQLSAPTKQLFPGGTFPEDFSILFTVKPKKGIQSFLLSIY
NEHGIQQIGVEVGRSPVFLFEDHTGKPAPEDYPLFRTVNIADGKWHRVAISVEKKTVTM
IVDCKKKTTKPLDRSERAIVDTNGITVFGTRILDEEVFEGDIQQFLITGDPKAAYDYCEH
YSPDCDSSAPKAAQAQEPQIDEYAPEDIIEYDYEYGEAEYKEAESVTEGPTVTEETIAQT
EANIVDDFQEYNYGTMESYQTEAPRHVSGTNEPNPVEEIFTEEYLTGEDYDSQRKNSED
TLYENKEIDGRDSDLLVDGDLGEYDFYEYKEYEDKPTSPPNEEFGPGVPAETDITETSIN
GHGAYGEKGQKGEPAVVEPGMLVEGPPGPAGPAGIMGPPGLQGPTGPPGDPGDRGPPG
RPGLPGADGLPGPPGTMLMLPFRYGGDGSKGPTISAQEAQAQAILQQARIALRGPPGPM
GLTGRPGPVGGPGSSGAKGESGDPGPQGPRGVQGPPGPTGKPGKRGRPGADGGRGMP
GEPGAKGDRGFDGLPGLPGDKGHRGERGPQGPPGPPGDDGMRGEDGEIGPRGLPGEAG
PRGLLGPRGTPGAPGQPGMAGVDGPPGPKGNMGPQGEPGPPGQQGNPGPQGLPGPQG
PIGPPGEK corresponding to amino acids 1 - 714 of CA1B HUMAN, which also
corresponds
to amino acids 1 - 714 of HUMCA1XIA_P15, and a second amino acid sequence
being at least
70%, optionally at least 80%, preferably at least 85%, more preferably at
least 90% and most
preferably at least 95% homologous to a polypeptide having the sequence

CA 02555509 2006-07-26
MCCNLSFGILIPLQK corresponding to amino acids 715 - 729 of HUMCA1XIA P15,
wherein
said first amino acid sequence and second amino acid sequence are contiguous
and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
5 isolated polypeptide encoding for a tail of HUMCA1XIA P15, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
MCCNLSFGILIPLQK in HLJMCA1XIA P15.
According to preferred embodiments of the present invention, there is provided
an
10 isolated chimeric polypeptide encoding for HUMCA1XIA P16, comprising a
first amino acid
sequence being at least 90 % homologous to
MEPWSSRWKTKRWLWDFTVTTLALTFLFQAREVRGAAPVDVLKALDFHNSPEGISKTT
GFCTNRKNSKGSDTAYRVSKQAQLSAPTKQLFPGGTFPEDFSILFTVKPKKGIQSFLLSIY
NEHGIQQIGVEVGRSPVFLFEDHTGKPAPEDYPLFRTVNIADGKWHRVAISVEKKTVTM
15 IVDCKKKTTKPLDRSERAIVDTNGITVFGTRILDEEVFEGDIQQFLITGDPKAAYDYCEH
YSPDCDSSAPKAAQAQEPQIDEYAPEDIIEYDYEYGEAEYKEAESVTEGPTVTEETIAQT
EANIVDDFQEYNYGTMESYQTEAPRHVSGTNEPNPVEEIFTEEYLTGEDYDSQRKNSED
TLYENKEIDGRDSDLLVDGDLGEYDFYEYKEYEDKPTSPPNEEFGPGVPAETDITETSIN
GHGAYGEKGQKGEPAVVEPGMLVEGPPGPAGPAGIMGPPGLQGPTGPPGDPGDRGPPG
20 RPGLPGADGLPGPPGTMLMLPFRYGGDGSKGPTISAQEAQAQAILQQARIALRGPPGPM
GLTGRPGPVGGPGSSGAKGESGDPGPQGPRGVQGPPGPTGKPGKRGRPGADGGRGMP
GEPGAKGDRGFDGLPGLPGDKGHRGERGPQGPPGPPGDDGMRGEDGEIGPRGLPGEA
corresponding to amino acids 1 - 648 of CA1B HUMAN, which also corresponds to
amino
acids 1 - 648 of HUMCA1XIA P16, a second amino acid sequence being at least 90
25 homologous to GMAGVDGPPGPKGNMGPQGEPGPPGQQGNPGPQGLPGPQGPIGPPGEK
corresponding to amino acids 667 - 714 of CA1B HUMAN, which also corresponds
to amino
acids 649 - 696 of HUMCA1 XIA P 16, and a third amino acid sequence being at
least 70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence
30 VSFSFSLFYKKVIKFACDKRFVGRHDERKVVKLSLPLYLIYE corresponding to amino

CA 02555509 2006-07-26
31
acids 697 - 738 of HLJMCA1XIA P16, wherein said first amino acid sequence,
second amino
acid sequence and third amino acid sequence are contiguous and in a sequential
order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of HUMCA1XIA P16,
comprising a
polypeptide having a length "n", wherein n is at least about 10 amino acids in
length, optionally
at least about 20 amino acids in length, preferably at least about 30 amino
acids in length, more
preferably at least about 40 amino acids in length and most preferably at
least about 50 amino
acids in length, wherein at least two amino acids comprise AG, having a
structure as follows: a
sequence starting from any of amino acid numbers 648-x to 648; and ending at
any of amino
acid numbers 649+ ((n-2) - x), in which x varies from 0 to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of HUMCA1XIA P16, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
VSFSFSLFYKKVIKFACDKRFVGRHDERKVVKLSLPLYLIYE in HUMCA1XIA P16.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMCA1XIA P17, comprising a first
amino acid
sequence being at least 90 % homologous to
MEPWSSRWKTKRWLWDFTVTTLALTFLFQAREVRGAAPVDVLKALDFHNSPEGISKTT
GFCTNRKNSKGSDTAYRVSKQAQLSAPTKQLFPGGTFPEDFSILFTVKPKKGIQSFLLSIY
NEHGIQQIGVEVGRSPVFLFEDHTGKPAPEDYPLFRTVNIADGKWHRVAISVEKKTVTM
IVDCKKKTTKPLDRSERAIVDTNGITVFGTRILDEEVFEGDIQQFLITGDPKAAYDYCEH
YSPDCDSSAPKAAQAQEPQIDE corresponding to amino acids 1 - 260 of CA1B HUMAN,
which also corresponds to amino acids 1 - 260 of HUMCA1XIA P17, and a second
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
VRSTRPEKVFVFQ corresponding to amino acids 261 - 273 of HUMCA1XIA P17, wherein
said first amino acid sequence and second amino acid sequence are contiguous
and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of HUMCA1XIA P17, comprising a
polypeptide being

CA 02555509 2006-07-26
32
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
VRSTRPEKVFVFQ in HUMCA1XIA P17.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 820779 P2, comprising a first amino
acid sequence
being at least 90 % homologous to
MCAERLGQFMTLALVLATFDPARGTDATNPPEGPQDRSSQQKGRLSLQNTAEIQHCLV
NAGDVGCGVFECFENNSCEIRGLHGICMTFLHNAGKFDAQGKSFIKDALKCKAHALRH
RFGCISRKCPAIREMV SQLQRECYLKHDLCAAAQENTRVIVEMIHFKDLLLHE
corresponding to amino acids 1 - 169 of STC2 HUMAN, which also corresponds to
amino
acids 1 - 169 of 820779 P2, and a second amino acid sequence being at least
70%, optionally at
least 80%, preferably at least 85%, more preferably at least 90% and most
preferably at least
95% homologous to a polypeptide having the sequence CYKIEITMPKRRKVKLRD
corresponding to amino acids 170 - 187 of 820779 P2, wherein said first amino
acid sequence
and second amino acid sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 820779 P2, comprising a
polypeptide being at least
70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least about
90% and most preferably at least about 95% homologous to the sequence
CYKIEITMPKRRKVKLRD in 820779 P2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMOSTRO PEA 1 PEA 1 P21,
comprising a
first amino acid sequence being at least 90 % homologous to
MRIAVICFCLLGITCAIPVKQADSGSSEEKQLYNKYPDAVATWLNPDPSQKQNLLAPQ
corresponding to amino acids 1 - 58 of OSTP HUMAN, which also corresponds to
amino acids
1 - 58 of HUMOSTRO PEA 1 PEA 1 P21, and a second amino acid sequence being at
least
70%, optionally at least 80%, preferably at least 85%, more preferably at
least 90% and most
preferably at least 95% homologous to a polypeptide having the sequence VFLNFS
corresponding to amino acids 59 - 64 of HUMOSTRO PEA 1 PEA 1 P21, wherein said
first
amino acid sequence and second amino acid sequence are contiguous and in a
sequential order.

CA 02555509 2006-07-26
33
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of HUMOSTRO PEA 1 PEA 1 P21,
comprising a
polypeptide being at least 70%, optionally at least about 80%, preferably at
least about 85%,
more preferably at least about 90% and most preferably at least about 95%
homologous to the
sequence VFLNFS in HUMOSTRO PEA 1 PEA 1 P21.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMOSTRO PEA 1 PEA 1 P25,
comprising a
first amino acid sequence being at least 90 % homologous to
MRIAVICFCLLGITCAIPVKQADSGSSEEKQ corresponding to amino acids 1 - 31 of
OSTP HUMAN, which also corresponds to amino acids 1 - 31 of
HUMOSTRO PEA 1 PEA 1 P25, and a second amino acid sequence being at least 70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence H
corresponding to
amino acids 32 - 32 of HUMOSTRO PEA 1 PEA 1 P25, wherein said first amino acid
sequence and second amino acid sequence are contiguous and in a sequential
order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMOSTRO PEA 1 PEA 1 P30,
comprising a
first amino acid sequence being at least 90 % homologous to
MRIAVICFCLLGITCAIPVKQADSGSSEEKQ corresponding to amino acids 1 - 31 of
OSTP HUMAN, which also corresponds to amino acids 1 - 31 of
HUMOSTRO PEA 1 PEA 1 P30, and a second amino acid sequence being at least 70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence
VSIFYVFI
corresponding to amino acids 32 - 39 of HUMOSTRO PEA 1 PEA 1 P30, wherein said
first
amino acid sequence and second amino acid sequence are contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of HUMOSTRO PEA 1 PEA 1 P30,
comprising a
polypeptide being at least 70%, optionally at least about 80%, preferably at
least about 85%,
more preferably at least about 90% and most preferably at least about 95%
homologous to the
sequence VSIFYVFI in HUMOSTRO PEA 1 PEA 1 P30.

CA 02555509 2006-07-26
34
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMPHOSLIP PEA 2 P10, comprising a
first
amino acid sequence being at least 90 % homologous to
MALFGALFLALLAGAHAEFPGCKIRVTSKALELVKQEGLRFLEQELETITIPDLRGKEGH
FYYNISE corresponding to amino acids 1 - 67 of PLTP HUMAN, which also
corresponds to
amino acids 1 - 67 of HUMPHOSLIP PEA 2 P10, and a second amino acid sequence
being at
least 90 % homologous to
KVYDFLSTFITSGMRFLLNQQICPVLYHAGTVLLNSLLDTVPVRSSVDELVGIDYSLMK
DPVASTSNLDMDFRGAFFPLTERNWSLPNRAVEPQLQEEERMVYVAFSEFFFDSAMES
YFRAGALQLLLVGDKVPHDLDMLLRATYFGSIVLLSPAVIDSPLKLELRVLAPPRCTIKP
SGTTISVTASVTIALVPPDQPEVQLSSMTMDARLSAKMALRGKALRTQLDLRRFRIYSN
HSALESLALIPLQAPLKTMLQIGVMPMLNERTWRGVQIPLPEGINFVHEVVTNHAGFLTI
GADLHFAKGLREVIEKNRPADVRASTAPTPSTAAV corresponding to amino acids 163 -
493 of PLTP HUMAN, which also corresponds to amino acids 68 - 398 of
HUMPHOSLIP PEA 2 P10, wherein said first amino acid sequence and second amino
acid
sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of HUMPHOSLIP PEA 2
P10,
comprising a polypeptide having a length "n", wherein n is at least about 10
amino acids in
length, optionally at least about 20 amino acids in length, preferably at
least about 30 amino
acids in length, more preferably at least about 40 amino acids in length and
most preferably at
least about 50 amino acids in length, wherein at least two amino acids
comprise EK, having a
structure as follows: a sequence starting from any of amino acid numbers 67-x
to 67; and ending
at any of amino acid numbers 68+ ((n-2) - x), in which x varies from 0 to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMPHOSLIP PEA 2 P12, comprising a
first
amino acid sequence being at least 90 % homologous to
MALFGALFLALLAGAHAEFPGCKIRVTSKALELVKQEGLRFLEQELETITIPDLRGKEGH
FYYNISEVKVTELQLTSSELDFQPQQELMLQITNASLGLRFRRQLLYWFFYDGGYINAS
AEGVSIRTGLELSRDPAGRMKVSNVSCQASVSRMHAAFGGTFKKVYDFLSTFITSGMRF
LLNQQICPVLYHAGTVLLNSLLDTVPVRSSVDELVGIDYSLMKDPVASTSNLDMDFRG

CA 02555509 2006-07-26
AFFPLTERNWSLPNRAVEPQLQEEERMVYVAFSEFFFDSAMESYFRAGALQLLLVGDK
VPHDLDMLLRATYFGSIVLLSPAVIDSPLKLELRVLAPPRCTIKPSGTTISVTASVTIALVP
PDQPEVQLSSMTMDARLSAKMALRGKALRTQLDLRRFRIYSNHSALESLALIPLQAPLK
TMLQIGVMPMLN corresponding to amino acids 1 - 427 of PLTP HUMAN, which also
5 corresponds to amino acids 1 - 427 of HLTMPHOSLIP PEA 2 P12, and a second
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
GKAGV corresponding to amino acids 428 - 432 of HUMPHOSLIP PEA 2 P12, wherein
said
first amino acid sequence and second amino acid sequence are contiguous and in
a sequential
10 order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of HUMPHOSLIP PEA 2 P 12, comprising
a
polypeptide being at least 70%, optionally at least about 80%, preferably at
least about 85%,
more preferably at least about 90% and most preferably at least about 95%
homologous to the
IS sequence GKAGV in HUMPHOSLIP PEA 2 P12.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMPHOSL)P-PEA 2 P31, comprising a
first
amino acid sequence being at least 90 % homologous to
MALFGALFLALLAGAHAEFPGCKIRVTSKALELVKQEGLRFLEQELETITIPDLRGKEGH
20 FYYNISE corresponding to amino acids 1 - 67 of PLTP HUMAN, which also
corresponds to
amino acids 1 - 67 of HUMPHOSLIP PEA 2 P31, and a second amino acid sequence
being at
least 70%, optionally at least 80%, preferably at least 85%, more preferably
at least 90% and
most preferably at least 95% homologous to a polypeptide having the sequence
PGLERGADKFPVVGGSSLFLALDLTLRPPVG corresponding to amino acids 68 - 98 of
25 HUMPHOSLIP PEA 2 P31, wherein said first amino acid sequence and second
amino acid
sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of HUMPHOSLIP PEA 2 P31, comprising a
polypeptide being at least 70%, optionally at least about 80%, preferably at
least about 85%,
30 more preferably at least about 90% and most preferably at least about 95%
homologous to the
sequence PGLERGADKFPVVGGSSLFLALDLTLRPPVG in HUMPHOSLIP PEA 2 P31.

CA 02555509 2006-07-26
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According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMPHOSLIP-PEA 2 P33, comprising a
first
amino acid sequence being at least 90 % homologous to
MALFGALFLALLAGAHAEFPGCKIRVTSKALELVKQEGLRFLEQELETITIPDLRGKEGH
FYYNISEVKVTELQLTSSELDFQPQQELMLQITNASLGLRFRRQLLYWFFYDGGYINAS
AEGVSIRTGLELSRDPAGRMKVSNVSCQASVSRMHAAFGGTFKKVYDFLSTFITSGMRF
LLNQQ corresponding to amino acids 1 - 183 of PLTP HUMAN, which also
corresponds to
amino acids 1 - 183 of HUMPHOSLIP PEA 2 P33, and a second amino acid sequence
being
at least 70%, optionally at least 80%, preferably at least 85%, more
preferably at least 90% and
most preferably at least 95% homologous to a polypeptide having the sequence
VWAATGRRVARVGMLSL corresponding to amino acids 184 - 200 of
HUMPHOSLIP PEA 2 P33, wherein said first amino acid sequence and second amino
acid
sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of HUMPHOSLIP PEA 2 P33, comprising a
polypeptide being at least 70%, optionally at least about 80%, preferably at
least about 85%,
more preferably at least about 90% and most preferably at least about 95%
homologous to the
sequence VWAATGRRVARVGMLSL in HUMPHOSLIP PEA 2 P33.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMPHOSLIP PEA 2 P34, comprising a
first
amino acid sequence being at least 90 % homologous to
MALFGALFLALLAGAHAEFPGCKIRVTSKALELVKQEGLRFLEQELETITIPDLRGKEGH
FYYNISEVKVTELQLTSSELDFQPQQELMLQITNASLGLRFRRQLLYWFFYDGGYINAS
AEGVSIRTGLELSRDPAGRMKVSNVSCQASVSRMHAAFGGTFKKVYDFLSTFITSGMRF
LLNQQICPVLYHAGTVLLNSLLDTVPV corresponding to amino acids 1 - 205 of
PLTP HUMAN, which also corresponds to amino acids 1 - 205 of
HUMPHOSLIP PEA 2 P34, and a second amino acid sequence being at least 70%,
optionally
at least 80%, preferably at least 85%, more preferably at least 90% and most
preferably at least
95% homologous to a polypeptide having the sequence LWTSLLALTIPS corresponding
to
amino acids 206 - 217 of HUMPHOSLIP PEA 2 P34, wherein said first amino acid
sequence
and second amino acid sequence are contiguous and in a sequential order.

CA 02555509 2006-07-26
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According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of HUMPHOSLIP PEA 2 P34, comprising a
polypeptide being at least 70%, optionally at least about 80%, preferably at
least about 85%,
more preferably at least about 90% and most preferably at least about 95%
homologous to the
sequence LWTSLLALTIPS in HUMPHOSLIP PEA 2 P34.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMPHOSLIP PEA 2 P35, comprising a
first
amino acid sequence being at least 90 % homologous to
MALFGALFLALLAGAHAEFPGCKIRVTSKALELVKQEGLRFLEQELETITIPDLRGKEGH
FYYNISEVKVTELQLTSSELDFQPQQELMLQITNASLGLRFRRQLLYWF corresponding to
amino acids 1 - 109 of PLTP HUMAN, which also corresponds to amino acids 1 -
109 of
HUMPHOSLIP PEA 2 P35, a second amino acid sequence bridging amino acid
sequence
comprising of L, a third amino acid sequence being at least 90 % homologous to
KVYDFLSTFITSGMRFLLNQQ corresponding to amino acids 163 - 183 of PLTP HUMAN,
which also corresponds to amino acids 111 - 131 of HCTMPHOSLIP PEA 2 P35, and
a fourth
amino acid sequence being at least 70%, optionally at least 80%, preferably at
least 85%, more
preferably at least 90% and most preferably at least 95% homologous to a
polypeptide having
the sequence VWAATGRRVARVGMLSL corresponding to amino acids 132 - 148 of
HUMPHOSLIP PEA 2 P35, wherein said first amino acid sequence, second amino
acid
sequence, third amino acid sequence and fourth amino acid sequence are
contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for an edge portion of HUMPHOSLIP PEA 2 P35,
comprising
a polypeptide having a length "n", wherein n is at least about 10 amino acids
in length,
optionally at least about 20 amino acids in length, preferably at least about
30 amino acids in
length, more preferably at least about 40 amino acids in length and most
preferably at least
about SO amino acids in length, wherein at least two amino acids comprise FLK
having a
structure as follows (numbering according to HUMPHOSLIP PEA 2 P35): a sequence
starting
from any of amino acid numbers 109-x to 109; and ending at any of amino acid
numbers 111 +
((n-2) - x), in which x varies from 0 to n-2.

CA 02555509 2006-07-26
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According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of HLJ1VIPHOSLIP PEA 2 P35,
comprising a
polypeptide being at least 70%, optionally at least about 80%, preferably at
least about 85%,
more preferably at least about 90% and most preferably at least about 95%
homologous to the
sequence VWAATGRRVARVGMLSL in HIJMPHOSLIP PEA 2 P35.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 838144 PEA 2 P6, comprising a first
amino acid
sequence being at least 90 % homologous to
MPFRLLIPLGLLCALLPQHHGAPGPDGSAPDPAHYRERVKAMFYHAYDSYLENAFPFD
ELRPLTCDGHDTWGSFSLTLIDALDTLLILGNVSEFQRVVEVLQDSVDFDIDVNASVFET
NIRVVGGLLSAHLLSKKAGVEVEAGWPCSGPLLRMAEEAARKLLPAFQTPTGMPYGTV
NLLHGVNPGETPVTCTAGIGTFIVEFATLSSLTGDPVFEDVARVALMRLWESRSDIGLV
GNHIDVLTGKWVAQDAGIGAGVDSYFEYLVKGAILLQDKKLMAMFLEYNKAIRNYTR
FDDWYLWVQMYKGTVSMPVFQSLEAYWPGLQSLIGDIDNAMRTFLNYYTVWKQFGG
LPEFYNIPQGYTVEKREGYPLRPELIESAMYLYRATGDPTLLELGRDAVESIEKISKVEC
GFAT corresponding to amino acids 1 - 412 of CT31 FfUMAN, which also
corresponds to
amino acids 1 - 412 of 838144 PEA 2 P6, and a second amino acid sequence being
at least
70%, optionally at least 80%, preferably at least 85%, more preferably at
least 90% and most
preferably at least 95% homologous to a polypeptide having the sequence
LASFSHMSDQRSARPQAGQPHGVVLPGRDCEIPLPPV corresponding to amino acids 413 -
449 of 838144 PEA 2 P6, wherein said first amino acid sequence and second
amino acid
sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 838144 PEA 2 P6, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
LASFSHMSDQRSARPQAGQPHGVVLPGRDCEIPLPPV in 838144 PEA 2 P6.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 838144 PEA 2 P13, comprising a
first amino acid
sequence being at least 90 % homologous to
MPFRLLIPLGLLCALLPQHHGAPGPDGSAPDPAHYRERVk;AMFYHAYDSYLENAFPFD

CA 02555509 2006-07-26
39
ELRPLTCDGHDTWGSFSLTLIDALDTLLILGNVSEFQRWEVLQDSVDFDIDVNASVFET
NIRVVGGLLSAHLLSKKAGVEVEAGWPCSGPLLRMAEEAARKLLPAFQTPTGMPYGTV
NLLHGVNPGETPVTCTAGIGTFIVEFATLSSLTGDPVFEDVARVALMRLWESRSDIGLV
GNHIDVLTGKW VAQDAGIGAGVDSYFEYLVKGAILLQDKKLMAMFLEYNKAIRNYTR
FDDWYLWVQMYKGTVSMPVFQSLEAYWPGLQ corresponding to amino acids 1 - 323 of
CT31 HUMAN, which also corresponds to amino acids 1 - 323 ofR38I44 PEA 2 PI3,
and a
second amino acid sequence being at least 70%, optionally at least 80%,
preferably at least 85%,
more preferably at least 90% and most preferably at least 95% homologous to a
polypeptide
having the sequence NLLKAQCTSTVPRGIPPS corresponding to amino acids 324 - 341
of
838144 PEA 2 P13, wherein said first amino acid sequence and second amino acid
sequence
are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 838144 PEA 2 P 13, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
NLLKAQCTSTVPRGIPPS in 838144 PEA 2 P13.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 838144 PEA 2 P15, comprising a
first amino acid
sequence being at least 90 % homologous to
MPFRLLIPLGLLCALLPQHHGAPGPDGSAPDPAHYRERVKAMFYHAYDSYLENAFPFD
ELRPLTCDGHDTWGSFSLTLIDALDTLLILGNVSEFQRVVEVLQDSVDFDIDVNASVFET
NIRVVGGLLSAHLLSKKAGVEVEAGWPCSGPLLRMAEEAARKLLPAFQTPTGMPYGTV
NLLHGVNPGETPVTCTAGIGTFIVEFATLSSLTGDPVFEDVARVALMRLWESRSDIGLV
GNHIDVLTGKWVAQDAGIGAGVDSYFEYLVKGAILLQDKKLMAMFLE corresponding
to amino acids 1 - 282 of CT31 HUMAN, which also corresponds to amino acids 1 -
282 of
838144 PEA 2 P15, and a second amino acid sequence being at least 70%,
optionally at least
80%, preferably at least 85%, more preferably at least 90% and most preferably
at least 95%
homologous to a polypeptide having the sequence PHWRH corresponding to amino
acids 283 -
287 of 838144 PEA 2 P15, wherein said first amino acid sequence and second
amino acid
sequence are contiguous and in a sequential order.

CA 02555509 2006-07-26
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 838144 PEA 2 P15, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence PHWRH
5 in R3 8144 PEA 2 P 15.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 838144 PEA 2 P19, comprising a
first amino acid
sequence being at least 90 % homologous to
MPFRLLIPLGLLCALLPQHHGAPGPDGSAPDPAHYRERVKAMFYHAYDSYLENAFPFD
10 ELRPLTCDGHDTWGSFSLTLIDALDTLLILGNVSEFQRVVEVLQDSVDFDIDVNASVFET
NIRVVGGLLSAHLLSKKAGVEVEAGWPCSGPLLRMAEEAARKLLPAFQTPTGMPYGTV
NLLHGVNPGETPVTCTAGIGTFIVEFATLSSLTGDPVFEDVARVALMRLWESRSDIGLV
GNHIDVLTGKWVAQDAGIGAGVDSYFEYLVKGAILLQDKKLMAMFLEYNKAIRNYTR
FDDWYLWVQMYKGTVSMPVFQSLEAYWPGLQSLIGDIDNAMRTFLNYYTVWKQFGG
15 LPEFYNIPQGYTVEKREGYPLRPELIESAMYLYRATGDPTLLELGRDAVESIEKISKVEC
GFAT corresponding to amino acids 1 - 412 of CT31 HUMAN, which also
corresponds to
amino acids 1 - 412 of 838144 PEA 2 P19, and a second amino acid sequence
being at least
70%, optionally at least 80%, preferably at least 85%, more preferably at
least 90% and most
preferably at least 95% homologous to a polypeptide having the sequence
20 KRSRSVAQAGVQWCDHDSPQP corresponding to amino acids 413 - 433 of
838144 PEA 2 P19, wherein said first amino acid sequence and second amino acid
sequence
are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 838144 PEA 2 P19, comprising a
polypeptide being
25 at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
KRSRSVAQAGVQWCDHDSPQP in 838144 PEA 2 P19.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 838144 PEA 2 P24, comprising a
first amino acid
30 sequence being at least 90 % homologous to
MPFRLLIPLGLLCALLPQHHGAPGPDGSAPDPAHYRERVKAMFYHAYDSYLENAFPFD

CA 02555509 2006-07-26
41
ELRPLTCDGHDTWGSFSLTLIDALDTLLILGNVSEFQRVVEVLQDSVDFDIDVNASVFET
NIR corresponding to amino acids 1 - 121 of CT31 HUMAN, which also corresponds
to amino
acids 1 - 121 of 838144 PEA 2 P24, and a second amino acid sequence being at
least 90
homologous to
EYNKAIRNYTRFDDWYLWVQMYKGTVSMPVFQSLEAYWPGLQSLIGDIDNAMRTFLN
YYTVWKQFGGLPEFYNIPQGYTVEKREGYPLRPELIESAMYLYRATGDPTLLELGRDA
VESIEKISKVECGFATIKDLRDHKLDNRMESFFLAETVKYLYLLFDPTNFIHNNGSTFDA
VITPYGECILGAGGYIFNTEAHPIDPAALHCCQRLKEEQWEVEDLMREFYSLKRSRSKFQ
KNTVSSGPWEPPARPGTLFSPENHDQARERKPAKQKVPLLSCPSQPFTSKLALLGQVFL
DSS corresponding to amino acids 282 - 578 of CT31 HUMAN, which also
corresponds to
amino acids 122 - 418 of 838144 PEA 2 P24, wherein said first amino acid
sequence and
second amino acid sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of 838144 PEA 2
P24, comprising
a polypeptide having a length "n", wherein n is at least about 10 amino acids
in length,
optionally at least about 20 amino acids in length, preferably at least about
30 amino acids in
length, more preferably at least about 40 amino acids in length and most
preferably at least
about 50 amino acids in length, wherein at least two amino acids comprise RE,
having a
structure as follows: a sequence starting from any of amino acid numbers 121-x
to 121; and
ending at any of amino acid numbers 122+ ((n-2) - x), in which x varies from 0
to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 838144 PEA 2 P36, comprising a
first amino acid
sequence being at least 90 % homologous to
MPFRLLIPLGLLCALLPQHHGAPGPDGSAPDPAHYR corresponding to amino acids 1 - 36
of AAH16184, which also corresponds to amino acids 1 - 36 of 838144 PEA 2 P36,
and a
second amino acid sequence being at least 70%, optionally at least 80%,
preferably at least 85%,
more preferably at least 90% and most preferably at least 95% homologous to a
polypeptide
having the sequence FWGMSQNSKEWLKCSRTAWTLILM corresponding to amino acids 37
- 60 of 838144 PEA 2 P36, wherein said first amino acid sequence and second
amino acid
sequence are contiguous and in a sequential order.

CA 02555509 2006-07-26
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According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 838144 PEA 2 P36, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
FWGMSQNSKEWLKCSRTAWTLILM in 838144 PEA 2 P36.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 838144 PEA 2 P36, comprising a
first amino acid
sequence being at least 90 % homologous to
MPFRLLIPLGLLCALLPQHHGAPGPDGSAPDPAHY corresponding to amino acids 1 - 35 of
AAQ88943, which also corresponds to amino acids 1 - 35 of 838144 PEA 2 P36,
and a
second amino acid sequence being at least 70%, optionally at least 80%,
preferably at least 85%,
more preferably at least 90% and most preferably at least 95% homologous to a
polypeptide
having the sequence RFWGMSQNSKEWLKCSRTAWTLILM corresponding to amino acids
36 - 60 of 838144 PEA 2 P36, wherein said first amino acid sequence and second
amino acid
sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 838144 PEA 2 P36, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
RFWGMSQNSKEWLKCSRTAWTLILM in 838144 PEA 2 P36.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 838144 PEA 2 P36, comprising a
first amino acid
sequence being at least 90 % homologous to
MPFRLLIPLGLLCALLPQHHGAPGPDGSAPDPAHYR corresponding to amino acids 1 - 36
of CT31 HUMAN, which also corresponds to amino acids 1 - 36 of 838144 PEA 2
P36, and
a second amino acid sequence being at least 70%, optionally at least 80%,
preferably at least
85%, more preferably at least 90% and most preferably at least 95% homologous
to a
polypeptide having the sequence FWGMSQNSKEWLKCSRTAWTLILM corresponding to
amino acids 37 - 60 of 838144 PEA 2 P36, wherein said first amino acid
sequence and second
amino acid sequence are contiguous and in a sequential order.

CA 02555509 2006-07-26
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According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 838144 PEA 2 P36, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
FWGMSQNSKEWLKCSRTAWTLILM in 838144 PEA 2 P36.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for AA161187 P6, comprising a first
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
HTREGTLGGQKRAFPDGVEGEKGRGRAWGAASRGSAVPLTIR corresponding to amino
acids 1 - 42 of AA161187 P6, and a second amino acid sequence being at least
90
homologous to
GPCGRRVITSRIVGGEDAELGRWPWQGSLRLWDSHVCGVSLLSHRWALTAAHCFETYS
DLSDPSGWMVQFGQLTSMPSFWSLQAYYTRYFVSNIYLSPRYLGNSPYDIALVKLSAPV
TYTKHIQPICLQASTFEFENRTDCWVTGWGYIKEDEALPSPHTLQEVQVAIINNSMCNH
LFLKYSFRKDIFGDMVCAGNAQGGKDACFGDSGGPLACNKNGLWYQIGWSWGVGC
GRPNRPGVYTNISHHFEWIQKLMAQSGMSQPDPSWPLLFFPLLWALPLLGPV
corresponding to amino acids 31 - 314 of TEST HUMAN, which also corresponds to
amino
acids 43 - 326 of AA161187 P6, wherein said first amino acid sequence and
second amino acid
sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of AA161187 P6, comprising a
polypeptide being at
least 70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least
about 90% and most preferably at least about 95% homologous to the sequence
HTREGTLGGQKRAFPDGVEGEKGRGRAWGAASRGSAVPLTIR of AA161187 P6.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for AA161187 P13, comprising a first
amino acid
sequence being at least 90 % homologous to
MGARGALLLALLLARAGLRKPESQEAAPLSGPCGRRVITSRIVGGEDAELGRWPWQGS
LRLWDSHVCGVSLLSHRWALTAAHCFETYSDLSDPSGWMVQFGQLTSMPSFWSLQAY
YTRYFVSNIYLSPRYLGNSPYDIALVKLSAPVTYTKHIQPICLQASTFEFENRTDCWVTG

CA 02555509 2006-07-26
44
WGYIKEDE corresponding to amino acids 1 - 183 of TEST HUMAN, which also
corresponds
to amino acids 1 - 183 of AA161187 P13, and a second amino acid sequence being
at least
70%, optionally at least 80%, preferably at least 85%, more preferably at
least 90% and most
preferably at least 95% homologous to a polypeptide having the sequence
GSSGRHHKQLYVQPPLPQVQFPQGHLWRHG corresponding to amino acids 184 - 213 of
AA161187 P13, wherein said first amino acid sequence and second amino acid
sequence are
contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of AA161187_P13, comprising a
polypeptide being at
least 70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least
about 90% and most preferably at least about 95% homologous to the sequence
GSSGRHHKQLYVQPPLPQVQFPQGHLWRHG in AA161187_P13.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for AA161187 P14, comprising a first
amino acid
sequence being at least 90 % homologous to
MGARGALLLALLLARAGLRKPESQEAAPLSGPCGRRVITSRIVGGEDAELGRWPWQGS
LRLWDSHVCGVSLLSHRWALTAAHCFETYSDLSDPSGWMVQFGQLTSMPSFWSLQAY
YTRYFVSNIYLSPRYLGNSPYDIALVKLSAPVTYTKHIQPICLQASTFEFENRTDCWVTG
WGYIKEDE corresponding to amino acids 1 - 183 of TEST HUMAN, which also
corresponds
to amino acids 1 - 183 of AA161187 P14, and a second amino acid sequence being
at least
70%, optionally at least 80%, preferably at least 85%, more preferably at
least 90% and most
preferably at least 95% homologous to a polypeptide having the sequence
GCCLSPSHYRPHSTAISPHPPGSSGRHHKQLYVQPPLPQVQFPQGHLWRHGLCWQCPRR
EGCLLRECPCHHSQPRKASCVPVPYLTLMPTPGGGDCCPTLQMQKRRLGCCQGEEEDV
HPVYPAP corresponding to amino acids 184 - 307 of AA161187 P14, wherein said
first amino
acid sequence and second amino acid sequence are contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of AA161187_P14, comprising a
polypeptide being at
least 70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least
about 90% and most preferably at least about 95% homologous to the sequence
GCCLSPSHYRPHSTAISPHPPGSSGRHHKQLYVQPPLPQVQFPQGHLWRHGLCWQCPRR

CA 02555509 2006-07-26
EGCLLRECPCHHSQPRKASCVPVPYLTLMPTPGGGDCCPTLQMQKRRLGCCQGEEEDV
HPVYPAP in AA161187 P14.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for AA161187 P18, comprising a first
amino acid
5 sequence being at least 70%, optionally at least 80%, preferably at least
85%, more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
HTREGTLGGQKRAFPDGVEGEKGRGRAWGAASRGSAVPLTIR corresponding to amino
acids 1 - 42 of AA161187 P18, a second amino acid sequence being at least 90 %
homologous
to GPCGRRVITSRIVGGEDAELGRWPWQGSLRLWDSHVCGVSLLSHRWALTAAHCFET
10 corresponding to amino acids 31 - 86 of TEST HUMAN, which also corresponds
to amino
acids 43 - 98 of AA161187 P18, a third amino acid sequence being at least 90 %
homologous to
DLSDPSGWMVQFGQLTSMPSFWSLQAYYTRYFVSNIYLSPRYLGNSPYDIALVKLSAPV
TYTKHIQPICLQASTFEFENRTDCWVTGWGYIKEDEALPSPHTLQEVQVAIINNSMCNH
LFLKYSFRKDIFGDMVCAGNAQGGKDACF corresponding to amino acids 89 - 235 of
15 TEST IILJMAN, which also corresponds to amino acids 99 - 245 of AA161187
P18, and a
fourth amino acid sequence being at least 70%, optionally at least 80%,
preferably at least 85%,
more preferably at least 90% and most preferably at least 95% homologous to a
polypeptide
having the sequence VSVPATTPSPGKHPVSLCLI corresponding to amino acids 246 -
265 of
AA161187 P18, wherein said first amino acid sequence, second amino acid
sequence, third
20 amino acid sequence and fourth amino acid sequence are contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of AA161187 P18, comprising a
polypeptide being at
least 70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least
about 90% and most preferably at least about 95% homologous to the sequence
25 HTREGTLGGQKRAFPDGVEGEKGRGRAWGAASRGSAVPLTIR of AA161187 P18.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of AA161187_P18,
comprising a
polypeptide having a length "n", wherein n is at least about 10 amino acids in
length, optionally
at least about 20 amino acids in length, preferably at least about 30 amino
acids in length, more
30 preferably at least about 40 amino acids in length and most preferably at
least about 50 amino
acids in length, wherein at least two amino acids comprise TD, having a
structure as follows: a

CA 02555509 2006-07-26
46
sequence starting from any of amino acid numbers 98-x to 99; and ending at any
of amino acid
numbers 99+ ((n-2) - x), in which x varies from 0 to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of AA161187 P18, comprising a
polypeptide being at
least 70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least
about 90% and most preferably at least about 95% homologous to the sequence
VSVPATTPSPGKHPVSLCLI in AA161187 P18.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for AA161187 P19, comprising a first
amino acid
sequence being at least 90 % homologous to
MGARGALLLALLLARAGLRKPESQEAAPLSGPCGRRVITSRIVGGEDAELGRWPWQGS
LRLWDSHVCGVSLLSHRWALTAAHCFETYSDLSDPSGWMVQFGQLTSMPSFWSLQAY
YTRYFVSNIYLSPRYLGNSPYDIALVKLSAPVTYTKHIQPICLQASTFEFENRTDCWVTG
WGYIKEDE corresponding to amino acids 1 - 183 of TEST HUMAN, which also
corresponds
to amino acids 1 - 183 of AA161.187 P19, and a second amino acid sequence
being at least
70%, optionally at least 80%, preferably at least 85%, more preferably at
least 90% and most
preferably at least 95% homologous to a polypeptide having the sequence DKRTQ
corresponding to amino acids 184 - 188 of AA161187 P19, wherein said first
amino acid
sequence and second amino acid sequence are contiguous and in a sequential
order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of AA161187 P19, comprising a
polypeptide being at
least 70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least
about 90% and most preferably at least about 95% homologous to the sequence
DKRTQ in
AA161187 P19.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 225299 PEA 2 P2, comprising a first
amino acid
sequence being at least 90 % homologous to
MKSSGLFPFLVLLALGTLAPWAVEGSGKSFKAGVCPPKKSAQCLRYKKPECQSDWQCP
GKKRCCPDTCGIKCLDPVDTPNPTRRKPGKCPVTYGQCLMLNPPNFCEMDGQCKRDLK
CCMGMCGKSCVSPVK corresponding to amino acids 1 - 131 of ALK1 HUMAN, which also
corresponds to amino acids 1 - 131 of 225299 PEA 2 P2, and a second amino acid
sequence

CA 02555509 2006-07-26
47
being at least 70%, optionally at least 80%, preferably at least 85%, more
preferably at least
90% and most preferably at least 95% homologous to a polypeptide having the
sequence
GKQGMRAH corresponding to amino acids 132 - 139 of 225299 PEA 2 P2, wherein
said
first and second amino acid sequences are contiguous and in a sequential
order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 225299 PEA 2 P2, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
GKQGMRAH in 225299 PEA 2 P2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 225299 PEA 2 P3, comprising a first
amino acid
sequence being at least 90 % homologous to
MKSSGLFPFLVLLALGTLAPWAVEGSGKSFKAGVCPPKKSAQCLRYKKPECQSDWQCP
GKKRCCPDTCGIKCLDPVDTPNPTRRKPGKCPVTYGQCLMLNPPNFCEMDGQCKRDLK
CCMGMCGKSCVSPVK corresponding to amino acids 1 - 131 of ALKI HUMAN, which also
corresponds to amino acids 1 - 131 of 225299 PEA 2 P3, and a second amino acid
sequence
being at least 70%, optionally at least 80%, preferably at least 85%, more
preferably at least
90% and most preferably at least 95% homologous to a polypeptide having the
sequence
GEKRHHKQLRDQEVDPLEMRRHSAG corresponding to amino acids 132 - 156 of
225299 PEA 2 P3, wherein said first and second amino acid sequences are
contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 225299 PEA 2 P3, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
GEKRHHKQLRDQEVDPLEMRRHSAG in 225299 PEA 2 P3.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 225299 PEA 2 P7, comprising a first
amino acid
sequence being at least 90 % homologous to
MKSSGLFPFLVLLALGTLAPWAVEGSGKSFKAGVCPPKKSAQCLRYKKPECQSDWQCP
GKKRCCPDTCGIKCLDPVDTPNP corresponding to amino acids 1 - 81 of ALKl HUMAN,

CA 02555509 2006-07-26
48
which also corresponds to amino acids 1 - 81 of 225299 PEA 2 P7, and a second
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
RGSLGSAQ corresponding to amino acids 82 - 89 of 225299 PEA 2 P7, wherein said
first
and second amino acid sequences are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 225299 PEA 2 P7, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
RGSLGSAQ in 225299 PEA 2 P7.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 225299 PEA 2 P10, comprising a
first amino acid
sequence being at least 90 % homologous to
MKSSGLFPFLVLLALGTLAPWAVEGSGKSFKAGVCPPKKSAQCLRYKKPECQSDWQCP
GKKRCCPDTCGIKCLDPVDTPNPT corresponding to amino acids 1 - 82 of ALKl HUMAN,
which also corresponds to amino acids 1 - 82 of 225299 PEA 2 P10.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 866178 P3, comprising a first amino
acid sequence
being at least 90 % homologous to
MARMGLAGAAGRWWGLALGLTAFFLPGVHSQWQVNDSMYGFIGTDVVLHCSFANP
LPSVKITQVTWQKSTNGSKQNVAIYNPSMGVSVLAPYRERVEFLRPSFTDGTIRLSRLEL
EDEGVYICEFATFPTGNRESQLNLTVMAKPTNWIEGTQAVLRAKKGQDDKVLVATCTS
ANGKPPSVVSWETRLKGEAEYQEIRNPNGTVTVISRYRLVPSREAHQQSLACIVNYHM
DRFKESLTLNVQYEPEVTIEGFDGNWYLQRMDVKLTCKADANPPATEYHWTTLNGSLP
KGVEAQNRTLFFKGPINYSLAGTYICEATNPIGTRSGQVEVNIT corresponding to amino
acids 1 - 334 of PVR1 HUMAN, which also corresponds to amino acids 1 - 334 of
866178 P3,
and a second amino acid sequence being at least 70%, optionally at least 80%,
preferably at least
85%, more preferably at least 90% and most preferably at least 95% homologous
to a
polypeptide having the sequence GEGHSLPISPGVLQTQNCGP corresponding to amino
acids
335 - 354 of 866178 P3, wherein said first amino acid sequence and second
amino acid
sequence are contiguous and in a sequential order.

CA 02555509 2006-07-26
49
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 866178 P3, comprising a
polypeptide being at least
70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least about
90% and most preferably at least about 95% homologous to the sequence
GEGHSLPISPGVLQTQNCGP in 866178 P3.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 866178 P4, comprising a first amino
acid sequence
being at least 90 % homologous to
MARMGLAGAAGRWWGLALGLTAFFLPGVHSQVVQVNDSMYGFIGTDWLHCSFANP
LPSVKITQVTWQKSTNGSKQNVAIYNPSMGVSVLAPYRERVEFLRPSFTDGTIRLSRLEL
EDEGVYICEFATFPTGNRESQLNLTVMAKPTNWIEGTQAVLRAKKGQDDKVLVATCTS
ANGKPPSVVSWETRLKGEAEYQEIRNPNGTVTVISRYRLVPSREAHQQSLACIVNYHM
DRFKESLTLNVQYEPEVTIEGFDGNWYLQRMDVKLTCKADANPPATEYHWTTLNGSLP
KGVEAQNRTLFFKGPINYSLAGTYICEATNPIGTRSGQVEVNIT corresponding to amino
acids 1 - 334 of PVRl HUMAN, which also corresponds to amino acids 1 - 334 of
866178 P4,
and a second amino acid sequence being at least 70%, optionally at least 80%,
preferably at least
85%, more preferably at least 90% and most preferably at least 95% homologous
to a
polypeptide having the sequence AFCQLIYPGKGRTRARMF corresponding to amino
acids
335 - 352 of 866178 P4, wherein said first amino acid sequence and second
amino acid
sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 866178 P4, comprising a
polypeptide being at least
70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least about
90% and most preferably at least about 95% homologous to the sequence
AFCQLIYPGKGRTRARMF in 866178 P4.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 866178 P8, comprising a first amino
acid sequence
being at least 90 % homologous to
MARMGLAGAAGRWWGLALGLTAFFLPGVHSQVVQVNDSMYGFIGTDVVLHCSFANP
LPSVKITQVTWQKSTNGSKQNVAIYNPSMGVSVLAPYRERVEFLRPSFTDGTIRLSRLEL
EDEGVYICEFATFPTGNRESQLNLTVMAKPTNWIEGTQAVLRAKKGQDDKVLVATCTS

CA 02555509 2006-07-26
ANGKPPSVVSWETRLKGEAEYQEIRNPNGTVTVISRYRLVPSREAHQQSLACIVNYHM
DRFKESLTLNVQYEPEVTIEGFDGNWYLQRMDVKLTCKADANPPATEYHWTTLNGSLP
KGVEAQNRTLFFKGPINYSLAGTYICEATNPIGTRSGQVE corresponding to amino acids 1
- 330 of PVR1 HUMAN, which also corresponds to amino acids 1 - 330 of 866178
P8, and a
5 second amino acid sequence being at least 70%, optionally at least 80%,
preferably at least 85%,
more preferably at least 90% and most preferably at least 95% homologous to a
polypeptide
having the sequence NSPTPRLLPNMGGAPGRCPRPSLGAWRGASCWC corresponding to
amino acids 331 - 363 of 866178 P8, wherein said first amino acid sequence and
second amino
acid sequence are contiguous and in a sequential order.
10 According to preferred embodiments of the present invention, there is
provided an
isolated polypeptide encoding for a tail of 866178 P8, comprising a
polypeptide being at least
70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least about
90% and most preferably at least about 95% homologous to the sequence
NSPTPRLLPNMGGAPGRCPRPSLGAWRGASCWC in 866178 P8.
15 According to preferred embodiments of the present invention, there is
provided an
isolated chimeric polypeptide encoding for HSU33147 PEA 1 P5, comprising a
first amino
acid sequence being at least 90 % homologous to
MKLLMVLMLAALSQHCYAGSGCPLLENVISKTINPQVSKTEYKELLQEFIDDNATTNAI
DELKECFLNQTDETLSNVE corresponding to amino acids 1 - 78 of MGBA HUMAN, which
20 also corresponds to amino acids 1 - 78 of HSU33147 PEA 1 P5, and a second
amino acid
sequence being at least 90 % homologous to QLIYDSSLCDLF corresponding to amino
acids 82
- 93 of MGBA HUMAN, which also corresponds to amino acids 79 - 90 of
HSU33147 PEA 1 P5, wherein said first amino acid sequence and second amino
acid
sequence are contiguous and in a sequential order.
25 According to preferred embodiments of the present invention, there is
provided an
isolated chimeric polypeptide encoding for an edge portion of HSU33147 PEA 1
P5,
comprising a polypeptide having a length "n", wherein n is at least about 10
amino acids in
length, optionally at least about 20 amino acids in length, preferably at
least about 30 amino
acids in length, more preferably at least about 40 amino acids in length and
most preferably at
30 least about 50 amino acids in length, wherein at least two amino acids
comprise EQ, having a

CA 02555509 2006-07-26
51
structure as follows: a sequence starting from any of amino acid numbers 78-x
to 78; and ending
at any of amino acid numbers 79+ ((n-2) - x), in which x varies from 0 to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HSU33147 PEA 1 P5, comprising a
first amino
acid sequence being at least 90 % homologous to
MKLLMV LMLAALS QHCYAGS GCPLLENV ISKTINPQV SKTEYKELLQEFIDDNATTNAI
DELKECFLNQTDETLSNVE corresponding to amino acids 1 - 78 of MGBA HUMAN, which
also corresponds to amino acids 1 - 78 of HSU33147 PEA 1 P5, and a second
amino acid
sequence being at least 90 % homologous to QLIYDSSLCDLF corresponding to amino
acids 82
- 93 of MGBA HUMAN, which also corresponds to amino acids 79 - 90 of
HSU33147 PEA 1 P5, wherein said first amino acid sequence and second amino
acid
sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of HSU33147 PEA 1
P5,
1 S comprising a polypeptide having a length "n", wherein n is at least about
10 amino acids in
length, optionally at least about 20 amino acids in length, preferably at
least about 30 amino
acids in length, more preferably at least about 40 amino acids in length and
most preferably at
least about 50 amino acids in length, wherein at least two amino acids
comprise EQ, having a
structure as follows: a sequence starting from any of amino acid numbers 78-x
to 78; and ending
at any of amino acid numbers 79+ ((n-2) - x), in which x varies from 0 to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M78076 PEA 1 P3, comprising a first
amino acid
sequence being at least 90 % homologous to
MGPASPAARGLSRRPGQPPLPLLLPLLLLLLRAQPAIGSLAGGSPGAAEAPGSAQVAGL
CGRLTLHRDLRTGRWEPDPQRSRRCLRDPQRVLEYCRQMYPELQIARVEQATQAIPME
RWCGGSRSGSCAHPHHQVVPFRCLPGEFVSEALLVPEGCRFLHQERMDQCESSTRRHQ
EAQEACSSQGLILHGSGMLLPCGSDRFRGVEYVCCPPPGTPDPSGTAVGDPSTRSWPPG
SRVEGAEDEEEEESFPQPVDDYFVEPPQAEEEEETVPPPSSHTLAVVGKVTPTPRPTDGV
DIYFGMPGEISEHEGFLRAKMDLEERRMRQINEVMREWAMADNQSKNLPKADRQALN
EHFQSILQTLEEQVSGERQRLVETHATRVIALINDQRRAALEGFLAALQADPPQAERVLL
ALRRYLRAEQKEQRHTLRHYQHVAAVDPEKAQQMRFQVHTHLQVIEERVNQSLGLLD

CA 02555509 2006-07-26
52
QNPHLAQELRPQIQELLHSEHLGPSELEAPAPGGSSEDKGGLQPPDSKD corresponding to
amino acids 1 - 517 of APP 1 HUMAN, which also corresponds to amino acids 1 -
517 of
M78076 PEA 1 P3, and a second amino acid sequence being at least 70%,
optionally at least
80%, preferably at least 85%, more preferably at least 90% and most preferably
at least 95%
homologous to a polypeptide having the sequence GE corresponding to amino
acids 518 - 519
of M78076 PEA 1 P3, wherein said first amino acid sequence and second amino
acid
sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M78076 PEA_1 P4, comprising a first
amino acid
sequence being at least 90 % homologous to
MGPASPAARGLSRRPGQPPLPLLLPLLLLLLRAQPAIGSLAGGSPGAAEAPGSAQVAGL
CGRLTLHRDLRTGRWEPDPQRSRRCLRDPQRVLEYCRQMYPELQIARVEQATQAIPME
RWCGGSRSGSCAHPHHQVVPFRCLPGEFVSEALLVPEGCRFLHQERMDQCESSTRRHQ
EAQEACSSQGLILHGSGMLLPCGSDRFRGVEYVCCPPPGTPDPSGTAVGDPSTRSWPPG
SRVEGAEDEEEEESFPQPVDDYFVEPPQAEEEEETVPPPSSHTLAVVGKVTPTPRPTDGV
DIYFGMPGEISEHEGFLRAKMDLEERRMRQINEVMREWAMADNQSKNLPKADRQALN
EHFQSILQTLEEQVSGERQRLVETHATRVIALINDQRRAALEGFLAALQADPPQAERVLL
ALRRYLRAEQKEQRHTLRHYQHVAAVDPEKAQQMRFQVHTHLQVIEERVNQSLGLLD
QNPHLAQELRPQIQELLHSEHLGPSELEAPAPGGSSEDKGGLQPPDSKDDTPMTLPKG
corresponding to amino acids 1 - 526 of APP1 HUMAN, which also corresponds to
amino
acids 1 - 526 of M78076_PEA 1 P4, and a second amino acid sequence being at
least 70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence
ECLTVNPSLQIPLNP corresponding to amino acids 527 - 541 of M78076 PEA 1 P4,
wherein
said first amino acid sequence and second amino acid sequence are contiguous
and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of M78076 PEA 1 P4, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
ECLTVNPSLQIPLNP in M78076_PEA 1 P4.

CA 02555509 2006-07-26
53
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M78076 PEA 1 P12, comprising a
first amino acid
sequence being at least 90 % homologous to
MGPASPAARGLSRRPGQPPLPLLLPLLLLLLRAQPAIGSLAGGSPGAAEAPGSAQVAGL
S CGRLTLHRDLRTGRWEPDPQRSRRCLRDPQRVLEYCRQMYPELQIARVEQATQAIPME
RWCGGSRSGSCAHPHHQVVPFRCLPGEFVSEALLVPEGCRFLHQERMDQCESSTRRHQ
EAQEACSSQGLILHGSGMLLPCGSDRFRGVEYVCCPPPGTPDPSGTAVGDPSTRSWPPG
SRVEGAEDEEEEESFPQPVDDYFVEPPQAEEEEETVPPPSSHTLAWGKVTPTPRPTDGV
DIYFGMPGEISEHEGFLRAKMDLEERRMRQ1NEVMREWAMADNQSKNLPKADRQALN
EHFQSILQTLEEQVSGERQRLVETHATRVIALINDQRRAALEGFLAALQADPPQAERVLL
ALRRYLRAEQKEQRHTLRHYQHVAAVDPEKAQQMRFQVHTHLQVIEERVNQSLGLLD
QNPHLAQELRPQIQELLHSEHLGPSELEAPAPGGSSEDKGGLQPPDSKDDTPMTLPKG
corresponding to amino acids 1 - 526 of APP 1 HUMAN, which also corresponds to
amino
acids 1 - 526 of M78076 PEA 1 P 12, and a second amino acid sequence being at
least 70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence
ECVCSKGFPFPLIGDSEG corresponding to amino acids 527 - 544 of M78076 PEA 1 P12,
wherein said first amino acid sequence and second amino acid sequence are
contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of M78076 PEA 1 P12, comprising a
polypeptide
being at least 70%, optionally at, least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
ECVCSKGFPFPLIGDSEG in M78076 PEA 1 P12.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M78076 PEA 1 P14, comprising a
first amino acid
sequence being at least 90 % homologous to
MGPASPAARGLSRRPGQPPLPLLLPLLLLLLRAQPAIGSLAGGSPGAAEAPGSAQVAGL
CGRLTLHRDLRTGRWEPDPQRSRRCLRDPQRVLEYCRQMYPELQIARVEQATQAIPME
RWCGGSRSGSCAHPHHQVVPFRCLPGEFVSEALLVPEGCRFLHQERMDQCESSTRRHQ
EAQEACSSQGLILHGSGMLLPCGSDRFRGVEYVCCPPPGTPDPSGTAVGDPSTRSWPPG

CA 02555509 2006-07-26
54
SRVEGAEDEEEEESFPQPVDDYFVEPPQAEEEEETVPPPSSHTLAVVGKVTPTPRPTDGV
DIYFGMPGEISEHEGFLRAKMDLEERRMRQINEVMREWAMADNQSKNLPKADRQALN
EHFQSILQTLEEQVSGERQRLVETHATRVIALINDQRR.AALEGFLAALQADPPQAERVLL
ALRRYLRAEQKEQRHTLRHYQHVAAVDPEKAQQMRFQVHTHLQVIEERVNQSLGLLD
QNPHLAQELRPQIQELLHSEHLGPSELEAPAPGGSSEDKGGLQPPDSKDDTPMTLPKGST
EQDAASPEKEKMNPLEQYERKVNASVPRGFPFHSSEIQRDEL corresponding to amino
acids 1 - 570 of APP1 HUMAN, which also corresponds to amino acids 1 - 570 of
M78076 PEA 1 P14, and a second amino acid sequence being at least 70%,
optionally at least
80%, preferably at least 85%, more preferably at least 90% and most preferably
at least 95%
homologous to a polypeptide having the sequence
VRGGTAGYLGEETRGQRPGCDSQSHTGPSKKPSAPSPLPAGTSWDRGVP corresponding
to amino acids 571 - 619 of M78076 PEA 1 P14, wherein said first amino acid
sequence and
second amino acid sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
1 S isolated polypeptide encoding for a tail of M78076 PEA 1 P 14, comprising
a polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
VRGGTAGYLGEETRGQRPGCDSQSHTGPSKKPSAPSPLPAGTSWDRGVP in
M78076 PEA 1 P14.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M78076 PEA 1 P21, comprising a
first amino acid
sequence being at least 90 % homologous to
MGPASPAARGLSRRPGQPPLPLLLPLLLLLLRAQPAIGSLAGGSPGAAEAPGSAQVAGL
CGRLTLHRDLRTGRWEPDPQRSRRCLRDPQRVLEYCRQMYPELQIARVEQATQAIPME
RWCGGSRSGSCAHPHHQVVPFRCLPGEFVSEALLVPEGCRFLHQERMDQCESSTRRHQ
EAQEACSSQGLILHGSGMLLPCGSDRFRGVEYVCCPPPGTPDPSGTAVGDPSTRSWPPG
SRVEGAEDEEEEESFPQPVDDYFVEPPQAEEEEETVPPPSSHTLAVVGKVTPTPRPTDGV
DIYFGMPGEISEHEGFLRAKMDLEERRMRQ1NEVMREWAMADNQSKNLPKADRQALN
E corresponding to amino acids 1 - 352 of APP1 HUMAN, which also corresponds
to amino
acids 1 - 352 of M78076 PEA 1 P21, and a second amino acid sequence being at
least 90
homologous to

CA 02555509 2006-07-26
AERVLLALRRYLRAEQKEQRHTLRHYQHVAAVDPEKAQQMRFQVHTHLQVIEERVNQ
SLGLLDQNPHLAQELRPQIQELLHSEHLGPSELEAPAPGGSSEDKGGLQPPDSKDDTPMT
LPKGSTEQDAASPEKEKMNPLEQYERKVNASVPRGFPFHSSEIQRDELAPAGTGVSREA
VSGLLIMGAGGGSLIVLSMLLLRRKKPYGAISHGVVEVDPMLTLEEQQLRELQRHGYE
S NPTYRFLEERP corresponding to amino acids 406 - 650 of APP1 HUMAN, which also
corresponds to amino acids 353 - 597 of M78076 PEA 1 P21, wherein said first
amino acid
sequence and second amino acid sequence are contiguous and in a sequential
order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of M78076 PEA 1
P21,
10 comprising a polypeptide having a length "n", wherein n is at least about
10 amino acids in
length, optionally at least about 20 amino acids in length, preferably at
least about 30 amino
acids in length, more preferably at least about 40 amino acids in length and
most preferably at
least about 50 amino acids in length, wherein at least two amino acids
comprise EA, having a
structure as follows: a sequence starting from any of amino acid numbers 352-x
to 352; and
15 ending at any of amino acid numbers 353+ ((n-2) - x), in which x varies
from 0 to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M78076 PEA 1 P24, comprising a
first amino acid
sequence being at least 90 % homologous to
MGPASPAARGLSRRPGQPPLPLLLPLLLLLLRAQPAIGSLAGGSPGAAEAPGSAQVAGL
20 CGRLTLHRDLRTGRWEPDPQRSRRCLRDPQRVLEYCRQMYPELQIARVEQATQAIPME
RWCGGSRSGSCAHPHHQVVPFRCLPGEFVSEALLVPEGCRFLHQERMDQCESSTRRHQ
EAQEACSSQGLILHGSGMLLPCGSDRFRGVEYVCCPPPGTPDPSGTAVGDPSTRSWPPG
SRVEGAEDEEEEESFPQPVDDYFVEPPQAEEEEETVPPPSSHTLAVVGKVTPTPRPTDGV
DIYFGMPGEISEHEGFLRAKMDLEERRMRQINEVMREWAMADNQSKNLPKADRQALN
25 EHFQSILQTLEEQVSGERQRLVETHATRVIALINDQRRAALEGFLAALQADPPQAERVLL
ALRRYLRAEQKEQRHTLRHYQHVAAVDPEKAQQMRFQVHTHLQVIEERVNQSLGLLD
QNPHLAQELRPQI corresponding to amino acids 1 - 481 of APP1 HCTMAN, which also
corresponds to amino acids 1 - 481 of M78076_PEA 1 P24, and a second amino
acid sequence
being at least 70%, optionally at least 80%, preferably at least 85%, more
preferably at least
30 90% and most preferably at least 95% homologous to a polypeptide having the
sequence
RECLLPWLPLQISEGRS corresponding to amino acids 482 - 498 of M78076 PEA 1 P24,

CA 02555509 2006-07-26
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wherein said first amino acid sequence and second amino acid sequence are
contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of M78076 PEA 1 P24, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
RECLLPWLPLQISEGRS in M78076_PEA 1 P24.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M78076 PEA 1 P2, comprising a first
amino acid
sequence being at least 90 % homologous to
MGPASPAARGLSRRPGQPPLPLLLPLLLLLLRAQPAIGSLAGGSPGAAEAPGSAQVAGL
CGRLTLHRDLRTGRWEPDPQRSRRCLRDPQRVLEYCRQMYPELQIARVEQATQAIPME
RWCGGSRSGSCAHPHHQVVPFRCLPGEFVSEALLVPEGCRFLHQERMDQCESSTRRHQ
EAQEACSSQGLILHGSGMLLPCGSDRFRGVEYVCCPPPGTPDPSGTAVGDPSTRSWPPG
1 S SRVEGAEDEEEEESFPQPVDDYFVEPPQAEEEEETVPPPSSHTLAVVGKVTPTPRPTDGV
DIYFGMPGEISEHEGFLRAKMDLEERRMRQINEVMREWAMADNQSKNLPKADRQALN
EHFQSILQTLEEQVSGERQRLVETHATRVIALINDQRR.AALEGFLAALQADPPQAERVLL
ALRRYLRAEQKEQRHTLRHYQHVAAVDPEKAQQMRFQV corresponding to amino acids
1 - 449 of APP1 HCTMAN, which also corresponds to amino acids 1 - 449 of
M78076 PEA_1 P2, and a second amino acid sequence being at least 70%,
optionally at least
80%, preferably at least 85%, more preferably at least 90% and most preferably
at least 95%
homologous to a polypeptide having the sequence
LTSFQLPNAPLFLRRPRLRLFSCPLDPLSVSWTPSYPLNTASLPLPSLSAQLPDPETWTLT
CCVFDPCFLALGFLLPPPSILCSVPWIFTAFPRIVFFFFFFLRQVLALSPRQESSVRSWLIAT
STSWVQAILLPQPLE corresponding to amino acids 450 - 588 of M78076 PEA 1 P2,
wherein said first amino acid sequence and second amino acid sequence are
contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of M78076 PEA 1 P2, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence

CA 02555509 2006-07-26
57
LTSFQLPNAPLFLRRPRLRLFSCPLDPLSVSWTPSYPLNTASLPLPSLSAQLPDPETWTLT
CCVFDPCFLALGFLLPPPSILCSVPWIFTAFPRIVFFFFFFLRQVLALSPRQESSVRSWLIAT
STSWVQAILLPQPLE in M78076 PEA 1 P2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M78076 PEA 1 P25, comprising a
first amino acid
sequence being at least 90 % homologous to
MGPASPAARGLSRRPGQPPLPLLLPLLLLLLRAQPAIGSLAGGSPGAAEAPGSAQVAGL
CGRLTLHRDLRTGRWEPDPQRSRRCLRDPQRVLEYCRQMYPELQIARVEQATQAIPME
RWCGGSRSGSCAHPHHQVVPFRCLPGEFVSEALLVPEGCRFLHQERMDQCESSTRRHQ
EAQEACSSQGLILHGSGMLLPCGSDRFRGVEYVCCPPPGTPDPSGTAVGDPSTRSWPPG
SRVEGAEDEEEEESFPQPVDDYFVEPPQAEEEEETVPPPSSHTLAVVGKVTPTPRPTDGV
DIYFGMPGEISEHEGFLRAKMDLEERRMRQINEVMREWAMADNQSKNLPKADRQALN
EHFQSILQTLEEQVSGERQRLVETHATRVIALINDQRRAALEGFLAALQADPPQAERVLL
ALRRYLRAEQKEQRHTLRHYQHVAAVDPEKAQQMRFQ corresponding to amino acids 1
- 448 of APP1 HUMAN, which also corresponds to amino acids 1 - 448 of
M78076 PEA 1 P25, and a second amino acid sequence being at least 70%,
optionally at least
80%, preferably at least 85%, more preferably at least 90% and most preferably
at least 95%
homologous to a polypeptide having the sequence
PQNPNSQPRAAGSLEVIISHPFVRRLEILISPFQFQNSIPKNSQIVPAASPRGTSSP
corresponding to amino acids 449 - 505 of M78076_PEA 1 P25, wherein said first
amino acid
sequence and second amino acid sequence are contiguous and in a sequential
order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of M78076 PEA 1 P25, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
PQNPNSQPRAAGSLEVIISHPFVRRLEILISPFQFQNSIPKNSQIVPAASPRGTSSP in
M78076 PEA 1 P25.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M79217 PEA 1 P1, comprising a first
amino acid
sequence being at least 90 % homologous to
MTGYTMLRNGGAGNGGQTCMLRWSNRIRLTWLSFTLFVILVFFPLIAHYYLTTLDEAD

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EAGKRIFGPRV GNELCEVKHV LDLCRIRES V SEELLQLEAKRQELNSE1AKLNLKIEACK
KSIENAKQDLLQLKNVISQTEHSYKELMAQNQPKLSLPIRLLPEKDDAGLPPPKATRGC
RLHNCFDYSRCPLTSGFPVWYDSDQFVFGSYLDPLVKQAFQATARANVWTENADIA
CLWILVGEMQEPVVLRPAELEKQLYSLPHWRTDGHNHVIINLSRKSDTQNLLYNVSTG
RAMVAQSTFYTVQYRPGFDLWSPLVHAMSEPNFMEIPPQVPVKRKYLFTFQGEKIESL
RSSLQEARSFEEEMEGDPPADYDDRIIATLKAVQDSKLDQVLVEFTCKNQPKPSLPTEW
ALCGEREDRLELLKLSTFALIITPGDPRLVISSGCATRLFEALEVGAVPWLGEQVQLPY
QDMLQWNEAALVVPKPRVTEVHFLLRSLSDSDLLAMRRQGRFLWETYFSTADSIFNTV
LAMIRTRIQIPAAPIREEAAAEIPHRSGKAAGTDPNMADNGDLDLGPVETEPPYASPRYL
RNFTLTVTDFYRSWNCAPGPFHLFPHTPFDPVLPSEAKFLGSGTGFRPIGGGAGGSGKEF
QAALGGNVPREQFTV VMLTYEREEVLMNSLERLNGLPYLNKV V V V WNSPKLPSEDLL
WPDIGVPIMWRTEKNSLNNRFLPWNEIETEAILSIDDDAHLRHDEIMFGFRV WREARD
RIVGFPGRYHAWDIPHQSWLYNSNYSCELSMVLTGAAFFHKWAYLYSWMPQAIRD
MVDEYINCEDIAMNFLV SHITRKPPIKVTSRWTFRCPGCPQALSHDDSHFHERHKCINFF
VKVYGYMPLLYTQFRVDSVLFKTRLPHDKTKCFKFI corresponding to amino acids 13 -
931 of BAA25445, which also corresponds to amino acids 1 - 919 of M79217 PEA 1
P1.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M79217 PEA 1 P2, comprising a first
amino acid
sequence being at least 90 % homologous to
MTGYTMLRNGGAGNGGQTCMLRWSNRIRLTWLSFTLFVILVFFPLIAHWLTTLDEAD
EAGKRIFGPRVGNELCEVKHVLDLCRIRESVSEELLQLEAKRQELNSEIAKLNLKIEACK
KSIENAKQDLLQLKNVISQTEHSYKELMAQNQPKLSLPIRLLPEKDDAGLPPPKATRGC
RLHNCFDYSRCPLTSGFPVYVYDSDQFVFGSYLDPLVKQAFQATARANVWTENADIA
CLWILVGEMQEPWLRPAELEKQLYSLPHWRTDGHNHVIINLSRKSDTQNLLYNVSTG
RAMVAQSTFYTVQYRPGFDLVVSPLVHAMSEPNFMEIPPQVPVKRKYLFTFQGEKIESL
RSSLQEARSFEEEMEGDPPADYDDRIIATLKAVQDSKLDQVLVEFTCKNQPKPSLPTEW
ALCGEREDRLELLKLSTFALIITPGDPRLVISSGCATRLFEALEVGAVPVVLGEQVQLPY
QDMLQWNEAALVVPKPRVTEVHFLLRSLSDSDLLAMRRQGRFLWETYFSTADSIFNTV
LAMIRTRIQIPAAPIREEAAAEIPHRSGKAAGTDPNMADNGDLDLGPVETEPPYASPRYL
RNFTLTVTDFYRSWNCAPGPFHLFPHTPFDPVLPSEAKFLGSGTGFRPIGGGAGGSGKEF
QAALGGNVPREQFTV VMLTYEREEV LMNSLERLNGLPYLNKV W V WNSPKLP SEDLL

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WPDIGVPIMV VRTEKNSLNNRFLP WNEIETEAILS IDDDAHLRHDEIMFGFRV WREARD
RIVGFPGRYHAWDIPHQSWLYNSNYSCELSMVLTGAAFFHK corresponding to amino
acids 1 - 807 of EXL3 HUMAN, which also corresponds to amino acids 1 - 807 of
M79217 PEA 1 P2, and a second amino acid sequence being at least 90 %
homologous to
AIRDMVDEYINCEDIAMNFLVSHITRKPPIKVTSRWTFRCPGCPQALSHDDSHFHERHK
CINFFVKVYGYMPLLYTQFRVDSVLFKTRLPHDKTKCFKFI corresponding to amino acids
820 - 919 of EXL3 HUMAN, which also corresponds to amino acids 808 - 907 of
M79217 PEA 1 P2; wherein said first amino acid sequence and second amino acid
sequence
are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of M79217 PEA 1 P2,
comprising
a polypeptide having a length "n", wherein n is at least about 10 amino acids
in length,
optionally at least about 20 amino acids in length, preferably at least about
30 amino acids in
length, more preferably at least about 40 amino acids in length and most
preferably at least
about 50 amino acids in length, wherein at least two amino acids comprise KA,
having a
structure as follows: a sequence starting from any of amino acid numbers 807-x
to 807; and
ending at any of amino acid numbers 808+ ((n-2) - x), in which x varies from 0
to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M79217 PEA 1 P4, comprising a first
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
PELRQPARLGLPECWDYRHEPRCPAQMGSHFIVQAGLKLLASSKPPKCWDY
corresponding to amino acids 1 - 51 of M79217 PEA 1 P4, and a second amino
acid sequence
being at least 90 % homologous to
RVWREARDRIVGFPGRYHAWDIPHQSWLYNSNYSCELSMVLTGAAFFHKYYAYLYSY
VMPQAIRDMVDEYINCEDIAMNFLVSHITRKPPIKVTSRWTFRCPGCPQALSHDDSHFH
ERHKCINFFVKVYGYMPLLYTQFRVDSVLFKTRLPHDKTKCFKFI corresponding to
amino acids 759 - 919 of EXL3 HUMAN, which also corresponds to amino acids 52 -
212 of
M792I7 PEA 1 P4,~wherein said first amino acid sequence and second amino acid
sequence
are contiguous and in a sequential order.

CA 02555509 2006-07-26
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of M79217_PEA 1 P4, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
S PELRQPARLGLPECWDYRHEPRCPAQMGSHFIVQAGLKLLASSKPPKCWDY of
M79217 PEA 1 P4.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M79217_PEA 1 P8, comprising a first
amino acid
sequence being at least 90 % homologous to
10 MTGYTMLRNGGAGNGGQTCMLRWSNRIRLTWLSFTLFVILVFFPLIAHYYLTTLDEAD
EAGKRIFGPRVGNELCEVKHVLDLCRIRESVSEELLQLEAKRQELNSEIAKLNLKIEACK
KSIENAKQDLLQLKNVISQTEHSYKELMAQNQPKLSLPIRLLPEKDDAGLPPPKATRGC
RLHNCFDYSRCPLTSGFPVYVYDSDQFVFGSYLDPLVKQAFQATARANVYVTENADIA
CLYVILVGEMQEPVVLRPAELEKQLYSLPHWRTDGHNHVIINLSRKSDTQNLLYNVSTG
15 RAMVAQSTFYTVQYRPGFDLVVSPLVHAMSEPNFMEIPPQVPVKRKYLFTFQGEKIESL
RSSLQEARSFEEEMEGDPPADYDDRIIATLKAVQDSKLDQVLVEFTCKNQPKPSLPTEW
ALCGEREDRLELLKLSTFALIITPGDPRLVISSGCATRLFEALEVGAVPVVLGEQVQLPY
QDMLQWNEAALVVPKPRVTEVHFLLRSLSDSDLLAMRRQGRFLWETYFSTADSIFNTV
LAMIRTRIQIPAAPIREEAAAEIPHRSGKAAGTDPNMADNGDLDLGPVETEPPYASPRYL
20 RNFTLTVTDFYRSWNCAPGPFHLFPHTPFDPVLPSEAKFLGSGTGFRPIGGGAGGSGKEF
QAALGGNVPREQFTV VMLTYEREEVLMNSLERLNGLPYLNKW V V WNSPKLPSEDLL
WPDIGVPIMVVRTEKNSLNNRFLPWNEIETEAILSIDDDAHLRHDEIMFGFRVWREARD
RIVGFPGRYHAWDIPHQSWLYNSNYSCELSMVLTGAAFFHK corresponding to amino
acids 1 - 807 of EXL3 HUMAN, which also corresponds to amino acids 1 - 807 of
25 M79217 PEA 1 P8, and a second amino acid sequence being at least 70%,
optionally at least
80%, preferably at least 85%, more preferably at least 90% and most preferably
at least 95%
homologous to a polypeptide having the sequence VRKSW corresponding to amino
acids 808
812 of M79217 PEA 1 P8, wherein said first amino acid sequence and second
amino acid
sequence are contiguous and in a sequential order.
30 According to preferred embodiments of the present invention, there is
provided an
isolated polypeptide encoding for a tail of M79217 PEA 1 P8, comprising a
polypeptide being

CA 02555509 2006-07-26
61
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence VRKSW
in M79217 PEA 1 P8.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M62096 PEA 1 P4, comprising a first
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MATYIH corresponding to amino acids 1 - 6 of M62096 PEA 1 P4, and a second
amino acid
sequence being at least 90 % homologous to
VSKTGAEGAVLDEAKNINKSLSALGNVISALAEGTKTHVPYRDSKMTRILQDSLGGNC
RTTIVICCSPSVFNEAETKSTLMFGQRAKTIKNTVSVNLELTAEEWKKKYEKEKEKNKT
LKNVIQHLEMELNRWRNGEAVPEDEQISAKDQKNLEPCDNTPID~NIAPV VAGISTEEKE
KYDEEISSLYRQLDDKDDEINQQSQLAEKLKQQMLDQDELLASTRRDYEKIQEELTRLQ
IENEAAKDEVKEVLQALEELAVNYDQKSQEVEDKTRANEQLTDELAQKTTTLTTTQRE
LSQLQELSNHQKKRATEILNLLLKDLGEIGGIIGTNDVKTLADVNGVIEEEFTMARLYIS
KMKSEVKSLVNRSKQLESAQMDSNRKMNASERELAACQLLISQHEAKIKSLTDYMQN
MEQKRRQLEESQDSLSEELAKLRAQEKMHEVSFQDKEKEHLTRLQDAEEMKKALEQQ
MESHREAHQKQLSRLRDEIEEKQKImEIRDLNQKLQLEQEKLS SDYNKLKIEDQEREM
KLEKLLLLNDKREQAREDLKGLEETVSRELQTLHNLRKLFVQDLTTRVKKSVELDNDD
GGGSAAQKQKISFLENNLEQLTKVHKQLVRDNADLRCELPKLEKRLRATAERVKALES
ALKEAKENAMRDRKRYQQEVDRIKEAVRAKNMARRAHSAQIAKPIRPGHYPAS SPTA
VHAIRGGGGSSSNSTHYQK corresponding to amino acids 239 - 957 of KFSC_HUMAN,
which also corresponds to amino acids 7 - 725 of M62096 PEA 1 P4, wherein said
first amino
acid sequence and second amino acid sequence are contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of M62096 PEA 1 P4, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
MATYIH of M62096 PEA 1 P4.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M62096 PEA 1 P5, comprising a first
amino acid

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sequence being at least 90 % homologous to
MTRILQDSLGGNCRTTIVICCSPSVFNEAETKSTLMFGQRAKTIKNTVSVNLELTAEEWK
KKYEKEKEKNKTLKNVIQHLEMELNRWRNGEAVPEDEQISAKDQKNLEPCDNTPIIDNI
APWAGISTEEKEKYDEEISSLYRQLDDKDDEINQQSQLAEKLKQQMLDQDELLASTRR
DYEKIQEELTRLQIENEAAKDEVKEVLQALEELAVNYDQKSQEVEDKTRANEQLTDEL
AQKTTTLTTTQRELSQLQELSNHQKKRATEILNLLLKDLGEIGGIIGTNDVKTLADVNG
VIEEEFTMARLYISKMKSEVKSLVNRSKQLESAQMDSNRKMNASERELAACQLLISQHE
AKIKSLTDYMQNMEQKRRQLEESQDSLSEELAKLRAQEKMHEVSFQDKEKEHLTRLQ
DAEEMKKALEQQMESHREAHQKQLSRLRDEIEEKQKIIDEIRDLNQKLQLEQEKLSSDY
NKLKIEDQEREMKLEKLLLLNDKREQAREDLKGLEETVSRELQTLHNLRKLFVQDLTT
RVKKSVELDNDDGGGSAAQKQKISFLENNLEQLTKVHKQLVRDNADLRCELPKLEKRL
RATAERVKALESALKEAKENAMRDRKRYQQEVDRIKEAVRAKNMARRAHSAQIAKPI
RPGHYPASSPTAVHAIRGGGGSSSNSTHYQK corresponding to amino acids 284 - 957 of
KFSC_HUMAN, which also corresponds to amino acids 1 - 674 of M62096 PEA 1 P5.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M62096 PEA 1 P3, comprising a first
amino acid
sequence being at least 90 % homologous to
MELNRWRNGEAVPEDEQISAKDQKNLEPCDNTPIIDNIAPWAGISTEEKEKYDEEISSL
YRQLDDKDDE1NQQSQLAEKLKQQMLDQDELLASTRRDYEKIQEELTRLQIENEAAKD
EVKEVLQALEELAVNYDQKSQEVEDKTRANEQLTDELAQKTTTLTTTQRELSQLQELS
NHQKKRATEILNLLLKDLGEIGGIIGTNDVKTLADVNGVIEEEFTMARLYISKMKSEVKS
LVNRSKQLESAQMDSNRI~1VII~TASERELAACQLLISQHEAKIKSLTDYMQNMEQKRRQL
EESQDSLSEELAKLRAQEKMHEVSFQDKEKEHLTRLQDAEEMKKALEQQMESHREAH
QKQLSRLRDEIEEKQKIIDEIRDLNQKLQLEQEKLSSDYNKLKIEDQEREMKLEKLLLLN
DKREQAREDLKGLEETVSRELQTLHNLRKLFVQDLTTRVKKSVELDNDDGGGSAAQK
QKISFLENNLEQLTKVHKQLVRDNADLRCELPKLEKRLRATAERVKALESALKEAKEN
AMRDRKRYQQEVDRIKEAVRAKNMARRAHSAQIAKPIRPGHYPASSPTAVHAIRGGGG
SSSNSTHYQK corresponding to amino acids 365 - 957 of KFSC HUMAN, which also
corresponds to amino acids 1 - 593 of M62096 PEA 1 P3.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M62096 PEA 1 P7, comprising a first
amino acid

CA 02555509 2006-07-26
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sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MTQNFRLMWNILLFPLNFS corresponding to amino acids 1 - 19 of M62096_PEA 1 P7,
and
a second amino acid sequence being at least 90 % homologous to
LNQKLQLEQEKLSSDYNKLKIEDQEREMKLEKLLLLNDKREQAREDLKGLEETVSREL
QTLHNLRKLFVQDLTTRVKKSVELDNDDGGGSAAQKQKISFLENNLEQLTKVHKQLVR
DNADLRCELPKLEKRLRATAERVKALESALKEAKENAMRDRKRYQQEVDRIKEAVRA
KNMARRAHSAQIAKPIRPGHYPASSPTAVHAIRGGGGSSSNSTHYQK corresponding to
amino acids 738 - 957 of KFSC_HUMAN, which also corresponds to amino acids 20 -
239 of
M62096 PEA 1 P7, wherein said first amino acid sequence and second amino acid
sequence
are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of M62096 PEA 1 P7, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
MTQNFRLMWNILLFPLNFS of M62096 PEA 1 P7.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M62096_PEA 1 P8, comprising a first
amino acid
sequence being at least 90 % homologous to
MADPAECSIKVMCRFRPLNEAEILRGDKFIPKFKGDETVVIGQGKPYVFDRVLPPNTTQ
EQVYNACAKQIVKDVLEGYNGTIFAYGQTSSGKTHTMEGKLHDPQLMGIIPRIAHDIFD
HIYSMDENLEFHIKVSYFEIYLDKIRDLLDVSKTNLAVHEDKNRVPYVKGCTERFVSSPE
EVMDVIDEGKANRHVAVTNMNEHSSRSHSIFLINIKQENVETEKKLSGKLYLVDLAGSE
KVSKTGAEGAVLDEAKNINKSLSALGNVISALAEGTKTHVPYRDSKMTRILQDSLGGN
CRTTIVICCSPSVFNEAETKSTLMFGQRAKTIKNTVSVNLELTAEEWKKKYEKEKEKNK
TLKNVIQHLEMELNRWRNGEAVPEDEQISAKDQKNLEPCDNTPIIDNIAPWAGISTEEK
EKYDEEIS SLYRQLDDKDDEINQQSQLAEKLKQQMLDQDELLASTRRDYEKIQEELTRL
QIENEAAKDEVKEVLQALEELAVNYDQKSQEVEDKTRANEQLTDELAQKTTTLTTTQR
ELSQLQELSNHQKKRATEILNLLLKDLGEIGGIIGTNDVKTLADVNGVIEEEFTMARLYI
SKMKSEVKSLVNRSKQLESAQMDSNRKMNASERELAACQLLISQHEAKIKSLTDYMQN

CA 02555509 2006-07-26
64
MEQKRRQLEESQDSLSEELAKLRAQEKMHEVSFQDKEKEHLTRLQDAEEMKKALEQQ
MESHREAHQKQLSRLRDEIEEKQKIIDEIR corresponding to amino acids 1 - 736 of
KFSC HUMAN, which also corresponds to amino acids 1 - 736 of M62096 PEA 1 P8,
and a
second amino acid sequence being at least 70%, optionally at least 80%,
preferably at least 85%,
more preferably at least 90% and most preferably at least 95% homologous to a
polypeptide
having the sequence E corresponding to amino acids 737 - 737 of M62096 PEA 1
P8, wherein
said first amino acid sequence and second amino acid sequence are contiguous
and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M62096 PEA 1 P9, comprising a first
amino acid
sequence being at least 90 % homologous to
MADPAECSIKVMCRFRPLNEAEILRGDKFIPKFKGDETVVIGQGKPYVFDRVLPPNTTQ
EQVYNACAKQIVKDVLEGYNGTIFAYGQTSSGKTHTMEGKLHDPQLMGIIPRIAHDIFD
HIYSMDENLEFH1KVSYFEIYLDKIRDLLDVSKTNLAVHEDKNRVPYVKGCTERFVSSPE
EVMDVIDEGR;ANRHVAVTNMNEHSSRSHSIFLINIKQENVETEKKLSGKLYLVDLAGSE
KVSKTGAEGAVLDEAKNINI~SLSALGNVISALAEGTKTHVPYRDSKMTRILQDSLGGN
CRTTIV ICC SP S VFNEAETKS TLMFGQRAKTIKNTV S VNLELTAEE WKKKYEKEKEKNK
TLKNVIQHLEMELNRWRNGEAVPEDEQISAKDQKNLEPCDNTPIIDNIAPV VAGISTEEK
EKYDEEISSLYRQLDDKDDEINQQSQLAEKLKQQMLDQDE corresponding to amino acids
1 - 454 of KFSC HUMAN, which also corresponds to amino acids 1 - 454 of
M62096 PEA 1 P9, and a second amino acid sequence being at least 70%,
optionally at least
80%, preferably at least 85%, more preferably at least 90% and most preferably
at least 95%
homologous to a polypeptide having the sequence
VKNAIYFFFHKVLLLLFVVDVCSRNLIGIEAFHfNYRIMWKFLGRCPFTASYKLIITEFRK
corresponding to amino acids 455 - 514 of M62096 PEA 1 P9, wherein said first
amino acid
sequence and second amino acid sequence are contiguous and in a sequential
order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of M62096 PEA 1 P9, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence

CA 02555509 2006-07-26
VKNAIYFFFHKVLLLLFVVDVCSRNLIGIEAFHfNYRIMWKFLGRCPFTASYKLIITEFRK
in M62096 PEA 1 P9.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M62096 PEA 1 P10, comprising a
first amino acid
5 sequence being at least 70%, optionally at least 80%, preferably at least
85%, more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MTQNFRLMWNILLFPLNFS corresponding to amino acids 1 - 19 of M62096_PEA 1 P 10,
a
second amino acid sequence being at least 90 % homologous to
LNQKLQLEQEKLS SDYNKLKIEDQEREMKLEKLLLLNDKREQARED LKGLEETV SREL
10 QTLHNLRKLFVQDLTTRVKK corresponding to amino acids 738 - 81 S of KFSC HUMAN,
which also corresponds to amino acids 20 - 97 of M62096 PEA 1 P 10, and a
third amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
VSSLCLNGTEKKIKDGREESFSVEISLA corresponding to amino acids 98 - 125 of
15 M62096 PEA 1 P 10, wherein said first amino acid sequence, second amino
acid sequence and
third amino acid sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of M62096_PEA 1 P 10, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
20 at least about 90% and most preferably at least about 95% homologous to the
sequence
MTQNFRLMWNILLFPLNFS of M62096 PEA 1 P10.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of M62096 PEA 1 P10, comprising a
polypeptide
being at least 70%, optionally at.least about 80%, preferably at least about
85%, more preferably
25 at least about 90% and most preferably at least about 95% homologous to the
sequence
VSSLCLNGTEKKIKDGREESFSVEISLA in M62096 PEA 1 P10.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M62096 PEA 1 P11, comprising a
first amino acid
sequence being at least 90 % homologous to
30 MADPAECSIKVMCRFRPLNEAEILRGDKFIPKFKGDETVVIGQGKPYVFDRVLPPNTTQ
EQVYNACAKQIVKDVLEGYNGTIFAYGQTSSGKTHTMEGKLHDPQLMGIIPRIAHI~IFD

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HIYSMDENLEFHIKVSYFEIYLDKIRDLLDVSKTNLAVHEDKNRVPYVKGCTERFVSSPE
EVMDVIDEGKANRHVAVTNMNEHSSRSHSIFLINIKQENVETEKKLSGKLYLVDLAGSE
KVSKTGAEGAVLDEAKNINKSLSALGNVISALAEGTKTHVPYRDSKMTRILQDSLGGN
CRTTIV IC C SP S VFNEAETKS TLMFGQRAKTIKNTV S VNLELTAEE WKKKYEKEKEKNK
TLKNVIQHLEMELNRWRN corresponding to amino acids 1 - 372 of KFSC HUMAN, which
also corresponds to amino acids 1 - 372 of M62096 PEA 1 P11, and a second
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
DFLAAHVFGKLLE corresponding to amino acids 373 - 385 of M62096 PEA 1 P11,
wherein
said first amino acid sequence and second amino acid sequence are contiguous
and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of M62096 PEA 1 P11, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
DFLAAHVFGKLLE in M62096 PEA 1 P11.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M62096_PEA 1 P 12, comprising a
first amino acid
sequence being at least 90 % homologous to
MADPAECSIKVMCRFRPLNEAEILRGDKFIPKFKGDETVVIGQGKPYVFDRVLPPNTTQ
EQVYNACAKQIVKDVLEGYNGTIFAYGQTSSGKTHTMEGKLHDPQLMGIIPRIAHDIFD
HIYSMDENLEFHIKVSYFEIYLDKIRDLLDVSKTNLAVHEDKNRVPYVKGCTERFVSSPE
EVMDVIDEGKANRHVAVTNMNEHSSRSHSIFLINIKQENVETEKKLSGKLYLVDLAGSE
KVSKTGAEGAVLDEAKNINKSLSALGNVISALAEGTKTHVPYRDSKMTRILQDSLGGN
CRTTNICCSPSVFNEAETKSTLMFGQR corresponding to amino acids 1 - 323 of
KFSC_HUMAN, which also corresponds to amino acids 1 - 323 of M62096_PEA 1 P12,
and a
second amino acid sequence being at least 70%, optionally at least 80%,
preferably at least 85%,
more preferably at least 90% and most preferably at least 95% homologous to a
polypeptide
having the sequence V corresponding to amino acids 324 - 324 of M62096 PEA 1
P12,
wherein said first amino acid sequence and second amino acid sequence are
contiguous and in a
sequential order.

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According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for T99080 PEA 4 P5, comprising a first
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MPASARLAGAGLLLAFLRALGCAGRAPGLS corresponding to amino acids 1 - 30 of
T99080 PEA 4 PS, and a second amino acid sequence being at least 90 %
homologous to
MAEGNTLISVDYEIFGKVQGVFFRKHTQAEGKKLGLVGWVQNTDRGTVQGQLQGPIS
KVRHMQEWLETRGSPKSHIDKANFNNEKVILKLDYSDFQIVK corresponding to amino
acids 1 - 99 of ACYO HUMAN V1, which also corresponds to amino acids 31 - 129
of
T99080 PEA 4 P5, wherein said first amino acid sequence and second amino acid
sequence
are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of T99080 PEA 4 PS, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
MPASARLAGAGLLLAFLRALGCAGRAPGLS of T99080 PEA 4 P5.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for T99080 PEA 4 P8, comprising a first
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence M
corresponding to amino acids 1 - 1 of T99080 PEA 4 P8, and a second amino acid
sequence
being at least 90 % homologous to
QAEGKKLGLVGWVQNTDRGTVQGQLQGPISKVRHMQEWLETRGSPKSHIDR:~~NFNNE
KVILKLDYSDFQIVK corresponding to amino acids 28 - 99 of ACYO HUMAN V 1, which
also corresponds to amino acids 2 - 73 of T99080 PEA 4 P8, wherein said first
amino acid
sequence and second amino acid sequence are contiguous and in a sequential
order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for T08446 PEA 1 P18, comprising a
first amino acid
sequence being at least 90 % homologous to
MLSLSLCSHLWGPLILSALQARSTDSLDGPGEGSVQPLPTAGGPSVKGKPGKRLSAPRG
PFPRLADCAHFHYENVDFGHIQLLLSPDREGPSLSGENELVFGVQVTCQGRSWPVLRSY

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DDFRSLDAHLHRCIFDRRFSCLPELPPPPEGARAAQMLVPLLLQYLETLSGLVDSNLNC
GPVLTWME corresponding to amino acids 1 - 185 of SNXQ-HUMAN, which also
corresponds to amino acids 1 - 185 of T08446 PEA 1 P18, and a second amino
acid sequence
being at least 70%, optionally at least 80%, preferably at least 85%, more
preferably at least
90% and most preferably at least 95% homologous to a polypeptide having the
sequence
LDNHGRRLLLSEEASLNIPAVAAAHVIKRYTAQAPDELSFEVGDIVSVIDMPPTEDRSW
WRGKRGFQVGFFPSECVELFTERPGPGLKADADGPPCGIPAPQGISSLTSAVPRPRGKLA
GLLRTFMRSRPSRQRLRQRGILRQRVFGCDLGEHLSNSGQDVPQVLRCCSEFIEAHGVV
DGIYRLS GV S SNIQRLRHEFD SERIPELS GPAFLQDIHS V S S LCKLYFRELPNPLLTYQLY
GKFSEAMSVPGEEERLVRVHDVIQQLPPPHYRTLEYLLRHLARMARHSANTSMHARNL
AIVWAPNLLRSMELESVGMGGAAAFREVRVQSVVVEFLLTHVDVLFSDTFTSAGLDPA
GRCLLPRPKSLAGSCPSTRLLTLEEAQARTQGRLGTPTEPTTPKAPASPAERRKGERGEK
QRKPGGSSWKTFFALGRGPSVPRKKPLPWLGGTRAPPQPSGSRPDTVTLRSAKSEESLS
SQASGAGLQRLHRLRRPHSSSDAFPVGPAPAGSCESLSSSSSSESSSSESSSSSSESSAAGL
GALSGSPSHRTSAWLDDGDELDFSPPRCLEGLRGLDFDPLTFRCSSPTPGDPAPPASPAP
PAPASAFPPRVTPQAISPRGPTSPASPAALDISEPLAVSVPPAVLELLGAGGAPASATPTP
ALSPGRSLRPHLIPLLLRGAEAPLTDACQQEMCSKLRGAQGPLGPDMESPLPPPPLSLLR
PGGAPPPPPKNPARLMALALAERAQQVAEQQSQQECGGTPPASQSPFHRSLSLEVGGEP
LGTSGSGPPPNSLAHPGAWVPGPPPYLPRQQSDGSLLRSQRPMGTSRRGLRGPAQVSAQ
LRAGGGGRDAPEAAAQSPCSVPSQVPTPGFFSPAPRECLPPFLGVPKPGLYPLGPPSFQP
SSPAPVWRSSLGPPAPLDRGENLYYEIGASEGSPYSGPTRSWSPFRSMPPDRLNASYGM
LGQSPPLHRSPDFLLSYPPAPSCFPPDHLGYSAPQHPARRPTPPEPLYVNLALGPRGPSPA
SSSSSSPPAHPRSRSDPGPPVPRLPQKQRAPWGPRTPHRVPGPWGPPEPLLLYR.AAPPAY
GRGGELHRGSLYRNGGQRGEGAGPPPPYPTPSWSLHSEGQTRSYC corresponding to
amino acids 186 - 1305 of T08446_PEA 1 P18, wherein said first amino acid
sequence and
second amino acid sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of T08446 PEA 1 P18, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
LDNHGRRLLLSEEASLNIPAVAAAHVIKRYTAQAPDELSFEVGDIVSVIDMPPTEDRSW

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WRGKRGFQVGFFPSECVELFTERPGPGLKADADGPPCGIPAPQGISSLTSAVPRPRGKLA
GLLRTFMRSRPSRQRLRQRGILRQRVFGCDLGEHLSNSGQDVPQVLRCCSEFIEAHGV V
DGIYRLSGVSSNIQRLRHEFDSERIPELSGPAFLQDIHSVSSLCKLYFRELPNPLLTYQLY
GKFSEAMSVPGEEERLVRVHDVIQQLPPPHYRTLEYLLRHLARMARHSANTSMHARNL
AIVWAPNLLRSMELESVGMGGAAAFREVRVQSWVEFLLTHVDVLFSDTFTSAGLDPA
GRCLLPRPKSLAGSCPSTRLLTLEEAQARTQGRLGTPTEPTTPKAPASPAERRKGERGEK
QRKPGGSSWKTFFALGRGPSVPRKK.PLPWLGGTRAPPQPSGSRPDTVTLRSAKSEESLS
SQASGAGLQRLHRLRRPHSSSDAFPVGPAPAGSCESLSSSSSSESSSSESSSSSSESSAAGL
GALSGSPSHRTSAWLDDGDELDFSPPRCLEGLRGLDFDPLTFRCSSPTPGDPAPPASPAP
PAPASAFPPRVTPQAISPRGPTSPASPAALDISEPLAVSVPPAVLELLGAGGAPASATPTP
ALSPGRSLRPHLIPLLLRGAEAPLTDACQQEMCSKLRGAQGPLGPDMESPLPPPPLSLLR
PGGAPPPPPKNPARLMALALAERAQQVAEQQSQQECGGTPPASQSPFHRSLSLEVGGEP
LGTSGSGPPPNSLAHPGAWVPGPPPYLPRQQSDGSLLRSQRPMGTSRRGLRGPAQVSAQ
LRAGGGGRDAPEAAAQSPCSVPSQVPTPGFFSPAPRECLPPFLGVPKPGLYPLGPPSFQP
SSPAPVWRSSLGPPAPLDRGENLYYEIGASEGSPYSGPTRSWSPFRSMPPDRLNASYGM
LGQSPPLHRSPDFLLSYPPAPSCFPPDHLGYSAPQHPARRPTPPEPLYVNLALGPRGPSPA
SSSSSSPPAHPRSRSDPGPPVPRLPQKQRAPWGPRTPHRVPGPWGPPEPLLLYR.AAPPAY
GRGGELHRGSLYRNGGQRGEGAGPPPPYPTPSWSLHSEGQTRSYC in
T08446 PEA 1 P18.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for T08446 PEA 1 P18, comprising a
first amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MLSLSLCSHLWGPLILSALQARSTDSLDGPGEGSVQPLPTAGGPSVKGKPGKRLSAPRG
PFPRLADCAHFHYENVDFGHIQLLLSPDREGPSLSGENELVFGVQVTCQGRSWPVLRSY
DDFRSLDAHLHRCIFDRRFSCLPELPPPPEGARAAQMLVPLLLQYLETLSGLVDSNLNC
GPVLTWMELDNHGRRLLLSEEASLNIPAVAAAHVIKRYTAQAPDELSFEVGDIVSVIDM
PPTEDRSWWRGKRGFQVGFFPSECVELFTERPGPGLKADADGPPCGIPAPQGISSLTSAV
PRPRGKLAGLLRTFMRSRPSRQRLRQRGILRQRVFGCDLGEHLSNSGQDVPQVLRCCSE
FIEAHGVVDGIYRLSGVSSNIQRLRHEFDSER1PELSGPAFLQDIHSVSSLCKLYFRELPNP
LLTYQLYGKFSEAMS VPGEEERLVRV corresponding to amino acids 1 - 443 of

CA 02555509 2006-07-26
T08446 PEA 1 P18, a second amino acid sequence being at least 90 % homologous
to
HDVIQQLPPPHYRTLEYLLRHLA,RMARHSANTSI4gL~RNLAIVWAPNLLRSMELESVG
MGGAAAFREVRVQSVVVEFLLTHVDVLFSDTFTSAGLDPAGRCLLPRPKSLAGSCPSTR
LLTLEEAQARTQGRLGTPTEPTTPKAPASPAERRKGERGEKQRKPGGSSWKTFFALGRG
5 PSVPRKKPLPWLGGTRAPPQPSGSRPDTVTLRSAKSEESLSSQASGAGLQRLHRLRRPHS
SSDAFPVGPAPAGSCESLSSSSSSESSSSESSSSSSESSAAGLGALSGSPSHRTSAWLDDG
DELDFSPPRCLEGLRGLDFDPLTFRCSSPTPGDPAPPASPAPPAPASAFPPRVTPQAISPRG
PTSPASPAALDISEPLAVSVPPAVLELLGAGGAPASATPTPALSPGRSLRPHLIPLLLRGA
EAPLTDACQQEMCSKLRGAQGPLGPDMESPLPPPPLSLLRPGGAPPPPPKNPARLMALA
10 LAERAQQVAEQQSQQECGGTPPASQSPFHRSLSLEVGGEPLGTSGSGPPPNSLAHPGAW
VPGPPPYLPRQQSDGSLLRSQRPMGTSRRGLRGPAQVSAQLRAGGGGRDAPEAAAQSP
CSVPSQVPTPGFFS~APRECLPPFLGVPKPGLYPLGPPSFQPSSPAPVWRSSLGPPAPLDR
GENLYYEIGASEGSPYSG corresponding to amino acids 1 - 674 of Q9NT23, which also
corresponds to amino acids 444 - 1117 of T08446 PEA 1 P 18, a bridging amino
acid P
15 corresponding to amino acid 1118 of T08446 PEA 1 P18, and a third amino
acid sequence
being at least 90 % homologous to
TRSWSPFRSMPPDRLNASYGMLGQSPPLHRSPDFLLSYPPAPSCFPPDHLGYSAPQHPAR
RPTPPEPLYVNLALGPRGPSPASSSSSSPPAHPRSRSDPGPPVPRLPQKQRAPWGPRTPHR
VPGPWGPPEPLLLYRAAPPAYGRGGELHRGSLYRNGGQRGEGAGPPPPYPTPSWSLHS
20 EGQTRSYC corresponding to amino acids 676 - 862 of Q9NT23, which also
corresponds to
amino acids 1119 - 1305 of T08446 PEA 1 P18, wherein said first amino acid
sequence,
second amino acid sequence, bridging amino acid and third amino acid sequence
are contiguous
and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
25 isolated polypeptide encoding for a head of T08446 PEA 1 P 18, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
MLSLSLCSHLWGPLILSALQARSTDSLDGPGEGSVQPLPTAGGPSVKGKPGKRLSAPRG
PFPRLADCAHFHYENVDFGHIQLLLSPDREGPSLSGENELVFGVQVTCQGRSWPVLRSY
30 DDFRSLDAHLHRCIFDRRFSCLPELPPPPEGARAAQMLVPLLLQYLETLSGLVDSNLNC
GPVLTWMELDNHGRRLLLSEEASLNIPAVAAAHVIKRYTAQAPDELSFEVGDIVSVIDM

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PPTEDRSWWRGKRGFQVGFFPSECVELFTERPGPGLKADADGPPCGIPAPQGISSLTSAV
PRPRGKLAGLLRTFMRSRPSRQRLRQRGILRQRVFGCDLGEHLSNSGQDVPQVLRCCSE
FIEAHGVVDGIYRLSGVSSNIQRLRHEFDSERIPELSGPAFLQDIHSVSSLCKLYFRELPNP
LLTYQLYGKFSEAMSVPGEEERLVRV of T08446 PEA 1 P18.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for T08446 PEA 1 P18, comprising a
first amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MLSLSLCSHLWGPLILSALQARSTDSLDGPGEGSVQPLPTAGGPSVKGKPGKRLSAPRG
PFPRLADCAHFHYENVDFGHIQLLLSPDREGPSLSGENELVFGVQVTCQGRSWPVLRSY
DDFRSLDAHLHRCIFDRRFSCLPELPPPPEGARAAQMLVPLLLQYLETLSGLVDSNLNC
GPVLTWMELDNHGRRLLLSEEASLNIPAVAAAHVIKRYTAQAPDELSFEVGDIVSVIDM
PPTEDRSWWRGKRGFQVGFFPSECVELFTERPGPGLKADADGPPCGIPAPQGISSLTSAV
PRPRGKLAGLLRTFMRSRPSRQRLRQRGILRQRVFGCDLGEHLSNSGQDVPQVLRCCSE
FIEAHGVVDGIYRLSGVSSNIQRLRHEFDSERIPELSGPAFLQDIHSVSSLCKLYFRELPNP
LLTYQLYGKFSEAMS VPGEEERLVRVHDVIQQLPPPHYRTLEYLLRHLARMARHSANT
SMHARNLAIVWAPNLLRSMELESVGMGGAAAFREVRVQSVVVEFLLTHVDVLFSDTF
TSAGLDPAGRCLLPRPKSLAGSCPSTRLLTLEEAQARTQGRLGTPTEPTTPKAPASPAER
RKGERGEKQRKPGGSSWKTFFALGRGPSVPRKKPLPWLGGTRAPPQPSGSRPDTVTLRS
AKSEESLSSQASGAGLQRLHRLRRPHSSSDAFPVGPAPAGSCESLSSSSSSESSSSESSSSS
SESSAAGLGALSGSPSHRTSAWLDDGDELDFSPPRCLEGLRGLDFDPLTFRCSSPTPGDP
APPASPAPPAPASAFPPRVTPQAISPRGPTSPASPAALDISEPLAVSVPPAVLELLGAGGA
PASATPTPALSPGRSLRPHLIPLLLRGAEAPLTDACQQEMCSKLRGAQGPLGPDMESPLP
PPPLSLLRPGGAPPPPPKNPARLMALALAERAQQVAEQQSQQECGGTPPASQSPFHRSLS
LEVGGEPLGTSGSGPPPNSLAHPGAWVPGPPPYLPRQQSDGSLLRSQRPMGTSRRG
corresponding to amino acids 1 - 1010 of T08446_PEA 1 P 18, and a second amino
acid
sequence being at least 90 % homologous to
LRGPAQVSAQLR.AGGGGRDAPEAAAQSPCSVPSQVPTPGFFSPAPRECLPPFLGVPKPG
LYPLGPPSFQPSSPAPVWRSSLGPPAPLDRGENLYYEIGASEGSPYSGPTRSWSPFRSMPP
DRLNASYGMLGQSPPLHRSPDFLLSYPPAPSCFPPDHLGYSAPQHPARRPTPPEPLYVNL
ALGPRGPSPASSSSSSPPAHPRSRSDPGPPVPRLPQKQRAPWGPRTPHRVPGPWGPPEPL

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LLYRAAPPAYGRGGELHRGSLYRNGGQRGEGAGPPPPYPTPS WSLHSEGQTRSYC
corresponding to amino acids 1 - 295 of Q96CP3, which also corresponds to
amino acids 1011
1305 of T08446 PEA 1 P18, wherein said first amino acid sequence and second
amino acid
sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of T08446 PEA_1 P18, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
MLSLSLCSHLWGPLILSALQARSTDSLDGPGEGSVQPLPTAGGPSVKGKPGKRLSAPRG
PFPRLADCAHFHYENVDFGHIQLLLSPDREGPSLSGENELVFGVQVTCQGRSWPVLRSY
DDFRSLDAHLHRCIFDRRFSCLPELPPPPEGAR.AAQMLVPLLLQYLETLSGLVDSNLNC
GPVLTWMELDNHGRRLLLSEEASLNIPAVAAAHVIKRYTAQAPDELSFEVGDIVSVIDM
PPTEDRSWWRGKRGFQVGFFPSECVELFTERPGPGLKADADGPPCGIPAPQGISSLTSAV
PRPRGKLAGLLRTFMRSRPSRQRLRQRGILRQRVFGCDLGEHLSNSGQDVPQVLRCCSE
FIEAHGVVDGIYRLSGVSSNIQRLRHEFDSERIPELSGPAFLQDIHSVSSLCKLYFRELPNP
LLTYQLYGKFSEAMS VPGEEERLVRVHDVIQQLPPPHYRTLEYLLRHLARMARHSANT
SMHARNLAIVWAPNLLRSMELESVGMGGAAAFREVRVQSVVVEFLLTHVDVLFSDTF
TSAGLDPAGRCLLPRPKSLAGSCPSTRLLTLEEAQARTQGRLGTPTEPTTPKAPASPAER
RKGERGEKQRKPGGSSWKTFFALGRGPSVPRKKPLPWLGGTRAPPQPSGSRPDTVTLRS
AKSEESLSSQASGAGLQRLHRLRRPHSSSDAFPVGPAPAGSCESLSSSSSSESSSSESSSSS
SESSAAGLGALSGSPSHRTSAWLDDGDELDFSPPRCLEGLRGLDFDPLTFRCSSPTPGDP
APPASPAPPAPASAFPPRVTPQAISPRGPTSPASPAALDISEPLAVSVPPAVLELLGAGGA
PASATPTPALSPGRSLRPHLIPLLLRGAEAPLTDACQQEMCSKLRGAQGPLGPDMESPLP
PPPLSLLRPGGAPPPPPKNPARLMALALAERAQQVAEQQSQQECGGTPPASQSPFHRSLS
LEVGGEPLGTSGSGPPPNSLAHPGAWVPGPPPYLPRQQSDGSLLRSQRPMGTSRRG of
T08446 PEA 1 P 18.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for T08446_PEA 1 P18, comprising a
first amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MLSLSLCSHLWGPLILSALQARSTDSLDGPGEGSVQPLPTAGGPSVKGKPGKRLSAPRG

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PFPRLADCAHFHYENVDFGHIQLLLSPDREGPSLSGENELVFGVQVTCQGRSWPVLRSY
DDFRSLDAHLHRCIFDRRFSCLPELPPPPEGAR.AAQ corresponding to amino acids 1 - 154
of T08446 PEA 1 P18, a second amino acid sequence being at least 90 %
homologous to
MLVPLLLQYLETLSGLVDSNLNCGPVLTWMELDNHGRRLLLSEEASLNIPAVAAAHVI
S KRYTAQAPDELSFEVGDIVSVIDMPPTEDRSWWRGKRGFQVGFFPSECVELFTERPGPG
LKADADGPPCGIPAPQGISSLTSAVPRPRGKLAGLLRTFMRSRPSRQRLRQRGILRQRVF
GCDLGEHLSNSGQDVPQVLRCCSEFIEAHGVVDGIYRLSGVSSNIQRLRHEFDSERIPEL
S GPAFLQDIHS V S S LCKLYFRELPNPLLTYQLYGKFS EAMS VPGEEERLVRVHD V IQQLP
PPHYRTLEYLLRHLARMARHSANTSMHARNLAIVWAPNLLRSMELESVGMGGAAAFR
EVRVQSVVVEFLLTHVDVLFSDTFTSAGLDPAGRCLLPRPKSLAGSCPSTRLLTLEEAQ
ARTQGRLGTPTEPTTPKAPASPAERRKGERGEKQRKPGGS S WKTFFALGRGP S VPRKKP
LPWLGGTRAPPQPSGSRPDTVTLRSAKSEESLSSQASGAGLQRLHRLRRPHSSSDAFPVG
PAPAGSCESLSSSSSSESSSSESSSSSSESSAAGLGALSGSPSHRTSAWLDDGDELDFSPPR
CLEGLRGLDFDPLTFRCSSPTPGDPAPPASPAPPAPASAFPPRVTPQAISPRGPTSPASPAA
LDISEPLAVSVPPAVLELLGAGGAPASATPTPALSPGRSLRPHLIPLLLRGAEAPLTDACQ
QEMCSKLRGAQGPLGPDMESPLPPPPLSLLRPGGAPPPPPKNPARLMALALAERAQQVA
EQQSQQECGGTPPASQSPFHRSLSLEVGGEPLGTSGSGPPPNSLAHPGAWVPGPPPYLPR
QQSDGSLLRSQRPMGTSRRGLRGPA corresponding to amino acids 1 - 861 of BAC86902,
which also corresponds to amino acids 155 - 1015 of T08446 PEA 1 P18, a third
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
QVSAQLRAGGGGRDAPEAAAQSPCSVPS corresponding to amino acids 1016 - 1043 of
T08446 PEA 1 P 18, a fourth amino acid sequence being at least 90 % homologous
to
QVPTPGFFSPAPRECLPPFLGVPKPGLYPLGPPSFQPSSPAPVWRSSLGPPAPLDRGENLY
YEIGASEGSPYSGPTRSWSPFRSMPPDRLNASYGMLGQSPPLHRSPDFLLSYPPAPSCFPP
DHLGYS corresponding to amino acids 862 - 989 of BAC86902, which also
corresponds to
amino acids 1044 - 1171 of T08446 PEA 1 P18, and a fifth amino acid sequence
being at least
70%, optionally at least 80%, preferably at least 85%, more preferably at
least 90% and most
preferably at least 95% homologous to a polypeptide having the sequence
APQHPARRPTPPEPLYVNLALGPRGPSPASSSSSSPPAHPRSRSDPGPPVPRLPQKQRAP
WGPRTPHRVPGP WGPPEPLLLYRAAPPAYGRGGELHRGSLYRNGGQRGEGAGPPPPYP

CA 02555509 2006-07-26
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TPSWSLHSEGQTRSYC corresponding to amino acids 1172 - 1305 of T08446_PEA 1 P18,
wherein said first amino acid sequence, second amino acid sequence, third
amino acid sequence,
fourth amino acid sequence and fifth amino acid sequence are contiguous and in
a sequential
order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of T08446 PEA 1 P18, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
MLSLSLCSHLWGPLILSALQARSTDSLDGPGEGSVQPLPTAGGPSVKGKPGKRLSAPRG
PFPRLADCAHFHYENVDFGHIQLLLSPDREGPSLSGENELVFGVQVTCQGRSWPVLRSY
DDFRSLDAHLHRCIFDRRFSCLPELPPPPEGARAAQ of T08446_PEA 1 P18.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for an edge portion of T08446 PEA 1 P18,
comprising an amino
acid sequence being at least 70%, optionally at least about 80%, preferably at
least about 85%,
more preferably at least about 90% and most preferably at least about 95%
homologous to the
sequence encoding for QVSAQLRAGGGGRDAPEAAAQSPCSVPS, corresponding to
T08446 PEA 1 P 18.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of T08446_PEA 1 P18, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
APQHPARRPTPPEPLYVNLALGPRGPSPASSSSSSPPAHPRSRSDPGPPVPRLPQKQRAP
WGPRTPHRVPGPWGPPEPLLLYRAAPPAYGRGGELHRGSLYRNGGQRGEGAGPPPPYP
TPSWSLHSEGQTRSYC in T08446_PEA 1 P18.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for T11628 PEA 1 P2, comprising a first
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MGLSDGEWQLVLNV WGKVEADIPGHGQEVLIRLFKGHPETLEKFDKFKHLKSEDE
corresponding to amino acids 1 - 55 of T11628 PEA 1 P2, and a second amino
acid sequence
being at least 90 % homologous to

CA 02555509 2006-07-26
MKASEDLKKHGATVLTALGGILKKKGHHEAEIKPLAQSHATKHKIPVKYLEFISECIIQV
LQSKHPGDFGADAQGAMNKALELFRKDMASNYKELGFQG corresponding to amino
acids 1 - 99 of Q8WVH6, which also corresponds to amino acids 56 - 154 of
T11628 PEA 1 P2, wherein said first amino acid sequence and second amino acid
sequence
5 are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of T11628 PEA 1 P2, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
10 MGLSDGEWQLVLNVWGKVEADIPGHGQEVLIRLFKGHPETLEKFDKFKHLKSEDE of
T11628 PEA 1 P2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for T11628 PEA 1 P5, comprising a first
amino acid
sequence being at least 90 % homologous to
15 MKASEDLKKHGATVLTALGGILKKKGHHEAEIKPLAQSHATKHKIPVKYLEFISECIIQV
LQSKHPGDFGADAQGAMNKALELFRKDMASNYKELGFQG corresponding to amino
acids 56 - 154 of MYG HUMAN V 1, which also corresponds to amino acids 1 - 99
of
T11628 PEA 1 P5.
According to preferred embodiments of the present invention, there is provided
an
20 isolated chimeric polypeptide encoding for T11628 PEA 1 P7, comprising a
first amino acid
sequence being at least 90 % homologous to
MGLSDGEWQLVLNVWGKVEADIPGHGQEVLIRLFKGHPETLEKFDKFKHLKSEDEMK
ASEDLKKHGATVLTALGGILKKKGHHEAEIKPLAQSHATKHKIPVKYLEFISECIIQVLQ
SKHPGDFGADAQGAMNK corresponding to amino acids 1 - 134 of MYG HUMAN V 1,
25 which also corresponds to amino acids 1 - 134 of T11628 PEA 1 P7, and a
second amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence G
corresponding to amino acids 135 - 135 of T11628 PEA 1 P7, wherein said first
amino acid
sequence and second amino acid sequence are contiguous and in a sequential
order.
30 According to preferred embodiments of the present invention, there is
provided an
isolated chimeric polypeptide encoding for T11628 PEA 1 P10, comprising a
first amino acid

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sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MGLSDGEWQLVLNV WGKVEADIPGHGQEVLIRLFKGHPETLEKFDKFKHLKSEDE
corresponding to amino acids 1 - 55 of Tl 1628 PEA 1 P10, and a second amino
acid sequence
being at least 90 % homologous to
MKASEDLKKHGATVLTALGGILKKKGHHEAEIKPLAQSHATKHKIPVKYLEFISECIIQV
LQSKHPGDFGADAQGAMNI~ALELFRKDMASNYKELGFQG corresponding to amino
acids 1 - 99 of Q8WVH6, which also corresponds to amino acids 56 - 154 of
T 11628 PEA 1 P 10, wherein said first amino acid sequence and second amino
acid sequence
are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of T11628 PEA 1 P10, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
MGLSDGEWQLVLNVWGKVEADIPGHGQEVLIRLFKGHPETLEKFDKFKHLKSEDE of
T11628 PEA 1 P10.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 835137 PEA 1 PEA 1 PEA 1 P9,
comprising a
first amino acid sequence being at least 90 % homologous to
MASSTGDRSQAVRHGLRAKVLTLDGMNPRVRRVEYAVRGPIVQRALELEQELRQGVK
KPFTEVIRANIGDAQAMGQRPITFLRQVLALCVNPDLLSSPNFPDDAKKRAERILQACG
GHSLGAYSVSSGIQLIREDVARYIERRDGGIPADPNNVFLSTGASDAIVTVLKLLVAGEG
HTRTGVLIPIPQYPLYSATLAELGAVQVDYYLDEERAWALDVAELHRALGQARDHCRP
RALCVINPGNPTGQVQTRECIEAVIRFAFEERLFLLADEV corresponding to amino acids 1
274 of ALAT HUMAN V 1, which also corresponds to amino acids 1 - 274 of
835137 PEA 1 PEA_1 PEA 1 P9, and a second amino acid sequence being at least
70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence
RGAGEREAGQQSAPVTPCALPGVPGQRVRRGFAVPLIQEGAHGDGAALRRAAGACLLP
LHLQGLHGRVRAYEAGGGSRAMARPSSPDGPPPPPHLTWPCAGAGSAAAMWRW
corresponding to amino acids 275 - 385 of 835137 PEA 1 PEA-1 PEA 1 P9, wherein
said

CA 02555509 2006-07-26
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first amino acid sequence and second amino acid sequence are contiguous and in
a sequential
order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 835137 PEA 1 PEA 1 PEA 1 P9,
comprising a
polypeptide being at least 70%, optionally at least about 80%, preferably at
least about 85%,
more preferably at least about 90% and most preferably at least about 95%
homologous to the
sequence
RGAGEREAGQQSAPVTPCALPGVPGQRVRRGFAVPLIQEGAHGDGAALRR.AAGACLLP
LHLQGLHGRVRAYEAGGGSF;AMARPSSPDGPPPPPHLTWPCAGAGSAAAMVVRW in
835137 PEA 1 PEA 1 PEA 1 P9.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 835137 PEA 1 PEA_I PEA 1 P8,
comprising a
first amino acid sequence being at least 90 % homologous to
MASSTGDRSQAVRHGLRAKVLTLDGMNPRVRRVEYAVRGPIVQRALELEQELRQGVK
KPFTEVIRANIGDAQAMGQRPITFLRQVLALCVNPDLLSSPNFPDDAKI~RAERILQACG
GHSLGAYSVSSGIQLIREDVARYIERRDGGIPADPNNVFLSTGASDAIVTVLKLLVAGEG
HTRTGVLIPIPQYPLYSATLAELGAVQVDYYLDEERAWALDVAELHRALGQARDHCRP
RALCVINPGNPTGQVQTRECIEAVIRFAFEERLFLLADEVYQDNVYAAGSQFHSFKKVL
MEMGPPYAGQQELASFHSTSKGYMGEC corresponding to amino acids 1 - 320 of
ALAT HUMAN_V1, which also corresponds to amino acids 1 - 320 of
835137 PEA 1 PEA 1 PEA 1 P8, and a second amino acid sequence being at least
70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence
VRTRRVGARGPWPGPPRPMGHPLLRT corresponding to amino acids 321 - 346 of
835137 PEA 1 PEA-1 PEA ~1 P8, wherein said first amino acid sequence and
second amino
acid sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 835137 PEA 1 PEA 1 PEA 1 P8,
comprising a
polypeptide being at least 70%, optionally at least about 80%, preferably at
least about 85%,
more preferably at least about 90% and most preferably at least about 95%
homologous to the
sequence VRTRRVGARGPWPGPPRPMGHPLLRT in 835137 PEA 1 PEA 1 PEA 1 P8.

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78
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for R3S137_PEA 1 PEA 1 PEA 1 P11,
comprising a
first amino acid sequence being at least 90 % homologous to
S MASSTGDRSQAVRHGLRAKVLTLDGMNPRVRRVEYAVRGPIVQRALELEQELRQGVK
KPFTEVIRANIGDAQAMGQRPITFLRQVLALCVNPDLLSSPNFPDDAKKRAERILQACG
GHSLGAYSVSSGIQLIREDVARYIERRDGGIPADPNNVFLSTGASDAIVTVLKLLVAGEG
HTRTGVLIPIPQYPLYSATLAELGAVQVDYYLDEERAWALDVAELHRALGQAR
corresponding to amino acids 1 - 229 of ALAT_HUMAN V 1, which also corresponds
to amino
acids 1 - 229 of R3S137 PEA 1 PEA 1 PEA 1 P11, and a second amino acid
sequence being
at least 90 % homologous to SGFGQREGTYHFRMTILPPLEKLRLLLEKLSRFHAKFTLEYS
corresponding to amino acids 4SS - 496 of ALAT HUMAN V 1, which also
corresponds to
amino acids 230 - 271 of R3S 137 PEA 1 PEA 1 PEA 1 P1 l, wherein said first
amino acid
sequence and second amino acid sequence are contiguous and in a sequential
order.
1 S According to preferred embodiments of the present invention, there is
provided an
isolated chimeric polypeptide encoding for an edge portion of
R3S 137 PEA 1 PEA 1 PEA 1 P11, comprising a polypeptide having a length "n",
wherein n
is at least about 10 amino acids in length, optionally at least about 20 amino
acids in length,
preferably at least about 30 amino acids in length, more preferably at least
about 40 amino acids
in length and most preferably at least about SO amino acids in length, wherein
at least two amino
acids comprise RS, having a structure as follows: a sequence starting from any
of amino acid
numbers 229-x to 229; and ending at any of amino acid numbers 230+ ((n-2) -
x), in which x
varies from 0 to n-2.
According to preferred embodiments of the present invention, there is provided
an
2S isolated chimeric polypeptide encoding for R3S137_PEA 1 PEA 1 PEA 1 P2,
comprising a
first amino acid sequence being at least 90 % homologous to
MASSTGDRSQAVRHGLRAKVLTLDGMNPRVRRVEYAVRGPIVQRALELEQELRQGVK
KPFTEVIRANIGDAQAMGQRPITFLRQVLALCVNPDLLSSPNFPDDAKKRAERILQACG
GHSLGAYSVSSGIQLIREDVARYIERRDGGIPADPNNVFLSTGASDAIVTVLKLLVAGEG
HTRTGVLIPIPQYPLYSATLAELGAVQVDYYLDEERAWALDVAELHRALGQARDHCRP
RALCVINPGNPTGQVQTRECIEAVIRFAFEERLFLLADEV corresponding to amino acids 1

CA 02555509 2006-07-26
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79
274 of ALAT HUMAN V1, which also corresponds to amino acids 1 - 274 of
835137 PEA 1 PEA 1 PEA 1 P2, and a second amino acid sequence being at least
70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence
RGAGEREAGQQSAPVTPCALPGVPGQRVRRGFAVPLIQEGAHGDGAALRRAAGACLLP
LHLQGLHGRVRVPRRLCGGGEHGRCSAAADAEADECAAVPAGARTGPAGPGGQPAR
AHRPLLCAVPG corresponding to amino acids 275 - 399 of
835137 PEA 1 PEA 1 PEA 1 P2, wherein said first amino acid sequence and second
amino
acid sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 835137 PEA 1 PEA 1 PEA 1 P2,
comprising a
polypeptide being at least 70%, optionally at least about 80%, preferably at
least about 85%,
more preferably at least about 90% and most preferably at least about 95%
homologous to the
sequence
RGAGEREAGQQSAPVTPCALPGVPGQRVRRGFAVPLIQEGAHGDGAALRRAAGACLLP
LHLQGLHGRVRVPRRLCGGGEHGRCSAAADAEADECAAVPAGARTGPAGPGGQPAR
AHRPLLCAVPG in 835137 PEA 1 PEA 1 PEA 1 P2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 835137 PEA 1 PEA 1 PEA 1 P4,
comprising a
first amino acid sequence being at least 90 % homologous to
MASSTGDRSQAVRHGLRAKVLTLDGMNPRVRRVEYAVRGPIVQRALELEQELRQGVK
KPFTEVIRANIGDAQAMGQRPITFLRQVLALCVNPDLLSSPNFPDDAKKRAERILQACG
GHSLGAYSVSSGIQLIREDVARYIERRDGGIPADPNNVFLSTGASDAIVTVLKLLVAGEG
HTRTGVLIPIPQYPLYSATLAELGAVQVDYYLDEERAWALDVAELHRALGQARDHCRP
RALCVINPGNPTGQVQTRECIEAVIRFAFEERLFLLADEVYQDNVYAAGSQFHSFKKVL
MEMGPPYAGQQELASFHSTSKGYMGECGFRGGYVEVVNMDAAVQQQMLKLMSVRL
CPPVPGQALLDLVVSPPAPTDPSFAQFQAEKQAVLAELAAKAKLTEQVFNEAPGISCNP
VQGAMYSFPRVQLPPRAVERAQELGLAPDMFFCLRLLEETGICVVPGSGFGQREGTYH
FRMTILPPLEKLRLLLEKLSRFHAKFTLE corresponding to amino acids 1 - 494 of
ALAT HUMAN V1, which also corresponds to amino acids 1 - 494 of
835137 PEA 1 PEA 1 PEA 1 P4, and a second amino acid sequence being at least
70%,

CA 02555509 2006-07-26
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence
SPGRLWSPLYLLLMPGGVGWGGCWAPASLQVPNKAVWQSDSKKEALAAAWPAPTCL
PFLQA corresponding to amino acids 495 - 555 of 835137 PEA 1 PEA 1 PEA 1 P4,
5 wherein said first amino acid sequence and second amino acid sequence are
contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 835137 PEA 1 PEA 1 PEA 1 P4,
comprising a
polypeptide being at least 70%, optionally at least about 80%, preferably at
least about 85%,
10 more preferably at least about 90% and most preferably at least about 95%
homologous to the
sequence
SPGRLWSPLYLLLMPGGVGWGGCWAPASLQVPNKAVWQSDSKKEALAAAWPAPTCL
PFLQA in 835137 PEA-1 PEA 1 PEA I P4.
According to preferred embodiments of the present invention, there is provided
an
1 S isolated chimeric polypeptide encoding for Rl 1723 PEA 1 P6, comprising a
first amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV
MEQSAGIMYRKSCASSAACLIASAGSPCRGLAPGREEQRALHKAGAVGGGVR
20 corresponding to amino acids 1 - 1 IO of Rl 1723 PEA 1 P6, and a second
amino acid sequence
being at least 90 % homologous to
MYAQALLVVGVLQRQAAAQHLHEHPPKLLRGHRVQERVDDRAEVEKRLREGEEDHV
RPEVGPRPVVLGFGRSHDPPNLVGHPAYGQCHNNQPWADTSRRERQRKEKHSMRTQ
corresponding to amino acids 1 - 112 of Q8IXM0, which also corresponds to
amino acids 111 -
25 222 of Rl 1723 PEA 1 P6, wherein said first and second amino acid sequences
are contiguous
and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of RI 1723 PEA 1 P6, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
30 at least about 90% and most preferably at least about 95% homologous to the
sequence
MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV

r
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81
MEQSAGIMYRKSCASSAACLIASAGSPCRGLAPGREEQRALHKAGAVGGGVR of
811723 PEA 1 P6.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 811723 PEA 1 P6, comprising a first
amino acid
sequence being at least 90 % homologous to
MWLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV
MEQSAGIMYRKSCASSAACLIASAG corresponding to amino acids 1 - 83 of Q96AC2,
which also corresponds to amino acids 1 - 83 of 811723 PEA 1 P6, and a second
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLWGVLQRQAAAQHLHEHPPKLL
RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPVVLGFGRSHDPPNLVGHPAYGQ
CHNNQPWADTSRRERQRKEKHSMRTQ corresponding to amino acids 84 - 222 of
Rl 1723 PEA 1 P6, wherein said first and second amino acid sequences are
contiguous and in
a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of Rl 1723 PEA 1 P6, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLWGVLQRQAAAQHLHEHPPKLL
RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPVVLGFGRSHDPPNLVGHPAYGQ
CHNNQPWADTSRRERQRKEKHSMRTQ in 811723 PEA 1 P6.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 811723 PEA_1 P6, comprising a first
amino acid
sequence being at least 90 % homologous to
MWLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV
MEQSAGIMYRKSCASSAACLIASAG corresponding to amino acids 1 - 83 of Q8N2G4,
which also corresponds to amino acids 1 - 83 of 811723 PEA 1 P6, and a second
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLWGVLQRQAAAQHLHEHPPKLL

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RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPVVLGFGRSHDPPNLVGHPAYGQ
CHNNQPWADTSRRERQRKEKHSMRTQ corresponding to amino acids 84 - 222 of
811723 PEA 1 P6, wherein said first and second amino acid sequences are
contiguous and in
a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 811723 PEA 1 P6, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
SPCRGLAP GREEQRALHKAGAV GGGVRMYAQALLV V GV LQRQAAAQHLHEHPPKLL
RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPVVLGFGRSHDPPNLVGHPAYGQ
CHNNQPWADTSRRERQRKEKHSMRTQ in 811723 PEA_1 P6.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 811723 PEA 1 P6, comprising a first
amino acid
sequence being at least 90 % homologous to
1 S MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV
MEQSAGIMYRKSCASSAACLIASAG corresponding to amino acids 24 - 106 of BAC85518,
which also corresponds to amino acids 1 - 83 of 811723 PEA 1 P6, and a second
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLVVGVLQRQAAAQHLHEHPPKLL
RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPVVLGFGRSHDPPNLVGHPAYGQ
CHNNQPWADTSRRERQRKEKHSMRTQ corresponding to amino acids 84 - 222 of
811723 PEA 1 P6, wherein said first and second amino acid sequences are
contiguous and in
a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 811723 PEA 1 P6, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
S PCRGLAPGREEQRALHKAGAV GGGVRMYAQALLV V GV LQRQAAAQHLHEHPPKLL
RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPVVLGFGRSHDPPNLVGHPAYGQ
CHNNQPWADTSRRERQRKEKHSMRTQ in 811723 PEA_1 P6.

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According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 811723 PEA 1 P7, comprising a first
amino acid
sequence being at least 90 % homologous to
MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV
MEQSAG corresponding to amino acids 1 - 64 of Q96AC2, which also corresponds
to amino
acids 1 - 64 of 811723 PEA 1 P7, and a second amino acid sequence being at
least 70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence
SHCVTRLECSGTISAHCNLCLPGSNDHPT corresponding to amino acids 65 - 93 of
811723 PEA 1 P7, wherein said first and second amino acid sequences are
contiguous and in
a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 811723 PEA 1 P7, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
SHCVTRLECSGTISAHCNLCLPGSNDHPT in 811723 PEA 1 P7.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 811723 PEA 1 P7, comprising a first
amino acid
sequence being at least 90 % homologous to
MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV
MEQSAG corresponding to amino acids 1 - 64 of Q8N2G4, which also corresponds
to amino
acids 1 - 64 of 811723 PEA 1 P7, and a second amino acid sequence being at
least 70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence
SHCVTRLECSGTISAHCNLCLPGSNDHPT corresponding to amino acids 65 - 93 of
811723 PEA 1 P7, wherein said first and second amino acid sequences are
contiguous and in
a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 811723 PEA 1 P7, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at

CA 02555509 2006-07-26
84
least about 90% and most preferably at least about 95% homologous to the
sequence
SHCVTRLECSGTISAHCNLCLPGSNDHPT in 811723 PEA 1 P7.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for Rl 1723 PEA 1 P7, comprising a
first amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MWVLG corresponding to amino acids 1 - 5 of 811723 PEA 1 P7, second amino acid
sequence being at least 90 % homologous to
IAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEVMEQSAG
corresponding to amino acids 22 - 80 of BAC85273, which also corresponds to
amino acids 6 -
64 of 811723 PEA 1 P7, and a third amino acid sequence being at least 70%,
optionally at
least 80%, preferably at least 85%, more preferably at least 90% and most
preferably at least
95% homologous to a polypeptide having the sequence
SHCVTRLECSGTISAHCNLCLPGSNDHPT corresponding to amino acids 65 - 93 of
811723 PEA 1 P7, wherein said first, second and third amino acid sequences are
contiguous
and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of Rl 1723 PEA 1 P7, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
MWVLG of 811723 PEA 1 P7.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 811723 PEA 1 P7, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
SHCVTRLECSGTISAHCNLCLPGSNDHPT in 811723 PEA 1 P7.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for Rl 1723 PEA 1 P7, comprising a
first amino acid
sequence being at least 90 % homologous to
MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV

CA 02555509 2006-07-26
MEQSAG corresponding to amino acids 24 - 87 of BAC85518, which also
corresponds to
amino acids 1 - 64 of 811723 PEA 1 P7, and a second amino acid sequence being
at least
70%, optionally at least 80%, preferably at least 85%, more preferably at
least 90% and most
preferably at least 95% homologous to a polypeptide having the sequence
5 SHCVTRLECSGTISAHCNLCLPGSNDHPT corresponding to amino acids 65 - 93 of
811723 PEA 1 P7, wherein said first and second amino acid sequences are
contiguous and in
a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of Rl 1723 PEA-1 P7, comprising a
polypeptide being
10 at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
SHCVTRLECSGTISAHCNLCLPGSNDHPT in 811723 PEA 1 P7.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 811723 PEA 1 P13, comprising a
first amino acid
15 sequence being at least 90 % homologous to
MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV
MEQSA corresponding to amino acids 1 - 63 of Q96AC2, which also corresponds to
amino
acids 1 - 63 of 811723 PEA 1 P13, and a second amino acid sequence being at
least 70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
20 preferably at least 95% homologous to a polypeptide having the sequence
DTKRTNTLLFEMRHFAKQLTT corresponding to amino acids 64 - 84 of
811723 PEA 1 P13, wherein said first and second amino acid sequences are
contiguous and in
a sequential order.
According to preferred embodiments of the present invention, there is provided
an
25 isolated polypeptide encoding for a tail of Rl 1723 PEA 1 P13, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
DTKRTNTLLFEMRHFAKQLTT in 811723 PEA 1 P 13.
According to preferred embodiments of the present invention, there is provided
an
30 isolated chimeric polypeptide encoding for 811723 PEA 1 P10, comprising a
first amino acid
sequence being at least 90 % homologous to

CA 02555509 2006-07-26
86
MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV
MEQSA corresponding to amino acids 1 - 63 of Q96AC2, which also corresponds to
amino
acids 1 - 63 of 811723 PEA 1 P 10, and a second amino acid sequence being at
least 70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence
DRVSLCHEAGVQWNNFSTLQPLPPRLK corresponding to amino acids 64 - 90 of
811723 PEA 1 P 10, wherein said first and second amino acid sequences are
contiguous and in
a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of Rl 1723 PEA 1 P10, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
DRVSLCHEAGVQVVNNFSTLQPLPPRLK in 811723 PEA 1 P10.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 811723 PEA_1 P10, comprising a
first amino acid
sequence being at least 90 % homologous to
MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV
MEQSA corresponding to amino acids 1 - 63 of Q8N2G4, which also corresponds to
amino
acids 1 - 63 of 811723 PEA 1 P10, and a second amino acid sequence being at
least 70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence
DRVSLCHEAGVQWNNFSTLQPLPPRLK corresponding to amino acids 64 - 90 of
811723 PEA 1 P 10, wherein said first and second amino acid sequences are
contiguous and in
a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 811723 PEA 1 P10, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
DRVSLCHEAGVQWNNFSTLQPLPPRLK in 811723 PEA 1 P10.

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87
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 811723 PEA 1 P10, comprising a
first amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MWVLG corresponding to amino acids 1 - 5 of 811723 PEA 1 P10, second amino
acid
sequence being at least 90 % homologous to
IAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEVMEQSA
corresponding to amino acids 22 - 79 of BAC85273, which also corresponds to
amino acids 6 -
63 of 811723 PEA 1 P 10, and a third amino acid sequence being at least 70%,
optionally at
least 80%, preferably at least 85%, more preferably at least 90% and most
preferably at least
95% homologous to a polypeptide having the sequence
DRVSLCHEAGVQWNNFSTLQPLPPRLK corresponding to amino acids 64 - 90 of
811723 PEA 1 P 10, wherein said first, second and third amino acid sequences
are contiguous
and in a sequential order.
1 S According to preferred embodiments of the present invention, there is
provided an
isolated polypeptide encoding for a head of Rl 1723 PEA 1 P 10, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
MWVLG of 811723 PEA 1 P10.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 811723 PEA 1 P10, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
DRVSLCHEAGVQVVNNFSTLQPLPPRLK in 811723 PEA 1 P10.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 811723 PEA 1 P10, comprising a
first amino acid
sequence being at least 90 % homologous to
MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV
MEQSA corresponding to amino acids 24 - 86 of BAC85518, which also corresponds
to amino
acids 1 - 63 of 811723 PEA 1 P 10, and a second amino acid sequence being at
least 70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most

CA 02555509 2006-07-26
88
preferably at least 95% homologous to a polypeptide having the sequence
DRVSLCHEAGVQWNNFSTLQPLPPRLK corresponding to amino acids 64 - 90 of
811723 PEA 1 P10, wherein said first and second amino acid sequences are
contiguous and in
a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 811723 PEA 1 P10, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
DRVSLCHEAGVQWNNFSTLQPLPPRLK in 811723 PEA 1 P10.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 816276 PEA 1 P7, comprising a first
amino acid
sequence being at least 90 % homologous to
MQSVQSTSFCLRKQCLCLTFLLLHLLGQVAATQRCPPQCPG corresponding to amino
acids 1 - 41 of NOV HUMAN, which also corresponds to amino acids 1 - 41 of
816276 PEA 1 P7, a bridging amino acid Q corresponding to amino acid 42 of
816276 PEA 1 P7, a second amino acid sequence being at least 90 % homologous
to
CPATPPTCAPGVRAVLDGCSCCLVCARQRGESCSDLEPCDESSGLYCDRSADPSNQTGI
CT corresponding to amino acids 43 - 103 of NOV HUMAN, which also corresponds
to amino
acids 43 - 103 of 816276 PEA 1 P7, and a third amino acid sequence being at
least 70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence
GNPAPSAV
corresponding to amino acids 104 - 111 of 816276 PEA 1 P7, wherein said first
amino acid
sequence, bridging amino acid, second amino acid sequence and third amino acid
sequence are
contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 816276 PEA 1 P7, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
GNPAPSAV in 816276 PEA 1 P7.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 816276 PEA 1 P7, comprising a first
amino acid

CA 02555509 2006-07-26
89
sequence being at least 90 % homologous to
MQSVQSTSFCLRKQCLCLTFLLLHLLGQVAATQRCPPQCPG corresponding to amino
acids 1 - 41 of NOV HUMAN, which also corresponds to amino acids 1 - 41 of
816276 PEA 1 P7, a bridging amino acid Q corresponding to amino acid 42 of
816276 PEA 1 P7, a second amino acid sequence being at least 90 % homologous
to
CPATPPTCAPGVRAVLDGCSCCLVCARQRGESCSDLEPCDESSGLYCDRSADPSNQTGI
CT corresponding to amino acids 43 - 103 of NOV HUMAN, which also corresponds
to amino
acids 43 - 103 of 816276 PEA 1 P7, and a third amino acid sequence being at
least 70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence
GNPAPSAV
corresponding to amino acids 104 - 111 of 816276 PEA 1 P7, wherein said first
amino acid
sequence, bridging amino acid, second amino acid sequence and third amino acid
sequence are
contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 816276 PEA 1 P7, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
GNPAPSAV in 816276 PEA 1 P7.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMCEA PEA 1 P4, comprising a first
amino
acid sequence being at least 90 % homologous to
MESPSAPPHRWCIPWQRLLLTASLLTFWNPPTTAKLTIESTPFNVAEGKEVLLLVHNLPQ
HLFGYSWYKGERVDGNRQIIGYVIGTQQATPGPAYSGREIIYPNASLLIQNIIQNDTGFYT
LHVIKSDLVNEEATGQFRVYPELPKPSISSNNSKPVEDKDAVAFTCEPETQDATYLWWV
NNQSLPVSPRLQLSNGNRTLTLFNVTRNDTASYKCETQNPVSARRSDSVILNVL
corresponding to amino acids 1 - 234 of CEAS HUMAN, which also corresponds to
amino
acids 1 - 234 of HUMCEA PEA 1 P4, and a second amino acid sequence being at
least 70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence
CEYICSSLAQAASPNPQGQRQDFSVPLRFKYTDPQPWTSRLSVTFCPRKTWADQVLTKN
RRGGAASVLGGSGSTPYDGRNR corresponding to amino acids 235 - 315 of

CA 02555509 2006-07-26
HUMCEA PEA 1 P4, wherein said first amino acid sequence and second amino acid
sequence
are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of HUMCEA PEA 1 P4, comprising a
polypeptide
5 being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
CEYICSSLAQAASPNPQGQRQDFSVPLRFKYTDPQPWTSRLSVTFCPRKTWADQVLTKN
RRGGAASVLGGSGSTPYDGRNR in HUMCEA PEA 1 P4.
According to preferred embodiments of the present invention, there is provided
an
10 isolated chimeric polypeptide encoding for HUMCEA PEA 1 P5, comprising a
first amino
acid sequence being at least 90 % homologous to
MESPSAPPHRWCIPWQRLLLTASLLTFWNPPTTAKLTIESTPFNVAEGKEVLLLVHNLPQ
HLFGYS WYKGERVDGNRQIIGYVIGTQQATPGPAYSGREIIYPNASLLIQNIIQNDTGFYT
LHVIKSDLVNEEATGQFRVYPELPKPSISSNNSKPVEDKDAVAFTCEPETQDATYLWWV
15 NNQSLPVSPRLQLSNGNRTLTLFNVTRNDTASYKCETQNPVSARRSDSVILNVLYGPDA
PTISPLNTSYRSGENLNLSCHAASNPPAQYSWFVNGTFQQSTQELFIPNITVNNSGSYTC
QAHNSDTGLNRTTVTTITVYAEPPKPFITSNNSNPVEDEDAVALTCEPEIQNTTYLWWV
NNQSLPVSPRLQLSNDNRTLTLLSVTRNDVGPYECGIQNELSVDHSDPVILNVLYGPDD
PTISPSYTYYRPGVNLSLSCHAASNPPAQYSWLIDGNIQQHTQELFISNITEKNSGLYTCQ
20 ANNSASGHSRTTVKTITVSAELPKPSISSNNSKPVEDKDAVAFTCEPEAQNTTYLWWVN
GQSLPVSPRLQLSNGNRTLTLFNVTRNDARAYVCGIQNSVSANRSDPVTLDVLYGPDTP
IISPPDSSYLSGANLNLSCHSASNPSPQYSWRINGIPQQHTQVLFIAKITPNNNGTYACFV
SNLATGRNNSIVKSITVS corresponding to amino acids 1 - 675 of CEAS HUMAN, which
also corresponds to amino acids 1 - 675 of HUMCEA PEA 1 P5, and a second amino
acid
25 sequence being at least 70%, optionally at least 80%, preferably at least
85%, more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
GKWLPGASASYSGVESIWFSPKSQEDIFFPSLCSMGTRKSQILS corresponding to amino
acids 676 - 719 of HUMCEA PEA_1 P5, wherein said first amino acid sequence and
second
amino acid sequence are contiguous and in a sequential order.
30 According to preferred embodiments of the present invention, there is
provided an
isolated polypeptide encoding for a tail of HUMCEA PEA 1 P5, comprising a
polypeptide

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91
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
GKWLPGASASYSGVESIWFSPKSQEDIFFPSLCSMGTRKSQILS in HUMCEA PEA 1 P5.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMCEA PEA 1 P19, comprising a
first amino
acid sequence being at least 90 % homologous to
MESPSAPPHRWCIPWQRLLLTASLLTFWNPPTTAKLTIESTPFNVAEGKEVLLLVHNLPQ
HLFGYSWYKGERVDGNRQIIGYVIGTQQATPGPAYSGREIIYPNASLLIQNIIQNDTGFYT
LHVIKSDLVNEEATGQFRVYPELPKPSISSNNSKPVEDKDAVAFTCEPETQDATYLWWV
NNQSLPVSPRLQLSNGNRTLTLFNVTRNDTASYKCETQNPVSARRSDSVILN
corresponding to amino acids 1 - 232 of CEAS HUMAN, which also corresponds to
amino
acids 1 - 232 of HUMCEA PEA 1 P19, and a second amino acid sequence being at
least 90
homologous to
VLYGPDTPIISPPDSSYLSGANLNLSCHSASNPSPQYSWRINGIPQQHTQVLFIAKITPNNN
GTYACFVSNLATGRNNSIVKSITVSASGTSPGLSAGATVGIMIGVLVGVALI
corresponding to amino acids 589 - 702 of CEAS HUMAN, which also corresponds
to amino
acids 233 - 346 of HUMCEA PEA 1 P19, wherein said first amino acid sequence
and second
amino acid sequence are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of HUMCEA PEA 1
P19,
comprising a polypeptide having a length "n", wherein n is at least about 10
amino acids in
length, optionally at least about 20 amino acids in length, preferably at
least about 30 amino
acids in length, more preferably at least about 40 amino acids in length and
most preferably at
least about 50 amino acids in length, wherein at least two amino acids
comprise NV, having a
structure as follows: a sequence starting from any of amino acid numbers 232-x
to 232; and
ending at any of amino acid numbers 233+ ((n-2) - x), in which x varies from 0
to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMCEA PEA 1 P20, comprising a
first amino
acid sequence being at least 90 % homologous to
MESPSAPPHRWCIPWQRLLLTASLLTFWNPPTTAKLTIESTPFNVAEGKEVLLLVHNLPQ
HLFGYSWYKGERVDGNRQIIGYVIGTQQATPGPAYSGREIIYPNASLLIQNIIQNDTGFYT

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92
LHVIKSDLVNEEATGQFRVYP corresponding to amino acids 1 - 142 of CEAS HUMAN,
which also corresponds to amino acids 1 - 142 of HUMCEA PEA 1 P20, and a
second amino
acid sequence being at least 90 % homologous to
ELPKPSISSNNSKPVEDKDAVAFTCEPEAQNTTYLWWVNGQSLPVSPRLQLSNGNRTLT
LFNVTRNDARAYVCGIQNSVSANRSDPVTLDVLYGPDTPIISPPDSSYLSGANLNLSCHS
ASNPSPQYSWRINGIPQQHTQVLFIAKITPNNNGTYACFVSNLATGRNNSIVKSITVSASG
TSPGLSAGATVGIMIGVLVGVALI corresponding to amino acids 499 - 702 of
CEAS HUMAN, which also corresponds to amino acids 143 - 346 of HUMCEA PEA_1
P20,
wherein said first amino acid sequence and second amino acid sequence are
contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of HUMCEA PEA 1
P20,
comprising a polypeptide having a length "n", wherein n is at least about 10
amino acids in
length, optionally at least about 20 amino acids in length, preferably at
least about 30 amino
acids in length, more preferably at least about 40 amino acids in length and
most preferably at
least about 50 amino acids in length, wherein at least two amino acids
comprise PE, having a
structure as follows: a sequence starting from any of amino acid numbers 142-x
to 142; and
ending at any of amino acid numbers 143+ ((n-2) - x), in which x varies from 0
to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 244808 PEA 1 P5, comprising a first
amino acid
sequence being at least 90 % homologous to
MLLPQLCWLPLLAGLLPPVPAQKFSALTFLRVDQDKDKDCSLDCAGSPQKPLCASDGR
TFLSRCEFQRAKCKDPQLEIAYRGNCKDVSRCVAERKYTQEQARKEFQQVFIPECNDD
GTYSQVQCHSYTGYCWCVTPNGRPISGTAVAHKTPRCPGSVNEKLPQREGTGKTDDAA
APALETQPQGDEEDIASRYPTLWTEQVKSRQNKTNKNSVSSCDQEHQSALEEAKQPKN
DNVVIPECAHGGLYKPVQCHPSTGYCWCVLVDTGRPIPGTSTRYEQPKCDNTARAHPA
KARDLYKGRQLQGCPGAKKHEFLTSVLDALSTDMVHAASDPSSSSGRLSEPDPSHTLEE
RVVHWYFKLLDKNSSGDIGKKEIKPFKRFLRKKSKPKKCVKKFVEYCDVNNDKSISVQ
ELMGCLGVAKEDGKADTKKRHTPRGHAESTSNRQ corresponding to amino acids 1 - 441
of SM02 HUMAN, which also corresponds to amino acids 1 - 441 of 244808 PEA 1
P5, and
a second amino acid sequence being at least 70%, optionally at least 80%,
preferably at least

CA 02555509 2006-07-26
93
85%, more preferably at least 90% and most preferably at least 95% homologous
to a
polypeptide having the sequence DAMVVSSRPKATTHRKSRTLSRR corresponding to amino
acids 442 - 464 of 244808 PEA 1 P5, wherein said first and second amino acid
sequences are
contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 244808 PEA 1 P5, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
DAMVVSSRPKATTHRKSRTLSRR in 244808 PEA 1 P5.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 244808 PEA 1 P6, comprising a first
amino acid
sequence being at least 90 % homologous to
MLLPQLCWLPLLAGLLPPVPAQKFSALTFLRVDQDKDKDCSLDCAGSPQKPLCASDGR
TFLSRCEFQRAKCKDPQLEIAYRGNCKDVSRCVAERKYTQEQARKEFQQVFIPECNDD
GTYSQVQCHSYTGYCWCVTPNGRPISGTAVAHKTPRCPGSVNEKLPQREGTGKTDDAA
APALETQPQGDEEDIASRYPTLWTEQVKSRQNKTNKNSVSSCDQEHQSALEEAKQPKN
DNVVIPECAHGGLYKPVQCHPSTGYCWCVLVDTGRPIPGTSTRYEQPKCDNTARAHPA
KARDLYKGRQLQGCPGAKKHEFLTSVLDALSTDMVHAASDPSSSSGRLSEPDPSHTLEE
RVVHWYFKLLDKNSSGDIGKKEIKPFKRFLRKKSKPKKCVKKFVEYCDVNNDKSISVQ
ELMGCLGVAKEDGKADTKKRH corresponding to amino acids 1 - 428 of SM02 HUMAN,
which also corresponds to amino acids 1 - 428 of 244808 PEA 1 P6, and a second
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
RSKRNL corresponding to amino acids 429 - 434 of 244808 PEA 1 P6, wherein said
first and
second amino acid sequences are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 244808 PEA 1 P6, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence RSKRNL
in 244808 PEA 1 P6.

CA 02555509 2006-07-26
94
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 244808 PEA 1 P7, comprising a first
amino acid
sequence being at least 90 % homologous to
MLLPQLCWLPLLAGLLPPVPAQKFSALTFLRVDQDKDKDCSLDCAGSPQKPLCASDGR
TFLSRCEFQRAKCKDPQLEIAYRGNCKDVSRCVAERKYTQEQARKEFQQVFIPECNDD
GTYSQVQCHSYTGYCWCVTPNGRPISGTAVAHKTPRCPGSVNEKLPQREGTGKTDDAA
APALETQPQGDEEDIASRYPTLWTEQVKSRQNKTNKNSVSSCDQEHQSALEEAKQPKN
DNVVIPECAHGGLYKPVQCHPSTGYCWCVLVDTGRPIPGTSTRYEQPKCDNTARAHPA
KARDLYKGRQLQGCPGAKKHEFLTSVLDALSTDMVHAASDPSSSSGRLSEPDPSHTLEE
RVVHWYFKLLDKNSSGDIGKKEIKPFKRFLRKKSKPKKCVKKFVEYCDVNNDKSISVQ
ELMGCLGVAKEDGKADTKKRHTPRGHAESTSNRQ corresponding to amino acids 1 - 441
of SM02 HUMAN, which also corresponds to amino acids 1 - 441 of 244808 PEA 1
P7, and
a second amino acid sequence being at least 70%, optionally at least 80%,
preferably at least
85%, more preferably at least 90% and most preferably at least 95% homologous
to a
polypeptide having the sequence LLWLRGKVSFYCF corresponding to amino acids 442
- 454
of 244808 PEA 1 P7, wherein said first and second amino acid sequences are
contiguous and
in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 244808 PEA 1 P7, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
LLWLRGKVSFYCF in 244808 PEA 1 P7.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 244808 PEA 1 P11, comprising a
first amino acid
sequence being at least 90 % homologous to
MLLPQLCWLPLLAGLLPPVPAQKFSALTFLRVDQDKDKDCSLDCAGSPQKPLCASDGR
TFLSRCEFQRAKCKDPQLEIAYRGNCKDVSRCVAERKYTQEQARKEFQQVFIPECNDD
GTYSQVQCHSYTGYCWCVTPNGRPISGTAVAHKTPRCPGSVNEKLPQREGTGKT
corresponding to amino acids 1 - 170 of SM02 HUMAN, which also corresponds to
amino
acids 1 - 170 of 244808 PEA 1 P11, and a second amino acid sequence being at
least 90
homologous to

CA 02555509 2006-07-26
DIASRYPTLWTEQVKSRQNKTNKNSVSSCDQEHQSALEEAKQPKNDNVVIPECAHGGL
YKPVQCHPSTGYCWCVLVDTGRPIPGTSTRYEQPKCDNTAR.AHPAKARDLYKGRQLQ
GCPGAKKHEFLTSVLDALSTDMVHAASDPSSSSGRLSEPDPSHTLEERVVHWYFKLLD
KNSSGDIGKKEIKPFKRFLRKKSKPKKCVKKFVEYCDVNNDKSISVQELMGCLGVAKE
5 DGKADTKKRHTPRGHAESTSNRQPRKQG corresponding to amino acids 188 - 446 of
SM02 HUMAN, which also corresponds to amino acids 171 - 429 of 244808 PEA 1
P11,
wherein said first and second amino acid sequences are contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of 244808 PEA 1
P11, comprising
10 a polypeptide having a length "n", wherein n is at least about 10 amino
acids in length,
optionally at least about 20 amino acids in length, preferably at least about
30 amino acids in
length, more preferably at least about 40 amino acids in length and most
preferably at least
about SO amino acids in length, wherein at least two amino acids comprise TD,
having a
structure as follows: a sequence starting from any of amino acid numbers 170-x
to -170; and
1 S ending at any of amino acid numbers 171+ ((n-2) - x), in which x varies
from 0 to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for H61775 P16, comprising a first
amino acid
sequence being at least 90 % homologous to
MVWCLGLAVLSLVISQGADGRGKPEVVSVVGRAGESWLGCDLLPPAGRPPLHVIEWL
20 RFGFLLPIFIQFGLYSPR>DPDYVG corresponding to amino acids 11 - 93 of Q9P2J2,
which
also corresponds to amino acids 1 - 83 of H61775 P 16, and a second amino acid
sequence being
at least 70%, optionally at least 80%, preferably at least 85%, more
preferably at least 90% and
most preferably at least 95% homologous to a polypeptide having the sequence
DCGFPAFRELKRAETVSPVFFTRRCIWEDLKSTGFSPAGGGRPPGGGPRTQEDSGLPCW
25 RSSCSVTLQV corresponding to amino acids 84 - 152 of H61775 P16, wherein
said first and
second amino acid sequences are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of H61775 P16, comprising a
polypeptide being at least
70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least about
30 90% and most preferably at least about 95% homologous to the sequence

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DCGFPAFRELKRAETVSPVFFTRRCIWEDLKSTGFSPAGGGRPPGGGPRTQEDSGLPCW
RSSCSVTLQV in H61775 P16.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for H61775 P16, comprising a first
amino acid
sequence being at least 90 % homologous to
MVWCLGLAVLSLVISQGADGRGKPEWSVVGRAGESVVLGCDLLPPAGRPPLHVIEWL
RFGFLLPIFIQFGLYSPRIDPDWG corresponding to amino acids 1 - 83 of AAQ88495,
which
also corresponds to amino acids 1 - 83 of H61775 P16, and a second amino acid
sequence being
at least 70%, optionally at least 80%, preferably at least 85%, more
preferably at least 90% and
most preferably at least 95% homologous to a polypeptide having the sequence
DCGFPAFRELKR.AETVSPVFFTRRCIWEDLKSTGFSPAGGGRPPGGGPRTQEDSGLPCW
RSSCSVTLQV corresponding to amino acids 84 - 152 of H61775 P16, wherein said
first and
second amino acid sequences are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of H6I775 P16, comprising a
polypeptide being at least
70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least about
90% and most preferably at least about 95% homologous to the sequence
DCGFPAFRELKRAETV SP VFFTRRCIWEDLKSTGFSPAGGGRPPGGGPRTQEDSGLPC W
RSSCSVTLQV in H61775 P16.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for H61775 P17, comprising a first
amino acid
sequence being at least 90 % homologous to
MVWCLGLAVLSLVISQGADGRGKPEVVSVVGRAGESVVLGCDLLPPAGRPPLHVIEWL
RFGFLLPIFIQFGLYSPRIDPDYVG corresponding to amino acids 11 - 93 of Q9P2J2,
which
also corresponds to amino acids 1 - 83 of H61775 P17.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for H61775 P17, comprising a first
amino acid
sequence being at least 90 % homologous to
MVWCLGLAVLSLVISQGADGRGKPEVVSVVGRAGESVVLGCDLLPPAGRPPLHVIEWL
RFGFLLPIFIQFGLYSPRIDPDYVG corresponding to amino acids 1 - 83 of AAQ88495,
which
also corresponds to amino acids 1 - 83 of H61775 P17.

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According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M85491 PEA 1 P 13, comprising a
first amino acid
sequence being at least 90 % homologous to
MALRRLGAALLLLPLLAAVEETLMDSTTATAELGWMVHPPSGWEEVSGYDENMNTIR
TYQVCNVFESSQNNWLRTKFIRRRGAHRIHVEMKFSVRDCSSIPSVPGSCKETFNLYYY
EADFDSATKTFPNWMENPWVKVDTIAADESFSQVDLGGRVMKINTEVRSFGPVSRSGF
YLAFQDYGGCMSLIAVRVFYRKCPRIIQNGAIFQETLSGAESTSLVAARGSCIANAEEVD
VPIKLYCNGDGEWLVPIGRCMCKAGFEAVENGTVCRGCPSGTFKANQGDEACTHCPIN
SRTTSEGATNCVCRNGYYRADLDPLDMPCTTIPSAPQAVISSVNETSLMLEWTPPRDSG
GREDLVYIVIICKSCGSGRGACTRCGDNVQYAPRQLGLTEPRIYISDLLAHTQYTFEIQAV
NGVTDQSPFSPQFASVNITTNQAAPSAVSIMHQVSRTVDSITLSWSQPDQPNGVILDYEL
QYYEK corresponding to amino acids 1 - 476 of EPB2 HUMAN, which also
corresponds to
amino acids 1 - 476 of M85491 PEA 1 P13, and a second amino acid sequence
being at least
70%, optionally at least 80%, preferably at least 85%, more preferably at
least 90% and most
1 S preferably at least 95% homologous to a polypeptide having the sequence
VPIGWVLSPSPTSLRAPLPG corresponding to amino acids 477 - 496 of
M85491 PEA 1 P13, wherein said first and second amino acid sequences are
contiguous and
in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of M85491 PEA 1 P13, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
VPIGWVLSPSPTSLRAPLPG in M85491 PEA 1 P13.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for M85491 PEA 1 P14, comprising a
first amino acid
sequence being at least 90 % homologous to
MALRRLGAALLLLPLLAAVEETLMDSTTATAELGWMVHPPSGWEEVSGYDENMNTIR
TYQVCNVFESSQNNWLRTKFIRRRGAHRIHVEMKFSVRDCSSIPSVPGSCKETFNLYYY
EADFDSATKTFPNWMENPWVKVDTIAADESFSQVDLGGRVMKINTEVRSFGPVSRSGF
YLAFQDYGGCMSLIAVRVFYRKCPRIIQNGAIFQETLSGAESTSLVAARGSCIANAEEVD
VPIKLYCNGDGEWLVPIGRCMCKAGFEAVENGTVCR corresponding to amino acids 1 -

CA 02555509 2006-07-26
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270 of EPB2 HUMAN, which also corresponds to amino acids 1 - 270 of
M85491 PEA 1 P 14, and a second amino acid sequence being at least 70%,
optionally at least
80%, preferably at least 85%, more preferably at least 90% and most preferably
at least 95%
homologous to a polypeptide having the sequence
ERQDLTMLSRLVLNSWPQMILPPQPPKVLEL corresponding to amino acids 271 - 301 of
M85491 PEA 1 P14, wherein said first and second amino acid sequences are
contiguous and
in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of M85491 PEA 1 P14, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
ERQDLTMLSRLVLNSWPQMILPPQPPKVLEL in M85491 PEA 1 P14.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for T39971 P6, comprising a first amino
acid sequence
being at least 90 % homologous to
MAPLRPLLILALLAWVALADQESCKGRCTEGFNVDKKCQCDELCSYYQSCCTDYTAEC
KPQVTRGDVFTMPEDEYTVYDDGEEKNNATVHEQVGGPSLTSDLQAQSKGNPEQTPV
LKPEEEAPAPEVGASKPEGIDSRPETLHPGRPQPPAEEELCSGKPFDAFTDLKNGSLFAFR
GQYCYELDEKAVRPGYPKLIRDVWGIEGPIDAAFTRINCQGKTYLFKGSQYWRFEDGV
LDPDYPRNISDGFDGIPDNVDAALALPAHSYSGRERVYFFKG corresponding to amino
acids 1 - 276 of VTNC HUMAN, which also corresponds to amino acids 1 - 276 of
T39971 P6, and a second amino acid sequence being at least 70%, optionally at
least 80%,
preferably at least 85%, more preferably at least 90% and most preferably at
least 95%
homologous to a polypeptide having the sequence TQGVVGD corresponding to amino
acids
277 - 283 of T39971 P6, wherein said first and second amino acid sequences are
contiguous
and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of T39971 P6, comprising a
polypeptide being at least
70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least about
90% and most preferably at least about 95% homologous to the sequence TQGVVGD
in
T39971 P6.

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According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for T39971 P9, comprising a first amino
acid sequence
being at least 90 % homologous to
MAPLRPLLILALLAWVALADQESCKGRCTEGFNVDKKCQCDELCSYYQSCCTDYTAEC
KPQVTRGDVFTMPEDEYTVYDDGEEKNNATVHEQVGGPSLTSDLQAQSKGNPEQTPV
LKPEEEAPAPEVGASKPEGIDSRPETLHPGRPQPPAEEELCSGKPFDAFTDLKNGSLFAFR
GQYCYELDEKAVRPGYPKLIRDVWGIEGPIDAAFTRINCQGKTYLFKGSQYWRFEDGV
LDPDYPRNISDGFDGIPDNVDAALALPAHSYSGRERVYFFKGKQYWEYQFQHQPSQEE
CEGSSLSAVFEHFAMMQRDSWEDIFELLFWGRT corresponding to amino acids 1 - 325 of
VTNC HUMAN, which also corresponds to amino acids 1 - 325 of T39971 P9, and a
second
amino acid sequence being at least 90 % homologous to~
SGMAPRPSLAKKQRFRHRNRKGYRSQRGHSRGRNQNSRRPSRATWLSLFSSEESNLGA
NNYDDYRMDWLVPATCEPIQSVFFFSGDKYYRVNLRTRRVDTVDPPYPRSIAQYWLGC
PAPGHL corresponding to amino acids 357 - 478 of VTNC HUNL~N, which also
corresponds
to amino acids 326 - 447 of T39971 P9, wherein said first and second amino
acid sequences are
contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of T39971 P9,
comprising a
polypeptide having a length "n", wherein n is at least about 10 amino acids in
length, optionally
at least about 20 amino acids in length, preferably at least about 30 amino
acids in length, more
preferably at least about 40 amino acids in length and most preferably at
least about 50 amino
acids in length, wherein at least two amino acids comprise TS, having a
structure as follows: a
sequence starting from any of amino acid numbers 325-x to 325; and ending at
any of amino
acid numbers 326 + ((n-2) - x), in which x varies from 0 to n-2.
2S According to preferred embodiments of the present invention, there is
provided an
isolated chimeric polypeptide encoding for T39971 P11, comprising a first
amino acid sequence
being at least 90 % homologous to
MAPLRPLLILALLAWVALADQESCKGRCTEGFNVDKKCQCDELCSYYQSCCTDYTAEC
KPQVTRGDVFTMPEDEYTVYDDGEEKNNATVHEQVGGPSLTSDLQAQSKGNPEQTPV
LKPEEEAPAPEVGASKPEGIDSRPETLHPGRPQPPAEEELCSGKPFDAFTDLKNGSLFAFR
GQYCYELDEKAVRPGYPKLIRDVWGIEGPIDAAFTRINCQGKTYLFKGSQYWRFEDGV

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100
LDPDYPRNISDGFDGIPDNVDAALALPAHSYSGRERVYFFKGKQYWEYQFQHQPSQEE
CEGSSLSAVFEHFAMMQRDSWEDIFELLFWGRTS corresponding to amino acids 1 - 326 of
VTNC_HUMAN, which also corresponds to amino acids 1 - 326 of T39971 P11, and a
second
amino acid sequence being at least 90 % homologous to
DKYYRVNLRTRRVDTVDPPYPRSIAQYWLGCPAPGHL corresponding to amino acids 442
- 478 of VTNC HUMAN, which also corresponds to amino acids 327 - 363 of T39971
P11,
wherein said first and second amino acid sequences are contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of T39971 P11,
comprising a
polypeptide having a length "n", wherein n is at least about 10 amino acids in
length, optionally
at least about 20 amino acids in length, preferably at least about 30 amino
acids in length, more
preferably at least about 40 amino acids in length and most preferably at
least about 50 amino
acids in length, wherein at least two amino acids comprise SD, having a
structure as follows: a
sequence starting from any of amino acid numbers 326-x to 326; and ending at
any of amino
acid numbers 327 + ((n-2) - x), in which x varies from 0 to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for T39971 P11, comprising a first
amino acid sequence
being at least 90 % homologous to
MAPLRPLLILALLAWVALADQESCKGRCTEGFNVDKKCQCDELCSYYQSCCTDYTAEC
KPQVTRGDVFTMPEDEYTVYDDGEEKNNATVHEQVGGPSLTSDLQAQSKGNPEQTPV
LKPEEEAPAPEVGASKPEGIDSRPETLHPGRPQPPAEEELCSGKPFDAFTDLKNGSLFAFR
GQYCYELDEKAVRPGYPKLIRDVWGIEGPIDAAFTRINCQGKTYLFKGSQYWRFEDGV
LDPDYPRNISDGFDGIPDNVDAALALPAHSYSGRERVYFFKGKQYWEYQFQHQPSQEE
CEGSSLSAVFEHFAMMQRDSWEDIFELLFWGRTS corresponding to amino acids 1 - 326 of
Q9BSH7, which also corresponds to amino acids 1 - 326 of T39971 P11, and a
second amino
acid sequence being at least 90 % homologous to
DKYYRVNLRTRRVDTVDPPYPRSIAQYWLGCPAPGHL corresponding to amino acids 442
- 478 of Q9BSH7, which also corresponds to amino acids 327 - 363 of T39971
P11, wherein
said first and second amino acid sequences are contiguous and in a sequential
order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of T39971 P11,
comprising a

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polypeptide having a length "n", wherein n is at least about 10 amino acids in
length, optionally
at least about 20 amino acids in length, preferably at least about 30 amino
acids in length, more
preferably at least about 40 amino acids in length and most preferably at
least about 50 amino
acids in length, wherein at least two amino acids comprise SD, having a
structure as follows: a
sequence starting from any of amino acid numbers 326-x to 326; and ending at
any of amino
acid numbers 327 + ((n-2) - x), in which x varies from 0 to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for T39971 P12, comprising a first
amino acid sequence
being at least 90 % homologous to
MAPLRPLLILALLAWVALADQESCKGRCTEGFNVDKKCQCDELCSYYQSCCTDYTAEC
KPQVTRGDVFTMPEDEYTVYDDGEEKNNATVHEQVGGPSLTSDLQAQSKGNPEQTPV
LKPEEEAPAPEVGASKPEGIDSRPETLHPGRPQPPAEEELCSGKPFDAFTDLKNGSLFAFR
GQYCYELDEKAVRPGYPKLIRDVWGIEGPIDAAFTRINCQGKTYLFK corresponding to
amino acids 1 - 223 of VTNC_HUMAN, which also corresponds to amino acids 1 -
223 of
T39971 P12, and a second amino acid sequence being at least 70%, optionally at
least 80%,
preferably at least 85%, more preferably at least 90% and most preferably at
least 95%
homologous to a polypeptide having the sequence VPGAVGQGRKHLGRV corresponding
to
amino acids 224 - 238 of T39971 P12, wherein said first and second amino acid
sequences are
contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of T39971 P12, comprising a
polypeptide being at least
70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least about
90% and most preferably at least about 95% homologous to the sequence
VPGAVGQGRKHLGRV in T39971 P12.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for T39971 P12, comprising a first
amino acid sequence
being at least 90 % homologous to
MAPLRPLLILALLAWVALADQESCKGRCTEGFNVDKKCQCDELCSYYQSCCTDYTAEC
KPQVTRGDVFTMPEDEYTVYDDGEEKNNATVHEQVGGPSLTSDLQAQSKGNPEQTPV
LKPEEEAPAPEVGASKPEGIDSRPETLHPGRPQPPAEEELCSGKPFDAFTDLKNGSLFAFR
GQYCYELDEKAVRPGYPKLIRI7VWGIEGPIDAAFTRINCQGKTYLFK corresponding to

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amino acids 1 - 223 of Q9BSH7, which also corresponds to amino acids 1 - 223
of T39971 P12,
and a second amino acid sequence being at least 70%, optionally at least 80%,
preferably at least
85%, more preferably at least 90% and most preferably at least 95% homologous
to a
polypeptide having the sequence VPGAVGQGRKHLGRV corresponding to amino acids
224 -
238 of T39971 P12, wherein said first and second amino acid sequences are
contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of T39971 P12, comprising a
polypeptide being at least
70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least about
90% and most preferably at least about 95% homologous to the sequence
VPGAVGQGRKHLGRV in T39971 P12.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 221368 PEA 1 P2, comprising a first
amino acid
sequence being at least 90 % homologous to
MKYSCCALVLAVLGTELLGSLCSTVRSPRFRGRIQQERKNIRPNIILVLTDDQDVELGSL
QVMNKTRKIMEHGGATFINAFVTTPMCCPSRSSMLTGKYVI~TNNENCSSPSW
QAMHEPRTFAVYLNNTGYRTAFFGKYLNEYNGSYIPPGWREWLGLIKNSRFYNYTVCR
NGIKEKHGFDYAKDYFTDLITNES1NYFKMSK:RMYPHRPVMMVISHAAPHGPEDSAPQ
FSKLYPNASQHITPSYNYAPNMDKHWIMQYTGPMLPIHMEFTNILQRKRLQTLMSVDD
SVERLYNMLVETGELENTYIIYTADHGYHIGQFGLVKGKSMPYDFDIRVPFFIRGPSVEP
GSIVPQIVLNIDLAPTILDIAGLDTPPDVDGKSVLKLLDPEKPGNRFRTNKKAKIWRDTFL
VERGKFLRKKEESSKNIQQSNHLPKYERVKELCQQARYQTACEQPGQKWQCIEDTSGK
LRIHKCKGPSDLLTVRQSTRNLYARGFHDKDKECSCRESGYRASRSQRKSQRQFLRNQ
GTPKYKPRFVHTRQTRSLSVEFEGEIYDINLEEEEELQVLQPRNIAKRHDEGHKGPRDLQ
ASSGGNRGRMLADSSNAVGPPTTVRVTHKCFILPNDSIHCERELYQSARAWKDHKAYI
DKEIEALQDKIKNLREVRGHLKRRKPEECSCSKQSYYNKEKGVKKQEKLKSHLHPFKE
AAQEVDSKLQLFKENNRRRKKERKEKRRQRKGEECSLPGLTCFTHDNNHWQTAPFWN
corresponding to amino acids 1 - 761 of SUL1 HUMAN, which also corresponds to
amino
acids 1 - 761 of 221368 PEA 1 P2, and a second amino acid sequence being at
least 70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence

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PHKYSAHGRTRHFESATRTTNGAQKLSRI corresponding to amino acids 762 - 790 of
221368 PEA 1 P2, wherein said first and second amino acid sequences are
contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 221368 PEA 1 P2, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
PHKYSAHGRTRHFESATRTTNGAQKLSRI in 221368 PEA 1 P2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 221368 PEA 1 P5, comprising a first
amino acid
sequence being at least 90 % homologous to
MKYSCCALVLAVLGTELLGSLCSTVRSPRFRGRIQQERKNIRPNIILVLTDDQDVEL
corresponding to amino acids 1 - 57 of Q7Z2W2, which also corresponds to amino
acids 1 - 57
of 221368 PEA 1 P5, second bridging amino acid sequence comprising A, and a
third amino
acid sequence being at least 90 % homologous to
FFGKYLNEYNGSYIPPGWREWLGLIKNSRFYNYTVCRNGIKEKHGFDYAKDYFTDLITN
ESINYFKMSKRMYPHRPVMMVISHAAPHGPEDSAPQFSKLYPNASQHITPSYNYAPNM
DKHWIMQYTGPMLPIHMEFTNILQRKRLQTLMSVDDSVERLYNMLVETGELENTYIIYT
ADHGYHIGQFGLVKGKSMPYDFDIRVPFFIRGPSVEPGSIVPQIVLNIDLAPTILDIAGLDT
PPDVDGKSVLKLLDPEKPGNRFRTNKKAKIWRDTFLVERGKFLRKKEESSKNIQQSNHL
PKYERVKELCQQARYQTACEQPGQKWQCIEDTSGKLRIHKCKGPSDLLTVRQSTRNLY
ARGFHDKDKECSCRESGYRASRSQRKSQRQFLRNQGTPKYKPRFVHTRQTRSLSVEFE
GEIYDINLEEEEELQVLQPRNIAKRHDEGHKGPRDLQASSGGNRGRMLADSSNAVGPPT
TVRVTHKCFILPNDSIHCERELYQSARAWKDHKAYIDKEIEALQDKIKNLREVRGHLKR
RKPEECSCSKQSYYNKEKGVKKQEKLKSHLHPFKEAAQEVDSKLQLFKENNRRRKKER
KEKRRQRKGEECSLPGLTCFTHDNNHWQTAPFWNLGSFCACTSSNNNTYWCLRTVNE
THNFLFCEFATGFLEYFDMNTDPYQLTNTVHTVERGILNQLHVQLMELRSCQGYKQCN
PRPKNLDVGNKDGGSYDLHRGQLWDGWEG corresponding to amino acids 139 - 871 of
Q7Z2W2, which also corresponds to amino acids 59 - 791 of 221368 PEA 1 P5,
wherein said
first, second and third amino acid sequences are contiguous and in a
sequential order.

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According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for an edge portion of 221368 PEA 1 PS,
comprising a
polypeptide having a length "n", wherein n is at least about 10 amino acids in
length, optionally
at least about 20 amino acids in length, preferably at least about 30 amino
acids in length, more
S preferably at least about 40 amino acids in length and most preferably at
least about 50 amino
acids in length, wherein at least two amino acids comprise LAF having a
structure as follows
(numbering according to 221368 PEA 1 PS): a sequence starting from any of
amino acid
numbers 57-x to 57; and ending at any of amino acid numbers 59 + ((n-2) - x),
in which x varies
from 0 to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 221368 PEA 1 P5, comprising a first
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MKYSCCALVLAVLGTELLGSLCSTVRSPRFRGRIQQERKNIRPNIILVLTDDQDVELAFF
GKYLNEYNGSYIPPGWREWLGLIKNSRFYNYTVCRNGIKEKHGFDYAKDYFTDLITNES
INYFKMSKRMYPHRPVMMVISHAAPHGPEDSAPQFSKLYPNASQHITPSYNYAPNMDK
HWIMQYTGPMLPIHMEFTNILQRKRLQTLMSVDDSVERLYNMLVETGELENTYIIYTAD
HGYHIGQFGLVKGKSMPYDFDIRVPFFIRGPSVEPGSIVPQIVLNIDLAPTILDIAGLDTPP
DVDGKSVLKLLDPEKPGNRFRTNKKAKIWRDTFLVERGKFLRKKEESSKNIQQSNHLP
KYERVKELCQQARYQTACEQPGQKWQCIEDTSGKLRIHKCKGPSDLLTVRQSTRNLYA
RGFHDKDKECSCRESGYRASRSQRKSQRQFLRNQGTPKYKPRFVHTRQTRSLSVEFEGE
IYDINLEEEEELQV LQPRNIAKRHDEGHKGPRDLQAS S GGNRGRMLAD S SNAV GPPTT V
RVTHKCFILPNDSIHCERELYQSARAWKDHKAY)DKEIEALQDKIKNLREVRGHLKRRK
PEECSCSKQSYYNKEKGVKKQEKLKSHLHPFKEAAQEVDSKLQLFKENNRRRKKERKE
KRRQRKGEECSLPGLTCFTHDNNHWQTAPFWNLGSFCACTSSNNNTYWCLRTVNETH
NFLFCEFATGFLEYFDMNTDPYQLTNTVHTVERGILNQLHVQLME corresponding to
amino acids 1 - 751 of 221368 PEA 1 P5, and a second amino acid sequence being
at least 90
homologous to LRSCQGYKQCNPRPKNLDVGNKDGGSYDLHRGQLWDGWEG
corresponding to amino acids 1 - 40 of AAH12997, which also corresponds to
amino acids 752 -
791 of 221368 PEA 1 P5, wherein said first and second amino acid sequences are
contiguous
and in a sequential order.

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According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of 221368 PEA 1 P5, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
MKYSCCALVLAVLGTELLGSLCSTVRSPRFRGRIQQERKNIRPNIILVLTDDQDVELAFF
GKYLNEYNGSYIPPGWREWLGLIKNSRFYNYTVCRNGIKEKHGFDYAKDYFTDLITNES
INYFKMSKRMYPHRPVMMVISHAAPHGPEDSAPQFSKLYPNASQHITPSYNYAPNMDK
HWIMQYTGPMLPIHMEFTNILQRKRLQTLMSVDDSVERLYNMLVETGELENTYIIYTAD
HGYHIGQFGLVKGKSMPYDFDIRVPFFIRGPSVEPGSIVPQIVLNIDLAPTILDIAGLDTPP
DVDGKSVLKLLDPEKPGNRFRTNKKAKIWRDTFLVERGKFLRKKEESSKNIQQSNHLP
KYERVKELCQQARYQTACEQPGQKWQCIEDTSGKLRIHKCKGPSDLLTVRQSTRNLYA
RGFHDKDKECSCRESGYRASRSQRKSQRQFLRNQGTPKYKPRFVHTRQTRSLSVEFEGE
IYDINLEEEEELQVLQPRNIAKRHDEGHKGPRDLQASSGGNRGRMLADSSNAVGPPTTV
RVTHKCFILPNDSIHCERELYQSARAWKDHKAYIDKEIEALQDKIKNLREVRGHLKRRK
PEECSCSKQSYYNKEKGVKKQEKLKSHLHPFKEAAQEVDSKLQLFKENNRRRKKERKE
KRRQRKGEECSLPGLTCFTHDNNHWQTAPFWNLGSFCACTSSNNNTYWCLRTVNETH
NFLFCEFATGFLEYFDMNTDPYQLTNTVHTVERGILNQLHVQLME of
221368 PEA 1 P5.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 221368 PEA 1 PS, comprising a first
amino acid
sequence being at least 90 % homologous to
MKYSCCALVLAVLGTELLGSLCSTVRSPRFRGRIQQERKNIRPNIILVLTDDQDVEL
corresponding to amino acids 1 - 57 of SUL1 HUMAN, which also corresponds to
amino acids
1 - 57 of 221368 PEA 1 P5, and a second amino acid sequence being at least 90
homologous to
AFFGKYLNEYNGSYIPPGWREWLGLIKNSRFYNYTVCRNGIKEKHGFDYAKDYFTDLIT
NESINYFKMSKRMYPHRPVMMVISHAAPHGPEDSAPQFSKLYPNASQHITPSYNYAPN
MDKHWIMQYTGPMLPIHMEFTNILQRKRLQTLMSVDDSVERLYNMLVETGELENTYII
YTADHGYHIGQFGLVKGKSMPYDFDIRVPFFIRGPSVEPGSIVPQNLNIDLAPTILDIAGL
DTPPDVDGKSVLKLLDPEKPGNRFRTNKKAKIWRDTFLVERGKFLRKKEESSKNIQQSN
HLPKYERVKELCQQARYQTACEQPGQKWQCIEDTSGKLRIHKCKGPSDLLTVRQSTRN

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LYARGFHDKDKECSCRESGYRASRSQRKSQRQFLRNQGTPKYKPRFVHTRQTRSLSVE
FEGEIYDINLEEEEELQVLQPRNIAKRHDEGHKGPRDLQASSGGNRGRMLADSSNAVGP
PTTVRVTHKCFILPNDSIHCERELYQSARAWKDHKAYIDKEIEALQDKIKNLREVRGHL
KRRKPEECSCSKQSYYNKEKGVKKQEKLKSHLHPFKEAAQEVDSKLQLFKENNRRRK
KERKEKRRQRKGEECSLPGLTCFTHDNNHWQTAPFWNLGSFCACTSSNNNTYWCLRT
VNETHNFLFCEFATGFLEYFDMNTDPYQLTNTVHTVERGILNQLHVQLMELRSCQGYK
QCNPRPKNLDVGNKDGGSYDLHRGQLWDGWEG corresponding to amino acids 138 - 871
of SUL1 HUMAN, which also corresponds to amino acids 58 - 791 of 221368 PEA 1
P5,
wherein said first and second amino acid sequences are contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of 221368 PEA 1 P5,
comprising a
polypeptide having a length "n", wherein n is at least about 10 amino acids in
length, optionally
at least about 20 amino acids in length, preferably at least about 30 amino
acids in length, more
preferably at least about 40 amino acids in length and most preferably at
least about 50 amino
acids in length, wherein at least two amino acids comprise LA, having a
structure as follows: a
sequence starting from any of amino acid numbers 57-x to 57; and ending at any
of amino acid
numbers 58 + ((n-2) - x), in which x varies from 0 to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 221368 PEA 1 P15, comprising a
first amino acid
sequence being at least 90 % homologous to
MKYSCCALVLAVLGTELLGSLCSTVRSPRFRGRIQQERKNIRPNIILVLTDDQDVELGSL
QVMNKTRKIMEHGGATF1NAFVTTPMCCPSRSSMLTGKYVHNHNVYTNNENCSSPSW
QAMHEPRTFAVYLNNTGYRTAFFGKYLNEYNGSYIPPGWREWLGLIKNSRFYNYTVCR
NGIKEKHGFDYAKDYFTDLITNESINYFKMSKRMYPHRPVMMVISHAAPHGPEDSAPQ
FSKLYPNASQHITPSYNYAPNMDKHWIMQYTGPMLPIHMEFTNILQRKRLQTLMSVDD
SVERLYNMLVETGELENTYIIYTADHGYHIGQFGLVKGKSMPYDFDIRVPFFIRGPSVEP
GSIVPQIVLNIDLAPTILDIAGLDTPPDVDGKSVLKLLDPEKPGNRFRTNKKAKIWRDTFL
VERG corresponding to amino acids 1 - 416 of SUL1 HI1MAN, which also
corresponds to
amino acids 1 - 416 of 221368 PEA 1 P15.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 221368 PEA 1 P16, comprising a
first amino acid

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sequence being at least 90 % homologous to
MKYSCCALVLAVLGTELLGSLCSTVRSPRFRGRIQQERKNIRPNIILVLTDDQDVELGSL
QVMNKTRKIMEHGGATFINAFVTTPMCCPSRSSMLTGKYVHNHNVYTNNENCSSPSW
QAMHEPRTFAVYLNNTGYRTAFFGKYLNEYNGSYIPPGWREWLGLIKNSRFYNYTVCR
NGIKEKHGFDYAKDYFTDLITNESINYFKMSKRMYPHRPVMMVISHAAPHGPEDSAPQ
FSKLYPNASQHITPSYNYAPNMDKHWIMQYTGPMLPIHMEFTNILQRKRLQTLMS VDD
SVERLYNMLVETGELENTYIIYTADHGYHIGQFGLVKGKSMPYDFDIRVPFFIRGPSVEP
GSIVPQIVLNIDLAPTILDIAGLDTPPDVDGKSVLKLLDPEKPGNR corresponding to amino
acids 1 - 397 of SULI HUMAN, which also corresponds to amino acids 1 - 397 of
221368 PEA 1 P16, and a second amino acid sequence being at least 70%,
optionally at least
80%, preferably at least 85%, more preferably at least 90% and most preferably
at least 95%
homologous to a polypeptide having the sequence CVIVPPLSQPQIH corresponding to
amino
acids 398 - 410 of 221368 PEA 1 P16, wherein said first and second amino acid
sequences are
contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 221368 PEA 1 P16, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
CVIVPPLSQPQIH in 221368 PEA 1 P16.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 221368 PEA 1 P22, comprising a
first amino acid
sequence being at least 90 % homologous to
MKYSCCALVLAVLGTELLGSLCSTVRSPRFRGRIQQERKNIRPNIILVLTDDQDVELGSL
QVMNKTRKIMEHGGATF1NAFVTTPMCCPSRSSMLTGKYVHNHNVYTNNENCSSPSW
QAMHEPRTFAVYLNNTGYRTAFFGKYLNEYNGSYIPPGWREWLGLIKNSRFYNYTVCR
NGIKEKHGFDYAK corresponding to amino acids 1 - 188 of SUL1 HUMAN, which also
corresponds to amino acids 1 - 188 of 221368 PEA 1 P22, and a second amino
acid sequence
being at least 70%, optionally at least 80%, preferably at least 85%, more
preferably at least
90% and most preferably at least 95% homologous to a polypeptide having the
sequence
ARYDGDQPRCAPRPRGLSPTVF corresponding to amino acids 189 - 210 of

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221368 PEA 1 P22, wherein said first and second amino acid sequences are
contiguous and in
a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 221368 PEA 1 P22, comprising a
polypeptide being
S at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
ARYDGDQPRCAPRPRGLSPTVF in 221368 PEA 1 P22.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 221368 PEA 1 P23, comprising a
first amino acid
sequence being at least 90 % homologous to
MKYSCCALVLAVLGTELLGSLCSTVRSPRFRGRIQQERKNIRPNIILVLTDDQDVELGSL
QVMNKTRKIMEHGGATFINAFVTTPMCCPSRSSMLTGKYVHNHNVYTNNENCSSPSW
QAMHEPRTFAVYLNNTGYRT corresponding to amino acids 1 - 137 of Q7Z2W2, which
also
corresponds to amino acids 1 - 137 of 221368 PEA 1 P23, and a second amino
acid sequence
being at least 70%, optionally at least 80%, preferably at least 85%, more
preferably at least
90% and most preferably at least 95% homologous to a polypeptide having the
sequence
GLLHRLNH corresponding to amino acids 138 - 145 of 221368 PEA 1 P23, wherein
said
first and second amino acid sequences are contiguous and in a sequential
order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 221368 PEA 1 P23, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
GLLHRLNH in 221368 PEA 1 P23.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 221368 PEA 1 P23, comprising a
first amino acid
sequence being at least 90 % homologous to
MKYSCCALVLAVLGTELLGSLCSTVRSPRFRGRIQQERKNIRPNIILVLTDDQDVELGSL
QVMNKTRKIMEHGGATFINAFVTTPMCCPSRSSMLTGKYVHNHNVYTNNENCSSPSW
QAMHEPRTFAVYLNNTGYRT corresponding to amino acids 1 - 137 of SUL1 HUMAN,
which also corresponds to amino acids 1 - 137 of 221368 PEA 1 P23, and a
second amino
acid sequence being at least 70%, optionally at least 80%, preferably at least
85%, more

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preferably at least 90% and most preferably at least 95% homologous to a
polypeptide having
the sequence GLLHRLNH corresponding to amino acids 138 - 145 of 221368 PEA 1
P23,
wherein said first and second amino acid sequences are contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
S isolated polypeptide encoding for a tail of 221368 PEA 1 P23, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
GLLHRLNH in 221368 PEA 1 P23.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMGRPSE P4, comprising a first
amino acid
sequence being at least 90 % homologous to
MRGSELPLVLLALVLCLAPRGRAVPLPAGGGTVLTKMYPRGNHWAVGHLMGKKSTG
ES S S V SERGS LKQQLREYIRWEEAARNLLGLIEAKENRNHQPPQPKALGNQQP S WDSED
SSNFKDVGSKGK corresponding to amino acids 1 - 127 of GRP_HUMAN, which also
corresponds to amino acids 1 - 127 of HUMGRPSE P4, and a second amino acid
sequence
being at least 90 % homologous to GSQREGRNPQLNQQ corresponding to amino acids
135 -
148 of GRP HUMAN, which also corresponds to amino acids 128 - 141 of HUMGRPSE
P4,
wherein said first and second amino acid sequences are contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of HUMGRPSE P4,
comprising a
polypeptide having a length "n", wherein n is at least about 10 amino acids in
length, optionally
at least about 20 amino acids in length, preferably at least about 30 amino
acids in length, more
preferably at least about 40 amino acids in length and most preferably at
least about 50 amino
acids in length, wherein at least two amino acids comprise KG, having a
structure as follows: a
sequence starting from any of amino acid numbers 127-x to 127; and ending at
any of amino
acid numbers 128 + ((n-2) - x), in which x varies from 0 to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMGRPSE P5, comprising a first
amino acid
sequence being at least 90 % homologous to
MRGSELPLVLLALVLCLAPRGRAVPLPAGGGTVLTKMYPRGNHWAVGHLMGKKSTG
ESSSVSERGSLKQQLREYIRWEEAARNLLGLIEAKENRNHQPPQPKALGNQQPSWDSED

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SSNFKDVGSKGK corresponding to amino acids 1 - 127 of GRP_HUMAN, which also
corresponds to amino acids 1 - 127 of HUMGRPSE_P5, and a second amino acid
sequence
being at least 70%, optionally at least 80%, preferably at least 85%, more
preferably at least
90% and most preferably at least 95% homologous to a polypeptide having the
sequence
S DSLLQVLNVKEGTPS corresponding to amino acids 128 - 142 of HUMGRPSE P5,
wherein
said first and second amino acid sequences are contiguous and in a sequential
order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of HUMGRPSE P5, comprising a
polypeptide being at
least 70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least
about 90% and most preferably at least about 95% homologous to the sequence
DSLLQVLNVKEGTPS in HUMGRPSE P5.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for D56406 PEA 1 P2, comprising a first
amino acid
sequence being at least 90 % homologous to
MMAGMKIQLVCMLLLAFSSWSLCSDSEEEMKALEADFLTNMHTSKISKAHVPSWKMT
LLNVCSLVNNLNSPAEETGEVHEEELVARRKLPTALDGFSLEAMLTIYQLHKICHSRAF
QHWE corresponding to amino acids 1 - 120 of NEUT HUMAN, which also
corresponds to
amino acids 1 - 120 of D56406 PEA 1 P2, second amino acid sequence being at
least 70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
preferably at least 95% homologous to a polypeptide having the sequence
ARWLTPVIPALWEAETGGSRGQEMETIPANT corresponding to amino acids 121 - 151 of
D56406 PEA 1 P2, and a third amino acid sequence being at least 90 %
homologous to
LIQEDILDTGNDKNGKEEVIKRKIPYILKRQLYENKPRRPYILKRDSYYY corresponding to
amino acids 121 - 170 of NEUT HUMAN, which also corresponds to amino acids 152
- 201 of
D56406 PEA-1 P2, wherein said first, second and third amino acid sequences are
contiguous
and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for an edge portion of D56406 PEA 1 P2,
comprising an amino
acid sequence being at least 70%, optionally at least about 80%, preferably at
least about 85%,
more preferably at least about 90% and most preferably at least about 95%
homologous to the

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sequence encoding for ARWLTPVIPALWEAETGGSRGQEMETIPANT, corresponding to
D56406 PEA 1 P2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for D56406 PEA 1 P5, comprising a first
amino acid
sequence being at least 90 % homologous to MMAGMKIQLVCMLLLAFSSWSLC
corresponding to amino acids 1 - 23 of NEUT HUMAN, which also corresponds to
amino acids
1 - 23 of D56406_PEA 1 P5, and a second amino acid sequence being at least 90
homologous to
SEEEMKALEADFLTNMHTSKISKAHVPSWKMTLLNVCSLVNNLNSPAEETGEVHEEEL
VARRKLPTALDGFSLEAMLTIYQLHKICHSRAFQHWELIQEDILDTGNDKNGKEEVIKR
KIPYILKRQLYENKPRRPYILKRDSYYY corresponding to amino acids 26 - 170 of
NEUT HUMAN, which also corresponds to amino acids 24 - 168 of D56406_PEA 1 P5,
wherein said first and second amino acid sequences are contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of D56406 PEA 1 P5,
comprising
a polypeptide having a length "n", wherein n is at least about 10 amino acids
in length,
optionally at least about 20 amino acids in length, preferably at least about
30 amino acids in
length, more preferably at least about 40 amino acids in length and most
preferably at least
about SO amino acids in length, wherein at least two amino acids comprise CS,
having a
structure as follows: a sequence starting from any of amino acid numbers 23-x
to 24; and ending
at any of amino acid numbers + ((n-2) - x), in which x varies from 0 to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for D56406 PEA 1 P6, comprising a first
amino acid
sequence being at least 90 % homologous to
MMAGMKIQLVCMLLLAFSSWSLCSDSEEEMKALEADFLTNMHTSK corresponding to
amino acids 1 - 45 of NEUT HUMAN, which also corresponds to amino acids 1 - 45
of
D56406 PEA 1 P6, and a second amino acid sequence being at least 90 %
homologous to
LIQEDILDTGNDKNGKEEVIKRKIPYILKRQLYENKPRRPYILKRDSYYY corresponding to
amino acids 121 - 170 of NEUT_HUMAN, which also corresponds to amino acids 46 -
95 of
D56406 PEA 1 P6, wherein said first and second amino acid sequences are
contiguous and in
a sequential order.

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According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for an edge portion of D56406_PEA 1 P6,
comprising
a polypeptide having a length "n", wherein n is at least about 10 amino acids
in length,
optionally at least about 20 amino acids in length, preferably at least about
30 amino acids in
length, more preferably at least about 40 amino acids in length and most
preferably at least
about 50 amino acids in length, wherein at least two amino acids comprise KL,
having a
structure as follows: a sequence starting from any of amino acid numbers 45-x
to 46; and ending
at any of amino acid numbers 46+ ((n-2) - x), in which x varies from 0 to n-2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for F05068 PEA 1 P7, comprising a first
amino acid
sequence being at least 90 % homologous to
MKLVSVALMYLGSLAFLGADTARLDVASEFRKK corresponding to amino acids 1 - 33 of
ADML HUMAN, which also corresponds to amino acids 1 - 33 of F05068 PEA-1 P7.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for F05068 PEA 1 P8, comprising a first
amino acid
sequence being at least 90 % homologous to
MKLVSVALMYLGSLAFLGADTARLDVASEFRKKWNKWALSRGKRELRMSSSYPTGLA
DVKAGPAQTLIRPQDMKGASRSPED corresponding to amino acids 1 - 82 of
ADML HUMAN, which also corresponds to amino acids 1 - 82 of F05068 PEA 1 P8,
and a
second amino acid sequence being at least 70%, optionally at least 80%,
preferably at least 85%,
more preferably at least 90% and most preferably at least 95% homologous to a
polypeptide
having the sequence R corresponding to amino acids 83 - 83 of F05068 PEA 1 P8,
wherein
said first and second amino acid sequences are contiguous and in a sequential
order.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for H14624 P15, comprising a first
amino acid
sequence being at least 90 % homologous to
MLQGPGSLLLLFLASHCCLGSARGLFLFGQPDFSYKRSNCKPIPANLQLCHGIEYQNMR
LPNLLGHETMKEVLEQAGAWIPLVMKQCHPDTKKFLCSLFAPVCLDDLDETIQPCHSLC
VQVKDRCAPVMSAFGFPWPDMLECDRFPQDNDLCIPLASSDHLLPATEE corresponding
to amino acids 1 - 167 of Q9HAP5, which also corresponds to amino acids 1 -
167 of
H 14624 P 15, and a second amino acid sequence being at least 70%, optionally
at least 80%,

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preferably at least 85%, more preferably at least 90% and most preferably at
least 95%
homologous to a polypeptide having the sequence GKPSLLLPHSLLG corresponding to
amino
acids 168 - 180 of H14624 P15, wherein said first and second amino acid
sequences are
contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of H14624 P15, comprising a
polypeptide being at least
70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least about
90% and most preferably at least about 95% homologous to the sequence
GKPSLLLPHSLLG
in H 14624 P 15 .
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for H38804 PEA 1 P5, comprising a first
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MGRVRTLAGECSAQAQAQSLLAVVLSAPPSGGTPSARLSVRSPSPRDPWGLWAPVLQ
corresponding to amino acids 1 - 57 of H38804 PEA 1 P5, and a second amino
acid sequence
being at least 90 % homologous to
MTGSNEFKLNQPPEDGISSVKFSPNTSQFLLVSSWDTSVRLYDVPANSMRLKYQHTGA
VLDCAFYDPTHAWSGGLDHQLKMHDLNTDQENLVGTHDAPIRCVEYCPEVNVMVTG
SWDQTVKLWDPRTPCNAGTFSQPEKVYTLSVSGDRLIVGTAGRRVLVWDLRNMGYVQ
QRRESSLKYQTRCIRAFPNKQGYVLSSIEGRVAVEYLDPSPEVQKKKYAFKCHRLKENN
IEQIYPVNAISFHNIHNTFATGGSDGFVNIWDPFNKKRLCQFHRYPTSIASLAFSNDGTTL
AIASSYMYEMDDTEHPEDGIFIRQVTDAETKPK corresponding to amino acids 1 - 324 of
BUB3 HUMAN, which also corresponds to amino acids 58 - 381 of H38804_PEA 1 P5,
wherein said first and second amino acid sequences are contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of H38804 PEA 1 P5, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
MGRVRTLAGECSAQAQAQSLLAVVLSAPPSGGTPSARLSVRSPSPRDPWGLWAPVLQ
of H38804 PEA 1 P5.

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According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for H38804 PEA 1 P17, comprising a
first amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MGRVRTLAGECSAQAQAQSLLAWLSAPPSGGTPSARLSVRSPSPRDPWGLWAPVLQ
corresponding to amino acids 1 - 57 of H38804 PEA 1 P17, and a second amino
acid sequence
being at least 90 % homologous to
MTGSNEFKLNQPPEDGISSVKFSPNTSQFLLVSSWDTSVRLYDVPANSMRLKYQHTGA
VLDCAFYDPTHAWSGGLDHQLKMHDLNTDQENLVGTHDAPIRCVEYCPEVNVMVTG
SWDQTVKLWDPRTPCNAGTFSQPEKWTLSVSGDRLIVGTAGRRVLVWDLRNMGWQ
QRRESSLKYQTRCIRAFPNKQGYVLSSIEGRVAVEYLDPSPEVQKKKYAFKCHRLKENN
IEQIYPVNAISFHNIHNTFATGGSDGFVNIWDPFNKKRLCQFHRYPTSIASLAFSNDGTTL
AIASSYMYEMDDTEHPEDGIFIRQVTDAETKPKSPCT corresponding to amino acids 1 -
328 of BUB3 HUMAN, which also corresponds to amino acids 58 - 385 of
H38804 PEA 1 P17, wherein said first and second amino acid sequences are
contiguous and in
a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of H38804 PEA 1 P17, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
MGRVRTLAGECSAQAQAQSLLAWLSAPPSGGTPSARLSVRSPSPRDPWGLWAPVLQ
of H38804 PEA 1 P17.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HSENA78 P2, comprising a first
amino acid
sequence being at least 90 % homologous to
MSLLSSRAARVPGPSSSLCALLVLLLLLTQPGPIASAGPAAAVLRELRCVCLQTTQGVHP
KMISNLQVFAIGPQCSKVEW corresponding to amino acids 1 - 81 of SZOS HUMAN,
which also corresponds to amino acids 1 - 81 of HSENA78 P2.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMODCA P9, comprising a first
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at

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least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MKSLTATSSMKVLLPRTFWTRKLMKFLLL corresponding to amino acids 1 - 29 of
HUMODCA P9, and a second amino acid sequence being at least 90 % homologous to
LVLRIATDDSKAVCRLSVKFGATLRTSRLLLERAKELNIDVVGVSFHVGSGCTDPETFV
QAISDARCVFDMGAEVGFSMYLLDIGGGFPGSEDVKLKFEEITGVINPALDKYFPSDSG
VRIIAEPGRYYVASAFTLAVNIIAKKIVLKEQTGSDDEDESSEQTFMYYVNDGVYGSFN
CILYDHAHVKPLLQKRPKPDEKYYSSSIWGPTCDGLDRIVERCDLPEMHVGDWMLFEN
MGAYTVAAASTFNGFQRPTIYYVMSGPAWQLMQQFQNPDFPPEVEEQDASTLPVSCA
WESGMKRHRAACASASINV corresponding to amino acids 151 - 461 of DCOR HUMAN,
which also corresponds to amino acids 30 - 340 of HUMODCA P9, wherein said
first and
second amino acid sequences are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of HUMODCA P9, comprising a
polypeptide being at
least 70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least
about 90% and most preferably at least about 95% homologous to the sequence
MKSLTATSSMKVLLPRTFWTRKLMKFLLL of HUMODCA P9.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMODCA P9, comprising a first
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MKSLTATSSMKVLLPRTFWTRKLMKFLLL corresponding to amino acids 1 - 29 of
HUMODCA P9, and a second amino acid sequence being at least 90 % homologous to
LVLRIATDDSKAVCRLSVKFGATLRTSRLLLERAKELNIDVVGVSFHVGSGCTDPETFV
QAISDARCVFDMGAEVGFSMYLLDIGGGFPGSEDVKLKFEEITGVINPALDKYFPSDSG
VRIIAEPGRYYVASAFTLAVNI1AKKIVLKEQTGSDDEDESSEQTFMYYVNDGVYGSFN
CILYDHAHVKPLLQKRPKPDEKYYSSSIWGPTCDGLDRIVERCDLPEMHVGDWMLFEN
MGAYTVAAASTFNGFQRPTIYYVMSGPAWQLMQQFQNPDFPPEVEEQDASTLPVSCA
WESGMKRHRAACASASINV corresponding to amino acids 40 - 350 of AAA59968, which
also corresponds to amino acids 30 - 340 of HUMODCA P9, wherein said first and
second
amino acid sequences are contiguous and in a sequential order.

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According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of HLtIVIODCA P9, comprising a
polypeptide being at
least 70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least
about 90% and most preferably at least about 95% homologous to the sequence
MKSLTATSSMKVLLPRTFWTRKLMKFLLL of HUMODCA P9.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for HUMODCA P9, comprising a first
amino acid
sequence being at least 70%, optionally at least 80%, preferably at least 85%,
more preferably at
least 90% and most preferably at least 95% homologous to a polypeptide having
the sequence
MKSLTATSSMKVLLPRTFWTRKLMKFLLL corresponding to amino acids 1 - 29 of
HUMODCA P9, and a second amino acid sequence being at least 90 % homologous to
LVLRIATDDSKAVCRLSVKFGATLRTSRLLLERAKELNIDVVGVSFHVGSGCTDPETFV
QAISDARCVFDMGAEVGFSMYLLDIGGGFPGSEDVKLKFEEITGV1NPALDKYFPSDSG
VRIIAEPGRYYVASAFTLAVNIIAKKIVLKEQTGSDDEDESSEQTFMYYVNDGVYGSFN
CILYDHAHVKPLLQKRPKPDEKYYSSSIWGPTCDGLDRIVERCDLPEMHVGDWMLFEN
MGAYTVAAASTFNGFQRPTIYYVMSGPAWQLMQQFQNPDFPPEVEEQDASTLPVSCA
WESGMKRHRAACASASINV corresponding to amino acids 86 - 396 of AAH14562, which
also corresponds to amino acids 30 - 340 of HUMODCA P9, wherein said first and
second
amino acid sequences are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of HUMODCA P9, comprising a
polypeptide being at
least 70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least
about 90% and most preferably at least about 95% homologous to the sequence
MKSLTATSSMKVLLPRTFWTRKLMKFLLL of HUMODCA P9.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 800299 P3, comprising a first amino
acid sequence
being at least 70%, optionally at least 80%, preferably at least 85%, more
preferably at least
90% and most preferably at least 95% homologous to a polypeptide having the
sequence
MAEKALLCPSSAGLGTWPWVLNSAWPVLPLAVDQGVDWRPRGPV corresponding to
amino acids 1 - 44 of 800299 P3, second amino acid sequence being at least 90
% homologous
to

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SSDQIEQLHRRFKQLSGDQPTIRKENFNNVPDLELNPIRSKIVRAFFDNRNLRKGPSGLA
DEINFEDFLTIMSYFRPIDTTMDEEQVELSRKEKLRFLFHMYDSDSDGRITLEEYRNV
corresponding to amino acids 74 - 191 of Q9NWT9, which also corresponds to
amino acids 45 -
162 of 800299 P3, and a third amino acid sequence being at least 70%,
optionally at least 80%,
preferably at least 85%, more preferably at least 90% and most preferably at
least 95%
homologous to a polypeptide having the sequence
VEELLSGNPHIEKESARSIADGAMMEAASVCMGQMEPDQVYEGITFEDFLKIWQGIDIE
TKMHVRFLNMETMALCH corresponding to amino acids 163 - 238 of 800299 P3, wherein
said first, second and third amino acid sequences are contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of 800299 P3, comprising a
polypeptide being at least
70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least about
90% and most preferably at least about 95% homologous to the sequence
MAEKALLCPSSAGLGTWPWVLNSAWPVLPLAVDQGVDWRPRGPV of 800299 P3.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 800299 P3, comprising a
polypeptide being at least
70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least about
90% and most preferably at least about 95% homologous to the sequence
VEELLSGNPHIEKESARSIADGAMMEAASVCMGQMEPDQVYEGITFEDFLKIWQGIDIE
TKMHVRFLNMETMALCH in 800299 P3.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 800299 P3, comprising a first amino
acid sequence
being at least 70%, optionally at least 80%, preferably at least 85%, more
preferably at least
90% and most preferably at least 95% homologous to a polypeptide having the
sequence
MAEKALLCPSSAGLGTWPWVLNSAWPVLPLAVDQGVDWRPRGPV corresponding to
amino acids 1 - 44 of 800299 P3, and a second amino acid sequence being at
least 90
homologous to
SSDQIEQLHRRFKQLSGDQPTIRKENFNNVPDLELNPIRSKIVRAFFDNRNLRKGPSGLA
DEINFEDFLTIMSYFRPIDTTMDEEQVELSRKEKLRFLFHMYDSDSDGRITLEEYRNVVE
ELLSGNPHIEKESARSIADGAMMEAASVCMGQMEPDQVYEGITFEDFLKIWQGIDIETK
MHVRFLNMETMALCH corresponding to amino acids 21 - 214 of TESC HUMAN, which

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also corresponds to amino acids 45 - 238 of 800299 P3, wherein said first and
second amino
acid sequences are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a head of 800299 P3, comprising a
polypeptide being at least
70%, optionally at least about 80%, preferably at least about 85%, more
preferably at least about
90% and most preferably at least about 95% homologous to the sequence
MAEKALLCPSSAGLGTWPWVLNSAWPVLPLAVDQGVDWRPRGPV of 800299 P3.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for W60282 PEA 1 P14, comprising a
first amino acid
sequence being at least 90 % homologous to
MRILQLILLALATGLVGGETRIIKGFECKPHSQPWQAALFEKTRLLCGATLIAPRWLLTA
AHCLKP corresponding to amino acids 1 - 66 of Q8IXD7, which also corresponds
to amino
acids 1 - 66 of W60282_PEA 1 P14, and a second amino acid sequence being at
least 70%,
optionally at least 80%, preferably at least 85%, more preferably at least 90%
and most
1 S preferably at least 95% homologous to a polypeptide having the sequence
TPASHLAMRQHHHH corresponding to amino acids 67 - 80 of W60282_PEA 1 P14,
wherein said first and second amino acid sequences are contiguous and in a
sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of W60282 PEA 1 P14, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
TPASHLAMRQHHHH in W60282 PEA_1 P14.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 241644 PEA 1 P10, comprising a
first amino acid
sequence being at least 90 % homologous to
MRLLAAALLLLLLALYTARVDGSKCKCSRKGPKIRYSDVKKLEMKPKYPHCEEKMVII
TTKSVSRYRGQEHCLHPKLQSTKRFIKWYNAWNEKRR corresponding to amino acids 1 -
95 of SZ14 HUMAN, which also corresponds to amino acids 1 - 95 of 241644 PEA 1
P10,
and a second amino acid sequence being at least 70%, optionally at least 80%,
preferably at least
85%, more preferably at least 90% and most preferably at least 95% homologous
to a
polypeptide having the sequence YAPPLLTFLPTRPSCGSQDGKGPPHQVI corresponding to

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amino acids 96 - 123 of 241644 PEA 1 P 10, wherein said first and second amino
acid
sequences are contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 241644 PEA 1 P10, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
YAPPLLTFLPTRPSCGSQDGKGPPHQVI in 241644 PEA 1 P10.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 241644 PEA 1 P10, comprising a
first amino acid
sequence being at least 90 % homologous to
MRLLAAALLLLLLALYTARVDGSKCKCSRKGPKIRYSDVKKLEMKPKYPHCEEKMVII
TTKSVSRYRGQEHCLHPKLQSTKRFIKWYNAWNEKRR corresponding to amino acids 13 -
107 of Q9NS21, which also corresponds to amino acids 1 - 95 of 241644 PEA 1
P10, and a
second amino acid sequence being at least 70%, optionally at least 80%,
preferably at least 85%,
more preferably at least 90% and most preferably at least 95% homologous to a
polypeptide
having the sequence YAPPLLTFLPTRPSCGSQDGKGPPHQVI corresponding to amino acids
96 - 123 of 241644 PEA_1 P10, wherein said first and second amino acid
sequences are
contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 241644 PEA_1 P10, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
YAPPLLTFLPTRPSCGSQDGKGPPHQVI in 241644 PEA 1 P10.
According to preferred embodiments of the present invention, there is provided
an
isolated chimeric polypeptide encoding for 241644 PEA 1 P10, comprising a
first amino acid
sequence being at least 90 % homologous to
MRLLAAALLLLLLALYTARVDGSKCKCSRKGPKIRYSDVKKLEMKPKYPHCEEKMVII
TTKSVSRYRGQEHCLHPKLQSTKRFIKWYNAWNEKRR corresponding to amino acids 13 -
107 of AAQ89265, which also corresponds to amino acids 1 - 95 of 241644 PEA 1
P10, and a
second amino acid sequence being at least 70%, optionally at least 80%,
preferably at least 85%,
more preferably at least 90% and most preferably at least 95% homologous to a
polypeptide

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having the sequence YAPPLLTFLPTRPSCGSQDGKGPPHQVI corresponding to amino acids
96 - 123 of 241644 PEA 1 P10, wherein said first and second amino acid
sequences are
contiguous and in a sequential order.
According to preferred embodiments of the present invention, there is provided
an
isolated polypeptide encoding for a tail of 241644 PEA 1 P10, comprising a
polypeptide being
at least 70%, optionally at least about 80%, preferably at least about 85%,
more preferably at
least about 90% and most preferably at least about 95% homologous to the
sequence
YAPPLLTFLPTRPSCGSQDGKGPPHQVI in 241644 PEA 1 P10.
According to preferred embodiments of the present invention, there is provided
an
antibody capable of specifically binding to an epitope of an amino acid
sequences.
Optionally the amino acid sequence corresponds to a bridge, edge portion,
tail, head or
insertion.
Optionally the antibody is capable of differentiating between a splice variant
having said
epitope and a corresponding known protein.
According to preferred embodiments of the present invention, there is provided
a kit for
detecting lung cancer, comprising a kit detecting overexpression of a splice
variant according to
any of the above claims.
Optionally the kit comprises a NAT-based technology.
Optionally the kit further comprises at least one primer pair capable of
selectively
hybridizing to a nucleic acid sequence according to any of the above claims.
Optionally the kit further comprises at least one oligonucleotide capable of
selectively
hybridizing to a nucleic acid sequence according to any of the above claims.
Optionally the kit comprises an antibody according to any of the above claims.
Optionally the kit further comprises at least one reagent for performing an
ELISA or a
Western blot.
According to preferred embodiments of the present invention, there is provided
a method
for detecting lung cancer, comprising detecting overexpression of a splice
variant according to
any of the above claims.
Optionally the detecting overexpression is performed with a NAT-based
technology.
Optionally detecting overexpression is performed with an immunoassay.

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Optionally the immunoassay comprises an antibody according to any of the above
claims.
According to preferred embodiments of the present invention, there is provided
a
biomarker capable of detecting lung cancer, comprising any of the above
nucleic acid sequences
or a fragment thereof, or any of the above amino acid sequences or a fragment
thereof.
According to preferred embodiments of the present invention, there is provided
a method
for screening for lung cancer, comprising detecting lung cancer cells with a
biomarker or an
antibody or a method or assay according to any of the above claims.
According to preferred embodiments of the present invention, there is provided
a method
for diagnosing lung cancer, comprising detecting lung cancer cells with a
biomarker or an
antibody or a method or assay according to any of the above claims.
According to preferred embodiments of the present invention, there is provided
a method
for monitoring disease progression and/or treatment efficacy and/or relapse of
lung cancer,
comprising detecting lung cancer cells with a biomarker or an antibody or a
method or assay
according to any of the above claims.
According to preferred embodiments of the present invention, there is provided
a method
of selecting a therapy for lung cancer, comprising detecting lung cancer cells
with a biomarker
or an antibody or a method or assay according to any of the above claims and
selecting a therapy
according to said detection.
Unless defined otherwise, all technical and scientific terms used herein have
the meaning
commonly understood by a person skilled in the art to which this invention
belongs. The
following references provide one of skill with a general definition of many of
the terms used in
this invention: Singleton et al., Dictionary of Microbiology and Molecular
Biology (2nd ed.
1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988);
The Glossary
of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and
Hale & Marham, The
Harper Collins Dictionary of Biology (1991). All of these are hereby
incorporated by reference
as if fully set forth herein. As used herein, the following terms have the
meanings ascribed to
them unless specified otherwise.
BRIEF DESCRIPTION OF DRAWINGS

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Figure 1 is schematic summary of cancer biomarkers selection engine and the
wet
validation stages.
Figure 2. Schematic illustration, depicting grouping of transcripts of a given
contig based
on presence or absence of unique sequence regions.
Figure 3 is schematic summary of quantitative real-time PCR analysis.
Figure 4 is schematic presentation of the oligonucleotide based microarray
fabrication.
Figure 5 is schematic summary of the oligonucleotide based microarray
experimental
flow.
Figure 6 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster H61775, demonstrating overexpression in brain malignant tumors and a
mixture of
malignant tumors from different tissues.
Figure 7 is a histogram showing expression of transcripts of variants of the
immunoglobulin superfamily, member 9,H61775 transcripts, which are detectable
by amplicon
1 S as depicted in sequence name H61775seg8, in normal and cancerous lung
tissues.
Figure 8 is a histogram showing expression of immunoglobulin superfamily,
member 9,
H61775 transcripts, which are detectable by amplicon as depicted in sequence
name
H61775seg8, in different normal tissues.
Figure 9 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster M85491, demonstrating overexpression in epithelial malignant tumors
and a mixture of
malignant tumors from different tissues.
Figure 10 is a histogram showing over expression of the above-indicated Ephrin
type-B
receptor 2 precursor M85491 transcripts, which are detectable by amplicon as
depicted in
sequence name M85491 seg24, in cancerous lung samples relative to the normal
samples.
Figure 11 is a histogram showing the expression of Ephrin type-B receptor 2
precursor
(Tyrosine-protein kinase receptor EPH-3) M85491 transcripts which are
detectable by amplicon
as depicted in sequence name M85491seg24 in different normal tissues.
Figure 12 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster T39971, demonstrating overexpression in liver cancer, lung malignant
tumors and
pancreas carcinoma. ,

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Figure 13 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster 221368, demonstrating overexpression in epithelial malignant tumors, a
mixture of
malignant tumors from different tissues and pancreas carcinoma.
Figure 14 is a histogram showing over expression of the Extracellular
sulfatase Sulf 1
221368 transcripts, which are detectable by amplicon as depicted in sequence
name
Z21368junc17-21, in cancerous lung samples relative to the normal samples.
Figure 15 is a histogram showing the expression of Extracellular sulfatase
Sulf 1
221368 transcripts, which are detectable by amplicon as depicted in sequence
name
221368 juncl7-21, in different normal tissues.
. Figure 16 is a histogram showing over expression of the SUL1 HUMAN -
Extracellular sulfatase Sulf 1, 221368 transcripts, which are detectable by
amplicon as depicted
in sequence name Z21368seg39, in cancerous lung samples relative to the normal
samples.
Figure 17 is a histogram showing expression of SUL1 HUMAN - Extracellular
sulfatase
Sulf 1, 221368 transcripts, which are detectable by amplicon as depicted in
sequence name
Z21368seg39, in different normal tissues.
Figurel8 is a histogram showing the expression of SM02 HUMAN SPARC related
modular calcium-binding protein 2 precursor (Secreted modular calcium-binding
protein 2)
(SMOC-2) (Smooth muscle-associated protein 2) 244808 transcripts which are
detectable by
amplicon as depicted in sequence name 244808 junc8-11 in different normal
tissues.
Figure 19 is a histogram showing over expression of the gastrin-releasing
peptide
(HUMGRPSE) transcripts, which are detectable by amplicon as depicted in
sequence name
HUMGRPSEjunc3-7, in several cancerous lung samples relative to the normal
samples.
Figure 20 is a histogram showing the expression of gastrin-releasing peptide
(HUMGRPSE) transcripts, which are detectable by amplicon as depicted in
sequence name
HUMGRPSEjunc3-7, in different normal tissues.
Figure 21 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster F05068, demonstrating overexpression in uterine malignancies.

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Figure 22 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster H14624, demonstrating overexpression in colorectal cancer, epithelial
malignant tumors,
a mixture of malignant tumors from different tissues, lung malignant tumors
and pancreas
carcinoma.
Figure 23 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster H38804, demonstrating overexpression in transitional cell carcinoma,
brain malignant
tumors, a mixture of malignant tumors from different tissues and gastric
carcinoma.
Figure 24 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster HSENA78, demonstrating overexpression in epithelial malignant tumors
and lung
malignant tumors.
Figure 25 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster HUMODCA, demonstrating overexpression in : brain malignant tumors,
colorectal
cancer, epithelial malignant tumors and a mixture of malignant tumors from
different tissues.
Figure 26 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster 800299, demonstrating overexpression in lung malignant tumors.
Figure 27 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster 241644, demonstrating overexpression in lung malignant tumors, breast
malignant
tumors and pancreas carcinoma.
Figure 28 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster 244808, demonstrating overexpression in colorectal cancer, lung cancer
and pancreas
carcinoma.
Figure 29 is a histogram showing over expression of the SM02 HUMAN SPARC
related
modular calcium-binding protein 2 244808 transcripts, which are detectable by
amplicon as
depicted in sequence name Z44808junc8-11, in cancerous lung samples relative
to the normal
samples.
Figure 30 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster AA161187, demonstrating overexpression in brain malignant tumors,
epithelial
malignant tumors and a mixture of malignant tumors from different tissues.
Figure 31 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster AA161187, demonstrating overexpression in brain malignant tumors and a
mixture of
malignant tumors from different tissues.

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Figure 32 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster HUMCA1XIA, demonstrating overexpression in bone malignant tumors,
epithelial
malignant tumors, a mixture of malignant tumors from different tissues and
lung malignant
tumors.
Figure 33 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster HUMCEA, demonstrating overexpression in epithelial malignant tumors, a
mixture of
malignant tumors from different tissues and pancreas carcinoma.
Figure 34 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster 835137, demonstrating overexpression in hepatocellular carcinoma.
Figure 35 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster 225299, demonstrating overexpression in brain malignant tumors, a
mixture of
malignant tumors from different tissues and ovarian carcinoma.
Figure 36 is a histogram showing down regulation of the Secretory leukocyte
protease
inhibitor Acid-stable proteinase inhibitor 225299 transcripts, which are
detectable by amplicon
as depicted in sequence name 225299 juncl3-14-21, in cancerous lung samples
relative to the
normal samples.
Figure 37 is a histogram showing down regulation of the Secretory leukocyte
protease
inhibitor Acid-stable proteinase inhibitor 225299 transcripts, which are
detectable by amplicon
as depicted in sequence name 225299 seg20, in cancerous lung samples relative
to the normal
samples.
Figure 38 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster HSSTROL3, demonstrating overexpression in transitional cell carcinoma,
epithelial
malignant tumors, a mixture of malignant tumors from different tissues and
pancreas carcinoma.
Figure 39 is a histogram showing over expression of the Stromelysin-3 HSSTROL3
transcripts, which are detectable by amplicon as depicted in sequence name
HSSTROL3 seg24,
in cancerous lung samples relative to the normal samples.
Figure 40 is a histogram showing the expression of Stromelysin-3
HSSTROL3 transcripts, which are detectable by amplicon as depicted in sequence
name
HSSTROL3 seg24, in different normal tissues.

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Figure 41 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster HUMTREFAC, demonstrating overexpression in a mixture of malignant
tumors from
different tissues, breast malignant tumors, pancreas carcinoma and prostate
cancer.
Figure 42 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster HSS 100PCB, demonstrating overexpression in a mixture of malignant
tumors from
different tissues.
Figure 43 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster HSU33147, demonstrating overexpression in a mixture of malignant
tumors from
different tissues.
Figure 44 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster 820779, demonstrating overexpression in epithelial malignant tumors, a
mixture of
malignant tumors from different tissues and lung malignant tumors.
Figure 45 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster 838144, demonstrating overexpression in epithelial malignant tumors,
lung malignant
tumors, skin malignancies and gastric carcinoma.
Figure 46 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster HUMOSTRO, demonstrating overexpression in epithelial malignant tumors,
a mixture
of malignant tumors from different tissues, lung malignant tumors, breast
malignant tumors,
ovarian carcinoma and skin malignancies.
Figure 47 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster HUMOSTRO, demonstrating overexpression in epithelial malignant tumors,
a mixture
of malignant tumors from different tissues and kidney malignant tumors.
Figure 48 is a histogram showing over expression of the 811723 transcripts,
which are
detectable by amplicon as depicted in sequence name 811723 segl3, in cancerous
lung samples
relative to the normal samples.
Figure 49 is a histogram showing the expression of 811723 transcripts which
are
detectable by amplicon as depicted in sequence name R11723seg13 in different
normal tissues.
Figure 50 is a histogram showing over expression of the 811723 transcripts,
which are
detectable by amplicon as depicted in sequence name Rl 1723 juncl 1-18 in
cancerous lung
samples relative to the normal samples.

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Figure S 1 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster 816276, demonstrating overexpression in: lung malignant tumors.
Figures 52-53 are histograms, showing differential expression of the 6
sequences
H61775seg8, HUMGRPSE junc3-7, M85491Seg24, 221368 juncl7-21, HSSTROL3seg24 and
Z25299seg20 in cancerous lung samples relative to the normal samples.
Figure 54a is a histogram showing the relative expression of trophinin
associated protein
(tastin) ) [T86235] variants (e.g., variant no. 23-26, 31, 32) in normal and
tumor derived lung
samples as determined by real time PCR using primers for SEQ >D NO: 1480.
Figure 54b is a histogram showing the relative expression of trophinin
associated protein
(tastin) ) [T86235] variants (e.g., variant no. 8-10, 22, 23, 26,27, 29-31,
33) in normal and tumor
derived lung samples as determined micro-array analysis using oligos detailed
in SEQ ID NO:
1512-1514.
Figure SS is a histogram showing the relative expression of Homeo box C10
(HOXC10)
[N31842] variants (e.g., variant no. 3) in normal and tumor derived lung
samples as determined
by real time PCR using primers for SEQ >D NO: 1517.
Figures 56a-b are histograms showing on two different scales the relative
expression of
Nucleolar protein 4 ~(NOL4) [T06014] variants (e.g., variant no. 3, 11 and 12)
in normal and
tumor derived lung samples as determined by real time PCR using primers for
SEQ >D NO:
1529. Figure 56a shows the results on scale:0-1200. Figure 56b shows the
results on scale:0-
24.
Figures 57a-b is a histogram showing on two different scales the relative
expression of
Nucleolar protein 4 (NOL4) [T06014] variants (e.g., variant no. 3, 11 and 12)
in normal and
tumor derived lung samples as determined by real time PCR using primers for
SEQ ID NO:
1532. Figure 57a shows the results on scale:0-2000. Figure 57b shows the
results on scale:0-
42.
Figure 58 is a histogram showing the relative expression of AA281370 variants
(e.g.,
variant no. 0, 1, 4 and 5) in normal and tumor derived lung samples as
determined by real time
PCR using primers for SEQ ID NO: 1558.

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Figure 59 is a histogram showing the relative expression of Sulfatase 1
(SULF1)-
[Z21368] variants (e.g., variant no. 13 and 14) in normal and tumor derived
lung samples as
determined by real time PCR using primers for SEQ 1D NO: 1574.
Figure 60 is a histogram showing the relative expression of SRY (sex
determining region
Y)-box 2 (SOX2))-[HUMHMGBOX] variants (e.g., variant no. 0) in normal and
tumor derived
lung samples as determined by real time PCR using primers for SEQ ID NO: 1594.
Figure 61 is a histogram showing the relative expression of Plakophilin 1
(ectodermal
dysplasia/skin fragility syndrome) (PKP1) -[HSB6PR] variants (e.g., variant
no. 0, 5 and 6) in
normal and tumor derived lung samples as determined by real time PCR using
primers for SEQ
ID NO: 1600.
Figure 62 is a histogram showing the relative expression of transcripts
detectable by SEQ
ID NOs: 1480, 1517, 1529, 1532, 1558, 1574, 1594, 1600, 1616, 1619, 1622, 1625
in normal and
tumor derived lung samples as determined by real time PCR.
Figure 63 is an amino acid sequence alignment, using NCBI BLAST default
parameters,
demonstrating similarity between the AA281370 lung cancer biomarker if the
present invention
to WD40 domains of various proteins involved in MAPK signal trunsduction
pathway. Figure
63a: amino acids at positions 40-790 of AA281370 polypeptide SEQ ID NO: 99 has
75%
homology to mouse Mapkbpl protein (gi~47124622). Figure 63b: amino acids at
positions 40-
886 of the AA281370 polypeptide SEQ ID NO: 99 has 70% homology to rat JNK-
binding
protein JNKBP1 (gi~34856717).
Figure 64 is a histogram showing over expression of the Homo Sapiens protease,
serine,
21 (testisin) (PRSS21) AA161187 transcripts, which are detectable by amplicon
as depicted in
sequence name AA161187 seg25, in cancerous lung samples relative to the normal
samples.
Figure 65 is a histogram showing over expression of the protein tyrosine
phosphatase,
receptor type, S (PTPRS) M62069 transcripts, which are detectable by amplicon
as depicted in
sequence name M62069 segl9, in cancerous lung samples relative to the normal
samples.
Figure 66 is a histogram showing over expression of the protein tyrosine
phosphatase,
receptor type, S (PTPRS) M62069 transcripts, which are detectable by amplicon
as depicted in
sequence name M62069 seg29, in cancerous lung samples relative to the normal
samples.

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129
Figure 67 is a histogram showing over expression of the above-indicated Homo
Sapiens
collagen, type XI, alpha 1 (COLIIAl) transcripts which are detectable by
amplicon as depicted
in sequence name HUMCA1X1A seg55 in cancerous lung samples relative to the
normal
samples.
Figure 68 is a histogram showing down regulation of the Homo Sapiens secretory
leukocyte protease inhibitor (antileukoproteinase) (SLPI) 225299 transcripts
which are
detectable by amplicon as depicted in sequence name 225299 seg23 in cancerous
lung samples
relative to the normal samples.
Figure 69 is a histogram showing the expression of Secretory leukocyte
protease
inhibitor Acid-stable proteinase inhibitor 225299 transcripts which are
detectable by amplicon
as depicted in sequence name Z25299seg20 in different normal tissues.
Figure 70 is a histogram showing the expression of Secretory leukocyte
protease
inhibitor Acid-stable proteinase inhibitor 225299 transcripts which are
detectable by amplicon
as depicted in sequence name Z25299seg23 in different normal tissues.
Figure 71 is a histogram showing over expression of the Homo Sapiens matrix
metalloproteinase 11 (stromelysin 3) (MMP11) HSSTROL3 transcripts which are
detectable by
amplicon as depicted in sequence name HSSTROL3 seg20-2 in cancerous lung
samples relative
to the normal samples.
Figure 72 is a histogram showing over expression of the Homo Sapiens matrix
metalloproteinase 11 (stromelysin 3) (MMP11) HSSTROL3 transcripts which are
detectable by
amplicon as depicted in sequence name HSSTROL3 junc2l-27 in cancerous lung
samples
relative to the normal samples.
Figure 73 is a histogram showing the expression of Rl 1723 transcripts, which
were
detected by amplicon as depicted in the sequence name 811723 juncl l-18 in
different normal
tissues.
Figure 74 is a histogram showing over expression of the Homo sapiens
fibroblast
growth factor receptor-like 1 (FGFRL1) H53626 transcripts, which are
detectable by amplicon
as depicted in sequence name H53626 junc24-27F1R3 in cancerous lung samples
relative to the
normal samples.
Figure 75 is a histogram showing the expression of the Homo Sapiens fibroblast
growth
factor receptor-like 1 (FGFRL1) H53626 transcripts, which are detectable by
amplicon as

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depicted in sequence name H53626 seg25 in cancerous lung samples relative to
the normal
samples.
Figure 76 is a histogram showing Cancer and cell-line vs. normal tissue
expression for
Cluster H53626, demonstrating overexpression in epithelial malignant tumors, a
mixture of
malignant tumors from different tissues and myosarcoma.
Figure 77 is a histogram showing the expression of of Homo Sapiens fibroblast
growth
factor receptor-like 1 (FGFRL1) H53626 transcripts, which are detectable by
amplicon as
depicted in sequence name H53626 seg25 in different normal tissues.
Figure 78 is a histogram showing the expression of of Homo Sapiens fibroblast
growth
factor receptor-like 1 (FGFRL1) H53626 transcripts, which are detectable by
amplicon as
depicted in sequence name H53626 junc24-27FIR3 in different normal tissues.
Figure 79 shows PSEC 811723 PEA 1 TS PCR product; Lane 1: PCR product; and
Lane 2: Low DNA Mass Ladder MW marker (InvitroQen Cat# 10068-013).
Figure 80: PSEC 811723 PEA 1 TS PCR product sequence; In Red- PSEC Forward
primer; In Blue- PSEC Reverse complementary sequence; and Highlighted sequence-
PSEC
variant 811723 PEA 1 TS ORF.
Figure 81- PRSEC PCR product digested with NheI and HindIII; Lane 1- PRSET PCR
product; Lane 2- Fermentas GeneRuler 1 Kb DNA Ladder #SM0313.
Figure 82 shows a plasmid map of His PSEC TS pRSETA.
Figure 83: Protein sequence of PSEC variant Rl 1723 PEA 1 T5;1n red- 6His tag;
In
blue- PSEC.
Figure 84 shows the DNA sequence of HisPSEC TS pRSETA; bold- HisPSEC TS open
reading frame; Italic- flanking DNA sequence which was verified by sequence
analysis.
Figure 85 shows Western blot analysis of recombinant HisPSEC variant 811723
PEA 1
T5; lane 1: molecular weight marker (ProSieve color, Cambrex, Cat #50550);
lane 2: HisPSEC
TS pRSETA T0; lane 3: His HisPSEC TS pRSETA T3; lane 4 :His HisPSEC TS pRSETA
To.n;
lane 5: pRSET empty vector TO (negative control); lane 6: pRSET empty vector
T3 (negative
control); lane 7: pRSET empty vector To.n (negative control); and lane 8: His
positive control
protein (HisTroponinT7 pRSETA T3).

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DESCRIPTION OF PREFERRED EMBODIMENTS
The present invention is of novel markers for lung cancer that are both
sensitive and
accurate. Furthermore, at least certain of these markers are able to
distinguish between various
types of lung cancer, such as small cell carcinoma; large cell carcinoma;
squamous cell
carcinoma; and adenocarcinoma, alone or in combination. These markers are
differentially
expressed, and preferably overexpressed, in lung cancer specifically, as
opposed to normal lung
tissue. The measurement of these markers, alone or in combination, in patient
samples provides
information that the diagnostician can correlate with a probable diagnosis of
lung cancer. The
markers of the present invention, alone or in combination, show a high degree
of differential
detection between lung cancer and non-cancerous states. The markers of the
present invention,
alone or in combination, can be used for prognosis, prediction, screening,
early diagnosis,
therapy selection and treatment monitoring of lung cancer. For example,
optionally and
preferably, these markers may be used for staging lung cancer and/or
monitoring the progression
of the disease. Furthermore, the markers of the present invention, alone or in
combination, can
be used for detection of the source of metastasis found in anatomical places
other than lung.
Also, one or more of the markers may optionally be used in combination with
one or more other
lung cancer markers (other than those described herein). According to an
optional embodiment
of the present invention, such a combination may be used to differentiate
between various types
of lung cancer, such as small cell carcinoma; large cell carcinoma; squamous
cell carcinoma;
and adenocarcinoma. Furthermore, the markers of the present invention, alone
or in
combination, can be used for detection of other types of tumors by elimination
(for example, for
such detection of carcinoid tumors, which are 5% of lung cancers).
The markers of the present invention, alone or in combination, can be used for
prognosis, prediction, screening, early diagnosis, staging, therapy selection
and treatment
monitoring of lung cancer. For example, optionally and preferably, these
markers may be used
for staging lung cancer and/or monitoring the progression of the disease.
Furthermore, the
markers of the present invention, alone or in combination, can be used for
detection of the
source of metastasis found in anatomical places other then lung. Also, one or
more of the
markers may optionally be used in combination with one or more other lung
cancer markers
(other than those described herein).

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Biomolecular sequences (amino acid and/or nucleic acid sequences) uncovered
using the
methodology of the present invention and described herein can be efficiently
utilized as tissue or
pathological markers and/or as drugs or drug targets for treating or
preventing a disease.
These markers are specifically released to the bloodstream under conditions of
lung
cancer, and/or are otherwise expressed at a much higher level and/or
specifically expressed in
lung cancer tissue or cells. The measurement of these markers, alone or in
combination, in
patient samples provides information that the diagnostician can correlate with
a probable
diagnosis of lung cancer.
The present invention therefore also relates to diagnostic assays for lung
cancer and/or
an indicative condition, and methods of use of such markers for detection of
lung cancer and/or
an indicative condition, optionally and preferably in a sample taken from a
subject (patient),
which is more preferably some type of blood sample.
In another embodiment, the present invention relates to bridges, tails, heads
and/or
insertions, and/or analogs, homologs and derivatives of such peptides. Such
bridges, tails, heads
and/or insertions are described in greater detail below with regard to the
Examples.
As used herein a "tail" refers to a peptide sequence at the end of an amino
acid sequence
that is unique to a splice variant according to the present invention.
Therefore, a splice variant
having such a tail may optionally be considered as a chimera, in that at least
a first portion of the
splice variant is typically highly homologous (often 100% identical) to a
portion of the
corresponding known protein, while at least a second portion of the variant
comprises the tail.
As used herein a "head" refers to a peptide sequence at the beginning of an
amino acid
sequence that is unique to a splice variant according to the present
invention. Therefore, a splice
variant having such a head may optionally be considered as a chimera, in that
at least a first
portion of the splice variant comprises the head, while at least a second
portion is typically
highly homologous (often 100% identical) to a portion of the corresponding
known protein.
As used herein "an edge portion" refers to a connection between two portions
of a splice
variant according to the present invention that were not joined in the wild
type or known
protein. An edge may optionally arise due to a join between the above "known
protein" portion
of a variant and the tail, for example, and/or may occur if an internal
portion of the wild type
sequence is no longer present, such that two portions of the sequence are now
contiguous in the
splice variant that were not contiguous in the known protein. A "bridge" may
optionally be an

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edge portion as described above, but may also include a join between a head
and a "known
protein" portion of a variant, or a join between a tail and a "known protein"
portion of a variant,
or a join between an insertion and a "known protein" portion of a variant.
Optionally and preferably, a bridge between a tail or a head or a unique
insertion, and a
"known protein" portion of a variant, comprises at least about 10 amino acids,
more preferably
at least about 20 amino acids, most preferably at least about 30 amino acids,
and even more
preferably at least about 40 amino acids, in which at least one amino acid is
from the
tail/head/insertion and at least one amino acid is from the "known protein"
portion of a variant.
Also optionally, the bridge may comprise any number of amino acids from about
10 to about 40
amino acids (for example, 10, 11, 12, 13...37, 38, 39, 40 amino acids in
length, or any number
in between).
It should be noted that a bridge cannot be extended beyond the length of the
sequence in
either direction, and it should be assumed that every bridge description is to
be read in such
manner that the bridge length does not extend beyond the sequence itself.
Furthermore, bridges are described with regard to a sliding window in certain
contexts
below. For example, certain descriptions of the bridges feature the following
format: a bridge
between two edges (in which a portion of the known protein is not present in
the variant) may
optionally be described as follows: a bridge portion of CONTIG-NAME P1
(representing the
name of the protein), comprising a polypeptide having a length "n", wherein n
is at least about
10 amino acids in length, optionally at least about 20 amino acids in length,
preferably at least
about 30 amino acids in length, more preferably at least about 40 amino acids
in length and most
preferably at least about 50 amino acids in length, wherein at least two amino
acids comprise
XX (2 amino acids in the center of the bridge, one from each end of the edge),
having a
structure as follows (numbering according to the sequence of CONTIG-NAME P1):
a sequence
starting from any of amino acid numbers 49-x to 49 (for example); and ending
at any of amino
acid numbers 50 + ((n-2) - x) (for example), in which x varies from 0 to n-2.
In this example, it
should also be read as including bridges in which n is any number of amino
acids between 10-50
amino acids in length. Furthermore, the bridge polypeptide cannot extend
beyond the sequence,
so it should be read such that 49-x (for example) is not less than 1, nor 50 +
((n-2) - x) (for
example) greater than the total sequence length.

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In another embodiment, this invention provides antibodies specifically
recognizing the
splice variants and polypeptide fragments thereof of this invention.
Preferably such antibodies
differentially recognize splice variants of the present invention but do not
recognize a
corresponding known protein (such known proteins are discussed with regard to
their splice
variants in the Examples below).
In another embodiment, this invention provides an isolated nucleic acid
molecule
encoding for a splice variant according to the present invention, having a
nucleotide sequence as
set forth in any one of the sequences listed herein, or a sequence
complementary thereto. In
another embodiment, this invention provides an isolated nucleic acid molecule,
having a
nucleotide sequence as set forth in any one of the sequences listed herein, or
a sequence
complementary thereto. In another embodiment, this invention provides an
oligonucleotide of at
least about 12 nucleotides, specifically hybridizable with the nucleic acid
molecules of this
invention. In another embodiment, this invention provides vectors, cells,
liposomes and
compositions comprising the isolated nucleic acids of this invention.
In another embodiment, this invention provides a method for detecting a splice
variant
according to the present invention in a biological sample, comprising:
contacting a biological
sample with an antibody specifically recognizing a splice variant according to
the present
invention under conditions whereby the antibody specifically interacts with
the splice variant in
the biological sample but do not recognize known corresponding proteins
(wherein the known
protein is discussed with regard to its splice variants) in the Examples
below), and detecting
said interaction; wherein the presence of an interaction correlates with the
presence of a splice
variant in the biological sample.
In another embodiment, this invention provides a method for detecting a splice
variant
nucleic acid sequences in a biological sample, comprising: hybridizing the
isolated nucleic acid
molecules or oligonucleotide fragments of at least about a minimum length to a
nucleic acid
material of a biological sample and detecting a hybridization complex; wherein
the presence of a
hybridization complex correlates with the presence of a splice variant nucleic
acid sequence in
the biological sample.
According to the present invention, the splice variants described herein are
non-limiting
examples of markers for diagnosing lung cancer. Each splice variant marker of
the present

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invention can be used alone or in combination, for various uses, including but
not limited to,
prognosis, prediction, screening, early diagnosis, determination of
progression, therapy selection
and treatment monitoring of lung cancer.
According to optional but preferred embodiments of the present invention, any
marker
according to the present invention may optionally be used alone or
combination. Such a
combination may optionally comprise a plurality of markers described herein,
optionally
including any subcombination of markers, and/or a combination featuring at
least one other
marker, for example a known marker. Furthermore, such a combination may
optionally and
preferably be used as described above with regard to determining a ratio
between a quantitative
or semi-quantitative measurement of any marker described herein to any other
marker described
herein, and/or any other known marker, and/or any other marker. With regard to
such a ratio
between any marker described herein (or a combination thereof) and a known
marker, more
preferably the known marker comprises the "known protein" as described in
greater detail
below with regard to each cluster or gene.
According to other preferred embodiments of the present invention, a splice
variant
protein or a fragment thereof, or a splice variant nucleic acid sequence or a
fragment thereof,
may be featured as a biomarker for detecting lung cancer, such that a
biomarker may optionally
comprise any of the above.
According to still other preferred embodiments, the present invention
optionally and
preferably encompasses any amino acid sequence or fragment thereof encoded by
a nucleic acid
sequence corresponding to a splice variant protein as described herein. Any
oligopeptide or
peptide relating to such an amino acid sequence or fragment thereof may
optionally also
(additionally or alternatively) be used as a biomarker, including but not
limited to the unique
amino acid sequences of these proteins that are depicted as tails, heads,
insertions, edges or
bridges. The present invention also optionally encompasses antibodies capable
of recognizing,
and/or being elicited by, such oligopeptides or peptides.
The present invention also optionally and preferably encompasses any nucleic
acid
sequence or fragment thereof, or amino acid sequence or fragment thereof,
corresponding to a
splice variant of the present invention as described above, optionally for any
application.
Non-limiting examples of methods or assays are described below.
The present invention also relates to kits based upon such diagnostic methods
or assays.

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Nucleic acid sequences and Oligonucleotides
Various embodiments of the present invention encompass nucleic acid sequences
described hereinabove; fragments thereof, sequences hybridizable therewith,
sequences
homologous thereto, sequences encoding similar polypeptides with different
codon usage,
altered sequences characterized by mutations, such as deletion, insertion or
substitution of one or
more nucleotides, either naturally occurring or artificially induced, either
randomly or in a
targeted fashion.
The present invention encompasses nucleic acid sequences described herein;
fragments
thereof, sequences hybridizable therewith, sequences homologous thereto [e.g.,
at least 50 %, at
least 55 %, at least 60%, at least 65 %, at least 70 %, at least 75 %, at
least 80 %, at least 85 %, at
least 95 % or more say 100 % identical to the nucleic acid sequences set forth
below], sequences
encoding similar polypeptides with different codon usage, altered sequences
characterized by
mutations, such as deletion, insertion or substitution of one or more
nucleotides, either naturally
occurring or man induced, either randomly or in a targeted fashion. The
present invention also
encompasses homologous nucleic acid sequences (i.e., which form a part of a
polynucleotide
sequence of the present invention) which include sequence regions unique to
the polynucleotides
of the present invention.
In cases where the polynucleotide sequences of the present invention encode
previously
unidentified polypeptides, the present invention also encompasses novel
polypeptides or portions
thereof, which are encoded by the isolated polynucleotide and respective
nucleic acid fragments
thereof described hereinabove.
A "nucleic acid fragment" or an "oligonucleotide" or a "polynucleotide" are
used herein
interchangeably to refer to a polymer of nucleic acids. A polynucleotide
sequence of the present
invention refers to a single or double stranded nucleic acid sequences which
is isolated and
provided in the form of an RNA sequence, a complementary polynucleotide
sequence (cDNA), a
genomic polynucleotide sequence and/or a composite polynucleotide sequences
(e.g., a
combination of the above).
As used herein the phrase "complementary polynucleotide sequence" refers to a
sequence, which results from reverse transcription of messenger RNA using a
reverse

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transcriptase or any other RNA dependent DNA polymerase. Such a sequence can
be
subsequently amplified in vivo or in vitro using a DNA dependent DNA
polymerase.
As used herein the phrase "genomic polynucleotide sequence" refers to a
sequence
derived (isolated) from a chromosome and thus it represents a contiguous
portion of a
chromosome.
As used herein the phrase "composite polynucleotide sequence" refers to a
sequence,
which is composed of genomic and cDNA sequences. A composite sequence can
include some
exonal sequences required to encode the polypeptide of the present invention,
as well as some
intronic sequences interposing therebetween. The intronic sequences can be of
any source,
including of other genes, and typically will include conserved splicing signal
sequences. Such
intronic sequences may further include cis acting expression regulatory
elements.
Preferred embodiments of the present invention encompass oligonucleotide
probes.
An example of an oligonucleotide probe which can be utilized by the present
invention is
a single stranded polynucleotide which includes a sequence complementary to
the unique
1 S sequence region of any variant according to the present invention,
including but not limited to a
nucleotide sequence coding for an amino sequence of a bridge, tail, head
and/or insertion
according to the present invention, and/or the equivalent portions of any
nucleotide sequence
given herein (including but not limited to a nucleotide sequence of a node,
segment or amplicon
described herein).
Alternatively, an oligonucleotide probe of the present invention can be
designed to
hybridize with a nucleic acid sequence encompassed by any of the above nucleic
acid sequences,
particularly the portions specified above, including but not limited to a
nucleotide sequence
coding for an amino sequence of a bridge, tail, head and/or insertion
according to the present
invention, and/or the equivalent portions of any nucleotide sequence given
herein (including but
not limited to a nucleotide sequence of a node, segment or amplicon described
herein).
Oligonucleotides designed according to the teachings of the present invention
can be
generated according to any oligonucleotide synthesis method known in the art
such as enzymatic
synthesis or solid phase synthesis. Equipment and reagents for executing solid-
phase synthesis
are commercially available from, for example, Applied Biosystems. Any other
means for such
synthesis may also be employed; the actual synthesis of the oligonucleotides
is well within the
capabilities of one skilled in the art and can be accomplished via established
methodologies as

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detailed in, for example, "Molecular Cloning: A laboratory Manual" Sambrook et
al., (1989);
"Current Protocols in Molecular Biology" Volumes I-III Ausubel, R. M., ed.
(1994); Ausubel et
al., "Current Protocols in Molecular Biology", John Wiley and Sons, Baltimore,
Maryland
(1989); Perbal, "A Practical Guide to Molecular Cloning", John Wiley & Sons,
New York
(1988) and "Oligonucleotide Synthesis" Gait, M. J., ed. (1984) utilizing solid
phase chemistry,
e.g. cyanoethyl phosphoramidite followed by deprotection, desalting and
purification by for
example, an automated trityl-on method or HPLC.
Oligonucleotides used according to this aspect of the present invention are
those having a
length selected from a range of about 10 to about 200 bases preferably about
15 to about 150
bases, more preferably about 20 to about 100 bases, most preferably about 20
to about 50 bases.
Preferably, the oligonucleotide of the present invention features at least 17,
at least 18, at least
19, at least 20, at least 22, at least 25, at least 30 or at least 40, bases
specifically hybridizable
with the biomarkers of the present invention.
The oligonucleotides of the present invention may comprise heterocylic
nucleosides
1 S consisting of purines and the pyrimidines bases, bonded in a 3' to 5'
phosphodiester linkage.
Preferably used oligonucleotides are those modified at one or more of the
backbone,
internucleoside linkages or bases, as is broadly described hereinunder.
Specific examples of preferred oligonucleotides useful according to this
aspect of the
present invention include oligonucleotides containing modified backbones or
non-natural
internucleoside linkages. Oligonucleotides having modified backbones include
those that retain
a phosphorus atom in the backbone, as disclosed in U.S. Pat. NOs: 4,469,863;
4,476,301;
5,023,243; 5,177,196; 5,188,897; 5,264,423; 5,276,0I9; 5,278,302; 5,286,717;
5,321,131;
5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466, 677; 5,476,925; 5,519,126;
5,536,821;
5,541,306; 5,550,111; 5,563,253; 5,571,799; 5,587,361; and 5,625,050.
Preferred modified oligonucleotide backbones include, for example,
phosphorothioates,
chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkyl
phosphotriesters,
methyl and other alkyl phosphonates including 3'-alkylene phosphonates and
chiral
phosphonates, phosphinates, .phosphoramidates including 3'-amino
phosphoramidate and
aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates,
thionoalkylphosphotriesters, and boranophosphates having normal 3'-5'
linkages, 2'-S' linked
analogs of these, and those having inverted polarity wherein the adjacent
pairs of nucleoside

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units are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'. Various salts, mixed salts
and free acid forms can
also be used.
Alternatively, modified oligonucleotide backbones that do not include a
phosphorus atom
therein have backbones that are formed by short chain alkyl or cycloalkyl
internucleoside
S linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages,
or one or more
short chain heteroatomic or heterocyclic internucleoside linkages. These
include those having
morpholino linkages (formed in part from the sugar portion of a nucleoside);
siloxane
backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and
thioformacetyl backbones;
methylene formacetyl and thioformacetyl backbones; alkene containing
backbones; sulfamate
backbones; methyleneimino and methylenehydrazino backbones; sulfonate and
sulfonamide
backbones; amide backbones; and others having mixed N, O, S and CH2 component
parts, as
disclosed in U.S. Pat. Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134;
5,216,141; 5,235,033;
5,264,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677;
5,541,307;
5,561,225; 5,596,086; 5,602,240; 5,610,289; 5,602,240; 5,608,046; 5,610,289;
5,618,704; 5,623,
070; 5,663,312; 5,633,360; 5,677,437; and 5,677,439.
Other oligonucleotides which can be used according to the present invention,
are those
modified in both sugar and the internucleoside linkage, i.e., the backbone, of
the nucleotide units
are replaced with novel groups. The base units are maintained for
complementation with the
appropriate polynucleotide target. An example for such an oligonucleotide
mimetic, includes
peptide nucleic acid (PNA). United States patents that teach the preparation
of PNA compounds
include, but are not limited to, U.S. Pat. Nos. 5,539,082; 5,714,331; and
5,719,262, each of
which is herein incorporated by reference. Other backbone modifications, which
can be used in
the present invention are disclosed in U.S. Pat. No: 6,303,374.
Oligonucleotides of the present invention may also include base modifications
or
substitutions. As used herein, "unmodified" or "natural" bases include the
purine bases adenine
(A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and
uracil (Ln.
Modified bases include but are not limited to other synthetic and natural
bases such as 5-
methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-
aminoadenine,
6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and
other alkyl derivatives
of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, S-
halouracil and
cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine,
5-uracil

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(pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-
hydroxyl and other 8-
substituted adenines and guanines, 5-halo particularly 5-bromo, 5-
trifluoromethyl and other 5-
substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-
azaguanine and 8-
azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-
deazaadenine.
S Further bases particularly useful for increasing the binding affinity of the
oligomeric compounds
of the invention include 5-substituted pyrimidines, 6-azapyrimidines and N-2,
N-6 and O-6
substituted purines, including 2-aminopropyladenine, 5-propynyluracil and S-
propynylcytosine.
5-methylcytosine substitutions have been shown to increase nucleic acid duplex
stability by 0.6-
1.2 °C and are presently preferred base substitutions, even more
particularly when combined
with 2'-O-methoxyethyl sugar modifications.
Another modification of the oligonucleotides of the invention involves
chemically
linking to the oligonucleotide one or more moieties or conjugates, which
enhance the activity,
cellular distribution or cellular uptake of the oligonucleotide. Such moieties
include but are not
limited to lipid moieties such as a cholesterol moiety, cholic acid, a
thioether, e.g., hexyl-S-
tritylthiol, a thiocholesterol, an aliphatic chain, e.g., dodecandiol or
undecyl residues, a
phospholipid, e.g., di-hexadecyl-rac-glycerol or triethylammonium 1,2-di-O-
hexadecyl-rac-
glycero-3-H-phosphonate, a polyamine or a polyethylene glycol chain, or
adamantane acetic
acid, a palmityl moiety, or an octadecylamine or hexylamino-carbonyl-
oxycholesterol moiety,
as disclosed in U.S. Pat. No: 6,303,374.
It is not necessary for all positions in a given oligonucleotide molecule to
be uniformly
modified, and in fact more than one of the aforementioned modifications may be
incorporated in
a single compound or even at a single nucleoside within an oligonucleotide.
It will be appreciated that oligonucleotides of the present invention may
include further
modifications for more efficient use as diagnostic agents and/or to increase
bioavailability,
therapeutic efficacy and reduce cytotoxicity.
To enable cellular expression of the polynucleotides of the present invention,
a nucleic
acid construct according to the present invention may be used, which includes
at least a coding
region of one of the above nucleic acid sequences, and further includes at
least one cis acting
regulatory element. As used herein, the phrase "cis acting regulatory element"
refers to a
polynucleotide sequence, preferably a promoter, which binds a trans acting
regulator and
regulates the transcription of a coding sequence located downstream thereto.

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Any suitable promoter sequence can be used by the nucleic acid construct of
the present
invention.
Preferably, the promoter utilized by the nucleic acid construct of the present
invention is
active in the specific cell population transformed. Examples of cell type-
specific and/or tissue
s specific promoters include promoters such as albumin that is liver specific,
lymphoid specific
promoters [Calame et al., (1988) Adv. Immunol. 43:235-275]; in particular
promoters of T-cell
receptors [Winoto et al., (1989) EMBO J. 8:729-733] and immunoglobulins;
[Banerji et al.
(1983) Cell 33729-740], neuron-specific promoters such as the neurofilament
promoter [Byrne
et al. (1989) Proc. Natl. Acad. Sci. USA 86:5473-5477], pancreas-specific
promoters [Edlunch
et al. (1985) Science 230:912-916] or mammary gland-specific promoters such as
the milk
whey promoter (U.S. Pat. No. 4,873,316 and European Application Publication
No. 264,166).
The nucleic acid construct of the present invention can fiirther include an
enhancer, which can
be adjacent or distant to the promoter sequence and can function in up
regulating the
transcription therefrom.
The nucleic acid construct of the present invention preferably further
includes an
appropriate selectable marker and/or an origin of replication. Preferably, the
nucleic acid
construct utilized is a shuttle vector, which can propagate both in E. coli
(wherein the construct
comprises an appropriate selectable marker and origin of replication) and be
compatible for
propagation in cells, or integration in a gene and a tissue of choice. The
construct according to
the present invention can be, for example, a plasmid, a bacmid, a phagemid, a
cosmid, a phage,
a virus or an artificial chromosome.
Examples of suitable constructs include, but are not limited to, pcDNA3,
pcDNA3.l
(+/-), pGL3, PzeoSV2 (+/-), pDisplay, pEF/myc/cyto, pCMV/myc/cyto each of
which is
commercially available from Invitrogen Co. (www.invitrogen.com). Examples of
retroviral
vector and packaging systems are those sold by Clontech, San Diego, Calif.,
includingRetro-X
vectors pLNCX and pLXSN, which permit cloning into multiple cloning sites and
the trasgene
is transcribed from CMV promoter. Vectors derived from Mo-MuLV are also
included such as
pBabe, where the transgene will be transcribed from the 5'LTR promoter.
Currently preferred in vivo nucleic acid transfer techniques include
transfection with
viral or non-viral constructs, such as adenovirus, lentivirus, Herpes simplex
I virus, or adeno
associated virus (AAV) and lipid-based systems. Useful lipids for lipid-
mediated transfer of the

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gene are, for example, DOTMA, DOPE, and DC-Chol [Tonkinson et al., Cancer
Investigation,
14(1): 54-65 (1996)]. The most preferred constructs for use in gene therapy
are viruses, most
preferably adenoviruses, AAV, lentiviruses, or retroviruses. A viral construct
such as a
retroviral construct includes at least one transcriptional promoter/enhancer
or locus-defining
element(s), or other elements that control gene expression by other means such
as alternate
splicing, nuclear RNA export, or post-translational modification of messenger.
Such vector
constructs also include a packaging signal, long terminal repeats (LTRs) or
portions thereof, and
positive and negative strand primer binding sites appropriate to the virus
used, unless it is
already present in the viral construct. In addition, such a construct
typically includes a signal
sequence for secretion of the peptide from a host cell in which it is placed.
Preferably the signal
sequence for this purpose is a mammalian signal sequence or the signal
sequence of the
polypeptide variants of the present invention. Optionally, the construct may
also include a
signal that directs polyadenylation, as well as one or more restriction sites
and a translation
termination sequence. By way of example, such constructs will typically
include a 5' LTR, a
tRNA binding site, a packaging signal, an origin of second-strand DNA
synthesis, and a 3' LTR
or a portion thereof. Other vectors can be used that are non-viral, such as
cationic lipids,
polylysine, and dendrimers.
Hybridization assays
Detection of a nucleic acid of interest in a biological sample may optionally
be effected
by hybridization-based assays using an oligonucleotide probe (non-limiting
examples of probes
according to the present invention were previously described).
Traditional hybridization assays include PCR, RT-PCR, Real-time PCR, RNase
protection, in-situ hybridization, primer extension, Southern blots (DNA
detection), dot or slot
blots (DNA, RNA), and Northern blots (RNA detection) (NAT type assays are
described in
greater detail below). More recently, PNAs have been described (Nielsen et al.
1999, Current
Opin. Biotechnol. 10:71-75). Other detection methods include kits containing
probes on a
dipstick setup and the like.
Hybridization based assays which allow the detection of a variant of interest
(i.e., DNA
or RNA) in a biological sample rely on the use of oligonucleotides which can
be 10, 15, 20, or

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30 to 100 nucleotides long preferably from 10 to 50, more preferably from 40
to 50 nucleotides
long.
Thus, the isolated polynucleotides (oligonucleotides) of the present invention
are
preferably hybridizable with any of the herein described nucleic acid
sequences under moderate
to stringent hybridization conditions.
Moderate to stringent hybridization conditions are characterized by a
hybridization
solution such as containing 10 % dextrane sulfate, 1 M NaCI, 1 % SDS and 5 x
106 cpm 32P
labeled probe, at 65 °C, with a final wash solution of 0.2 x SSC and
0.1 % SDS and final wash
at 65°C and whereas moderate hybridization is effected using a
hybridization solution
containing 10 % dextrane sulfate, 1 M NaCI, 1 % SDS and 5 x 106 cpm 32P
labeled probe, at 65
°C, with a final wash solution of 1 x SSC and 0.1 % SDS and final wash
at 50 °C.
More generally, hybridization of short nucleic acids (below 200 by in length,
e.g. 17-40
by in length) can be effected using the following exemplary hybridization
protocols which can
be modified according to the desired stringency; (i) hybridization solution of
6 x SSC and 1
SDS or 3 M TMACI, 0.01 M sodium phosphate (pH 6.8), 1 mM EDTA (pH 7.6), 0.5 %
SDS,
100 p,g/ml denatured salmon sperm DNA and 0.1 % nonfat dried milk,
hybridization temperature
of 1 - 1.5 °C below the Tm, final wash solution of 3 M TMACI, 0.01 M
sodium phosphate (pH
6.8), 1 mM EDTA (pH 7.6), 0.5 % SDS at 1 - 1.5 °C below the Tm; (ii)
hybridization solution
of 6 x SSC and 0.1 % SDS or 3 M TMACI, 0.01 M sodium phosphate (pH 6.8), 1 mM
EDTA
(pH 7.6), 0.5 % SDS, 100 ~g/ml denatured salmon sperm DNA and 0.1 % nonfat
dried milk,
hybridization temperature of 2 - 2.5 °C below the Tm, final wash
solution of 3 M TMACI, 0.01
M sodium phosphate (pH 6.8), 1 mM EDTA (pH 7.6), 0.5 % SDS at 1 - 1.5
°C below the Tm,
final wash solution of 6 x SSC, and final wash at 22 °C; (iii)
hybridization solution of 6 x SSC
and 1 % SDS or 3 M TMACI, 0.01 M sodium phosphate (pH 6.8), 1 mM EDTA (pH
7.6), 0.5
SDS, 100 p,g/ml denatured salmon sperm DNA and 0.1 % nonfat dried milk,
hybridization
temperature.
The detection of hybrid duplexes can be carried out by a number of methods.
Typically,
hybridization duplexes are separated from unhybridized nucleic acids and the
labels bound to the
duplexes are then detected. Such labels refer to radioactive, fluorescent,
biological or enzymatic

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tags or labels of standard use in the art. A label can be conjugated to either
the oligonucleotide
probes or the nucleic acids derived from the biological sample.
Probes can be labeled according to numerous well known methods. Non-limiting
examples of radioactive labels include 3H, 14C, 32P, and 355. Non-limiting
examples of
detectable markers include ligands, fluorophores, chemiluminescent agents,
enzymes, and
antibodies. Other detectable markers for use with probes, which can enable an
increase in
sensitivity of the method of the invention, include biotin and radio-
nucleotides. It will become
evident to the person of ordinary skill that the choice of a particular label
dictates the manner in
which it is bound to the probe.
For example, oligonucleotides of the present invention can be labeled
subsequent to
synthesis, by incorporating biotinylated dNTPs or rNTP, or some similar means
(e.g., photo-
cross-linking a psoralen derivative of biotin to RNAs), followed by addition
of labeled
streptavidin (e.g., phycoerythrin-conjugated streptavidin) or the equivalent.
Alternatively, when
fluorescently-labeled oligonucleotide probes are used, fluorescein, lissamine,
phycoerythrin,
rhodamine (Perkin Elmer Cetus), Cy2, Cy3, Cy3.5, CyS, Cy5.5, Cy7, FluorX
(Amersham) and
others [e.g., Kricka et al. (1992), Academic Press San Diego, CalifJ can be
attached to the
oligonucleotides.
Those skilled in the art will appreciate that wash steps may be employed to
wash away
excess target DNA or probe as well as unbound conjugate. Further, standard
heterogeneous assay
formats are suitable for detecting the hybrids using the labels present on the
oligonucleotide
primers and probes.
It will be appreciated that a variety of controls may be usefully employed to
improve
accuracy of hybridization assays. For instance, samples may be hybridized to
an irrelevant probe
and treated with RNAse A prior to hybridization, to assess false
hybridization.
Although the present invention is not specifically dependent on the use of a
label for the
detection of a particular nucleic acid sequence, such a label might be
beneficial, by increasing
the sensitivity of the detection. Furthermore, it enables automation. Probes
can be labeled
according to numerous well known methods.
As commonly known, radioactive nucleotides can be incorporated into probes of
the
invention by several methods. Non-limiting examples of radioactive labels
include 3H, 14C, 32P,
and 355.

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Those skilled in the art~will appreciate that wash steps may be employed to
wash away
excess target DNA or probe as well as unbound conjugate. Further, standard
heterogeneous assay
formats are suitable for detecting the hybrids using the labels present on the
oligonucleotide
primers and probes.
It will be appreciated that a variety of controls may be usefully employed to
improve
accuracy of hybridization assays.
Probes of the invention can be utilized with naturally occurnng sugar-
phosphate
backbones as well as modified backbones including phosphorothioates,
dithionates, alkyl
phosphonates and a-nucleotides and the like. Probes of the invention can be
constructed of either
ribonucleic acid (RNA) or deoxyribonucleic acid (DNA), and preferably of DNA.
NAT Assays
Detection of a nucleic acid of interest in a biological sample may also
optionally be
effected by NAT-based assays, which involve nucleic acid amplification
technology, such as
PCR for example (or variations thereof such as real-time PCR for example).
As used herein, a "primer" defines an oligonucleotide which is capable of
annealing to
(hybridizing with) a target sequence, thereby creating a double stranded
region which can serve
as an initiation point for DNA synthesis under suitable conditions.
Amplification of a selected, or target, nucleic acid sequence may be carried
out by a
number of suitable methods. See generally Kwoh et al., 1990, Am. Biotechnol.
Lab. 8:14
Numerous amplification techniques have been described and can be readily
adapted to suit
particular needs of a person of ordinary skill. Non-limiting examples of
amplification techniques
include polymerise chain reaction (PCR), ligase chain reaction (LCR), strand
displacement
amplification (SDA), transcription-based amplification, the q3 replicase
system and NASBA
(Kwoh et al., 1989, Proc. NatI. Acid. Sci. USA 86, 1173-1177; Lizardi et al.,
1988,
BioTechnology 6:1197-1202; Malek et al., 1994, Methods Mol. Biol., 28:253-260;
and
Sambrook et al., 1989, supra).
The terminology "amplification pair" (or "primer pair") refers herein to a
pair of
oligonucleotides (oligos) of the present invention, which are selected to be
used together in
amplifying a selected nucleic acid sequence by one of a number of types of
amplification
processes, preferably a polymerise chain reaction. Other types of
amplification processes

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include ligase chain reaction, strand displacement amplification, or nucleic
acid sequence-based
amplification, as explained in greater detail below. As commonly known in the
art, the oligos
are designed to bind to a complementary sequence under selected conditions.
In one particular embodiment, amplification of a nucleic acid sample from a
patient is
amplified under conditions which favor the amplification of the most abundant
differentially
expressed nucleic acid. In one preferred embodiment, RT-PCR is carried out on
an mRNA
sample from a patient under conditions which favor the amplification of the
most abundant
mRNA. In another preferred embodiment, the amplification of the differentially
expressed
nucleic acids is carried out simultaneously. It will be realized by a person
skilled in the art that
such methods could be adapted for the detection of differentially expressed
proteins instead of
differentially expressed nucleic acid sequences.
The nucleic acid (i.e. DNA or RNA) for practicing the present invention may be
obtained according to well known methods.
Oligonucleotide primers of the present invention may be of any suitable
length,
depending on the particular assay format and the particular needs and targeted
genomes
employed. Optionally, the oligonucleotide primers are at least 12 nucleotides
in length,
preferably between 1 S and 24 molecules, and they may be adapted to be
especially suited to a
chosen nucleic acid amplification system. As commonly known in the art, the
oligonucleotide
primers can be designed by taking into consideration the melting point of
hybridization thereof
with its targeted sequence (Sambrook et al., 1989, Molecular Cloning -A
Laboratory Manual,
2nd Edition, CSH Laboratories; Ausubel et al., 1989, in Current Protocols in
Molecular Biology,
John Wiley & Sons Inc., N.Y.).
It will be appreciated that antisense oligonucleotides may be employed to
quantify
expression of a splice isoform of interest. Such detection is effected at the
pre-mRNA level.
Essentially the ability to quantitate transcription from a splice site of
interest can be effected
based on splice site accessibility. Oligonucleotides may compete with splicing
factors for the
splice site sequences. Thus, low activity of the antisense oligonucleotide is
indicative of
splicing activity.
The polymerase chain reaction and other nucleic acid amplification reactions
are well
known in the art (various non-limiting examples of these reactions are
described in greater detail
below). The pair of oligonucleotides according to this aspect of the present
invention are

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preferably selected to have compatible melting temperatures (Tm), e.g.,
melting temperatures
which differ by less than that 7 °C, preferably less than 5 °C,
more preferably less than 4 °C,
most preferably less than 3 °C, ideally between 3 °C and 0
°C.
Polymerise Chain Reaction (PCR): The polymerise chain reaction (PCR), as
described
in U.S. Pat. Nos. 4,683,195 and 4,683,202 to Mullis and Mullis et al., is a
method of increasing
the concentration of a segment of target sequence in a mixture of genomic DNA
without cloning
or purification. This technology provides one approach to the problems of low
target sequence
concentration. PCR can be used to directly increase the concentration of the
target to an easily
detectable level. This process for amplifying the target sequence involves the
introduction of a
molar excess of two oligonucleotide primers which are complementary to their
respective strands
of the double-stranded target sequence to the DNA mixture containing the
desired target
sequence. The mixture is denatured and then allowed to hybridize. Following
hybridization, the
primers are extended with polymerise so as to form complementary strands. The
steps of
denaturation, hybridization (annealing), and polymerise extension (elongation)
can be repeated
as often as needed, in order to obtain relatively high concentrations of a
segment of the desired
target sequence.
The length of the segment of the desired target sequence is determined by the
relative
positions of the primers with respect to each other, and, therefore, this
length is a controllable
parameter. Because the desired segments of the target sequence become the
dominant sequences
(in terms of concentration) in the mixture, they are said to be "PCR-
amplified."
Ligase Chain Reaction (LCR or LAR): The ligase chain reaction [LCR; sometimes
referred to as "Ligase Amplification Reaction" (LAR)] has developed into a
well-recognized
alternative method of amplifying nucleic acids. In LCR, four oligonucleotides,
two adjacent
oligonucleotides which uniquely hybridize to one strand of target DNA, and a
complementary set
of adjacent oligonucleotides, which hybridize to the opposite strand are mixed
and DNA ligase is
added to the mixture. Provided that there is complete complementarity at the
junction, ligase
will covalently link each set of hybridized molecules. Importantly, in LCR,
two probes are
ligated together only when they base-pair with sequences in the target sample,
without gaps or
mismatches. Repeated cycles of denaturation, and ligation amplify a short
segment of DNA.
LCR has also been used in combination with PCR to achieve enhanced detection
of single-base
changes: see for example Segev, PCT Publication No. W09001069 A1 (1990).
However,

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because the four oligonucleotides used in this assay can pair to form two
short ligatable
fragments, there is the potential for the generation of target-independent
background signal. The
use of LCR for mutant screening is limited to the examination of specific
nucleic acid positions.
Self Sustained Synthetic Reaction (3SRlNASBA): The self sustained sequence
replication
reaction (3SR) is a transcription-based in vitro amplification system that can
exponentially
amplify RNA sequences at a uniform temperature. The amplified RNA can then be
utilized for
mutation detection. In this method, an oligonucleotide primer is used to add a
phage RNA
polymerase promoter to the 5' end of the sequence of interest. In a cocktail
of enzymes and
substrates that includes a second primer, reverse transcriptase, RNase H, RNA
polymerase and
ribo-and deoxyribonucleoside triphosphates, the target sequence undergoes
repeated rounds of
transcription, cDNA synthesis and second-strand synthesis to amplify the area
of interest. The
use of 3SR to detect mutations is kinetically limited to screening small
segments of DNA (e.g.,
200-300 base pairs).
Q-Beta (Q(3) Replicase: In this method, a probe which recognizes the sequence
of
interest is attached to the replicatable RNA template for Q(3 replicase. A
previously identified
major problem with false positives resulting from the replication of
unhybridized probes has
been addressed through use of a sequence-specific ligation step. However,
available
thermostable DNA ligases are not effective on this RNA substrate, so the
ligation must be
performed by T4 DNA ligase at low temperatures (37 degrees C.). This prevents
the use of high
temperature as a means of achieving specificity as in the LCR, the ligation
event can be used to
detect a mutation at the junction site, but not elsewhere.
A successful diagnostic method must be very specific. A straight-forward
method of
controlling the specificity of nucleic acid hybridization is by controlling
the temperature of the
reaction. While the 3SR/NASBA, and Q(3 systems are all able to generate a
large quantity of
signal, one or more of the enzymes involved in each cannot be used at high
temperature (i.e., >
55 degrees C). Therefore the reaction temperatures cannot be raised to prevent
non-specific
hybridization of the probes. If probes are shortened in order to make them
melt more easily at
low temperatures, the likelihood of having more than one perfect match in a
complex genome
increases. For these reasons, PCR and LCR currently dominate the research
field in detection
technologies.

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The basis of the amplification procedure in the PCR and LCR is the fact that
the products
of one cycle become usable templates in all subsequent cycles, consequently
doubling the
population with each cycle. The final yield of any such doubling system can be
expressed as:
(1+X)n =y, where "X" is the mean efficiency (percent copied in each cycle),
"n" is the number of
cycles, and "y" is the overall efficiency, or yield of the reaction. If every
copy of a target DNA is
utilized as a template in every cycle of a polymerase chain reaction, then the
mean efficiency is
100 %. If 20 cycles of PCR are performed, then the yield will be 220, or
1,048,576 copies of the
starting material. If the reaction conditions reduce the mean efficiency to 85
%, then the yield in
those 20 cycles will be only 1.8520, or 220,513 copies of the starting
material. In other words, a
PCR running at 85 % efficiency will yield only 21 % as much final product,
compared to a
reaction running at 100 % efficiency. A reaction that is reduced to 50 % mean
efficiency will
yield less than 1 % of the possible product.
In practice, routine polymerase chain reactions rarely achieve the theoretical
maximum
yield, and PCRs are usually run for more than 20 cycles to compensate for the
lower yield. At
50 % mean efficiency, it would take 34 cycles to achieve the million-fold
amplification
theoretically possible in 20, and at lower efficiencies, the number of cycles
required becomes
prohibitive. In addition, any background products that amplify with a better
mean efficiency
than the intended target will become the dominant products.
Also, many variables can influence the mean efficiency of PCR, including
target DNA
length and secondary structure, primer length and design, primer and dNTP
concentrations, and
buffer composition, to name but a few. Contamination of the reaction with
exogenous DNA
(e.g., DNA spilled onto lab surfaces) or cross-contamination is also a major
consideration.
Reaction conditions must be carefully optimized for each different primer pair
and target
sequence, and the process can take days, even for an experienced investigator.
The
laboriousness of this process, including numerous technical considerations and
other factors,
presents a significant drawback to using PCR in the clinical setting. Indeed,
PCR has yet to
penetrate the clinical market in a significant way. The same concerns arise
with LCR, as LCR
must also be optimized to use different oligonucleotide sequences for each
target sequence. In
addition, both methods require expensive equipment, capable of precise
temperature cycling.
Many applications of nucleic acid detection technologies, such as in studies
of allelic
variation, involve not only detection of a specific sequence in a complex
background, but also

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the discrimination between sequences with few, or single, nucleotide
differences. One method of
the detection of allele-specific variants by PCR is based upon the fact that
it is difficult for Taq
polymerase to synthesize a DNA strand when there is a mismatch between the
template strand
and the 3' end of the primer. An allele-specific variant may be detected by
the use of a primer
that is perfectly matched with only one of the possible alleles; the mismatch
to the other allele
acts to prevent the extension of the primer, thereby preventing the
amplification of that sequence.
This method has a substantial limitation in that the base composition of the
mismatch influences
the ability to prevent extension across the mismatch, and certain mismatches
do not prevent
extension or have only a minimal effect.
A similar 3'-mismatch strategy is used with greater effect to prevent ligation
in the LCR.
Any mismatch effectively blocks the action of the thermostable ligase, but LCR
still has the
drawback of target-independent background ligation products initiating the
amplification.
Moreover, the combination of PCR with subsequent LCR to identify the
nucleotides at individual
positions is also a clearly cumbersome proposition for the clinical
laboratory.
The direct detection method according to various preferred embodiments of the
present
invention may be, for example a cycling probe reaction (CPR) or a branched DNA
analysis.
When a sufficient amount of a nucleic acid to be detected is available, there
are
advantages to detecting that sequence directly, instead of making more copies
of that target,
(e.g., as in PCR and LCR). Most notably, a method that does not amplify the
signal
exponentially is more amenable to quantitative analysis. Even if the signal is
enhanced by
attaching multiple dyes to a single oligonucleotide, the correlation between
the final signal
intensity and amount of target is direct. Such a system has an additional
advantage that the
products of the reaction will not themselves promote further reaction, so
contamination of lab
surfaces by the products is not as much of a concern. Recently devised
techniques have sought to
eliminate the use of radioactivity and/or improve the sensitivity in
automatable formats. Two
examples are the "Cycling Probe Reaction" (CPR), and "Branched DNA" (bDNA).
Cycling probe reaction (CPR): The cycling probe reaction (CPR), uses a long
chimeric
oligonucleotide in which a central portion is made of RNA while the two
termini are made of
DNA. Hybridization of the probe to a target DNA and exposure to a thermostable
RNase H
causes the RNA portion to be digested. This destabilizes the remaining DNA
portions of the
duplex, releasing the remainder of the probe from the target DNA and allowing
another probe

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molecule to repeat the process. The signal, in the form of cleaved probe
molecules, accumulates
at a linear rate. While the repeating process increases the signal, the RNA
portion of the
oligonucleotide is vulnerable to RNases that may carned through sample
preparation.
Branched DNA: Branched DNA (bDNA), involves oligonucleotides with branched
structures that allow each individual oligonucleotide to carry 35 to 40 labels
(e.g., alkaline
phosphatase enzymes). While this enhances the signal from a hybridization
event, signal from
non-specific binding is similarly increased.
The detection of at least one sequence change according to various preferred
embodiments of the present invention may be accomplished by, for example
restriction fragment
length polymorphism (RFLP analysis), allele specific oligonucleotide (ASO)
analysis,
Denaturing/Temperature Gradient Gel Electrophoresis (DGGE/TGGE), Single-Strand
Conformation Polymorphism (SSCP) analysis or Dideoxy fingerprinting (ddF).
The demand for tests which allow the detection of specific nucleic acid
sequences and
sequence changes is growing rapidly in clinical diagnostics. As nucleic acid
sequence data for
1 S genes from humans and pathogenic organisms accumulates, the demand for
fast, cost-effective,
and easy-to-use tests for as yet mutations within specific sequences is
rapidly increasing.
A handful of methods have been devised to scan nucleic acid segments for
mutations.
One option is to determine the entire gene sequence of each test sample (e.g.,
a bacterial isolate).
For sequences under approximately 600 nucleotides, this may be accomplished
using amplified
material (e.g., PCR reaction products). This avoids the time and expense
associated with cloning
the segment of interest. However, specialized equipment and highly trained
personnel are
required, and the method is too labor-intense and expensive to be practical
and effective in the
clinical setting.
In view of the difficulties associated with sequencing, a given segment of
nucleic acid
may be characterized on several other levels. At the lowest resolution, the
size of the molecule
can be determined by electrophoresis by comparison to a known standard run on
the same gel. A
more detailed picture of the molecule may be achieved by cleavage with
combinations of
restriction enzymes prior to electrophoresis, to allow construction of an
ordered map. The
presence of specific sequences within the fragment can be detected by
hybridization of a labeled
probe, or the precise nucleotide sequence can be determined by partial
chemical degradation or
by primer extension in the presence of chain-terminating nucleotide analogs.

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Restriction fragment length polymorphism (RFLP): For detection of single-base
differences between like sequences, the requirements of the analysis are often
at the highest level
of resolution. For cases in which the position of the nucleotide in question
is known in advance,
several methods have been developed for examining single base changes without
direct
sequencing. For example, if a mutation of interest happens to fall within a
restriction recognition
sequence, a change in the pattern of digestion can be used as a diagnostic
tool (e.g., restriction
fragment length polymorphism [RFLP] analysis).
Single point mutations have been also detected by the creation or destruction
of RFLPs.
Mutations are detected and localized by the presence and size of the RNA
fragments generated
by cleavage at the mismatches. Single nucleotide mismatches in DNA
heteroduplexes are also
recognized and cleaved by some chemicals, providing an alternative strategy to
detect single
base substitutions, generically named the "Mismatch Chemical Cleavage" (MCC).
However, this
method requires the use of osmium tetroxide and piperidine, two highly noxious
chemicals
which are not suited for use in a.clinical laboratory.
RFLP analysis suffers from low sensitivity and requires a large amount of
sample. When
RFLP analysis is used for the detection of point mutations, it is, by its
nature, limited to the
detection of only those single base changes which fall within a restriction
sequence of a known
restriction endonuclease. Moreover, the majority of the available enzymes have
4 to 6 base-pair
recognition sequences, and cleave too frequently for many large-scale DNA
manipulations.
Thus, it is applicable only in a small fraction of cases, as most mutations do
not fall within such
sites.
A handful of rare-cutting restriction enzymes with 8 base-pair specificities
have been
isolated and these are widely used in genetic mapping, but these enzymes are
few in number, are
limited to the recognition of G+C-rich sequences, and cleave at sites that
tend to be highly
clustered. Recently, endonucleases encoded by group I introns have been
discovered that might
have greater than 12 base-pair specificity, but again, these are few in
number.
Allele specific oligonucleotide (ASO): If the change is not in a recognition
sequence,
then allele-specific oligonucleotides (ASOs), can be designed to hybridize in
proximity to the
mutated nucleotide, such that a primer extension or ligation event can bused
as the indicator of a
match or a mis-match. Hybridization with radioactively labeled allelic
specific oligonucleotides
(ASO) also has been applied to the detection of specific point mutations. The
method is based

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on the differences in the melting temperature of short DNA fragments differing
by a single
nucleotide. Stringent hybridization and washing conditions can differentiate
between mutant and
wild-type alleles. The ASO approach applied to PCR products also has been
extensively utilized
by various researchers to detect and characterize point mutations in ras genes
and gsp/gip
oncogenes. Because of the presence of various nucleotide. changes in multiple
positions, the
ASO method requires the use of many oligonucleotides to cover all possible
oncogenic
mutations.
With either of the techniques described above (i.e., RFLP and ASO), the
precise location
of the suspected mutation must be known in advance of the test. That is to
say, they are
inapplicable when one needs to detect the presence of a mutation within a gene
or sequence of
interest.
DenaturinglTemperature Gradient Gel Electrophoresis (DGGElTGGE): Two other
methods rely on detecting changes in electrophoretic mobility in response to
minor sequence
changes. One of these methods, termed "Denaturing Gradient Gel
Electrophoresis" (DGGE) is
based on the observation that slightly different sequences will display
different patterns of local
melting when electrophoretically resolved on a gradient gel. In this manner,
variants can be
distinguished, as differences in melting properties of homoduplexes versus
heteroduplexes
differing in a single nucleotide can detect the presence of mutations in the
target sequences
because of the corresponding changes in their electrophoretic mobilities. The
fragments to be
analyzed, usually PCR products, are "clamped" at one end by a long,stretch of
G-C base pairs
(30-80) to allow complete denaturation of the sequence of interest without
complete dissociation
of the strands. The attachment of a GC "clamp" to the DNA fragments increases
the fraction of
mutations that can be recognized by DGGE. Attaching a GC clamp to one primer
is critical to
ensure that the amplified sequence has a low dissociation temperature.
Modifications of the
technique have been developed, using temperature gradients, and the method can
be also applied
to RNA:RNA duplexes.
Limitations on the utility of DGGE include the requirement that the denaturing
conditions
must be optimized for each type of DNA to be tested. Furthermore, the method
requires
specialized equipment to prepare the gels and maintain the needed high
temperatures during
electrophoresis. The expense associated with the synthesis of the clamping
tail on one
oligonucleotide for each sequence to be tested is also a major consideration.
In addition, long

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running times are required for DGGE. The long running time of DGGE was
shortened in a
modification of DGGE called constant denaturant gel electrophoresis (CDGE).
CDGE requires
that gels be performed under different denaturant conditions in order to reach
high efficiency for
the detection of mutations.
A technique analogous to DGGE, termed temperature gradient gel electrophoresis
(TGGE), uses a thermal gradient rather than a chemical denaturant gradient.
TGGE requires the
use of specialized equipment which can generate a temperature gradient
perpendicularly oriented
relative to the electrical field. TGGE can detect mutations in relatively
small fragments of DNA
therefore scanning of large gene segments requires the use of multiple PCR
products prior to
running the gel.
Single-Strand Conformation Polymorphism (SSCP): Another common method, called
"Single-Strand Conformation Polymorphism" (SSCP) was developed by Hayashi,
Sekya and
colleagues and is based on the observation that single strands of nucleic acid
can take on
characteristic conformations in non-denaturing conditions, and these
conformations influence
electrophoretic mobility. The complementary strands assume sufficiently
different structures
that one strand may be resolved from the other. Changes in sequences within
the fragment will
also change the conformation, consequently altering the mobility and allowing
this to be used as
an assay for sequence variations.
The SSCP process involves denaturing a DNA segment (e.g., a PCR product) that
is
labeled on both strands, followed by slow electrophoretic separation on a non-
denaturing
polyacrylamide gel, so that infra-molecular interactions can form and not be
disturbed during the
run. This technique is extremely sensitive to variations in gel composition
and temperature. A
serious limitation of this method is the relative difficulty encountered in
comparing data
generated in different laboratories, under apparently similar conditions.
Dideoxy fingerprinting (ddF): The dideoxy fingerprinting (ddF) is another
technique
developed to scan genes for the presence of mutations. The ddF technique
combines
components of Sanger dideoxy sequencing with SSCP. A dideoxy sequencing
reaction is
performed using one dideoxy terminator and then the reaction products are
electrophoresed on
nondenaturing polyacrylamide gels to detect alterations in mobility of the
termination segments
as in SSCP analysis. While ddF is an improvement over SSCP in terms of
increased sensitivity,
ddF requires the use of expensive dideoxynucleotides and this technique is
still limited to the

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analysis of fragments of the size suitable for SSCP (i.e., fragments of 200-
300 bases for optimal
detection of mutations).
In addition to the above limitations, all of these methods are limited as to
the size of the
nucleic acid fragment that can be analyzed. For the direct sequencing
approach, sequences of
greater than 600 base pairs require cloning, with the consequent delays and
expense of either
deletion sub-cloning or primer walking, in order to cover the entire fragment.
SSCP and DGGE
have even more severe size limitations. Because of reduced sensitivity to
sequence changes,
these methods are not considered suitable for larger fragments. Although SSCP
is reportedly able
to detect 90 % of single-base substitutions within a 200 base-pair fragment,
the detection drops
to less than 50 % for 400 base pair fragments. Similarly, the sensitivity of
DGGE decreases as
the length of the fragment reaches 500 base-pairs. The ddF technique, as a
combination of direct
sequencing and SSCP, is also limited by the relatively small size of the DNA
that can be
screened.
According to a presently preferred embodiment of the present invention the
step of
searching for any of the nucleic acid sequences described here, in tumor cells
or in cells derived
from a cancer patient is effected by any suitable technique, including, but
not limited to, nucleic
acid sequencing, polymerase chain reaction, ligase chain reaction, self
sustained synthetic
reaction, Q(3-Replicase, cycling probe reaction, branched DNA, restriction
fragment length
polymorphism analysis, mismatch chemical cleavage, heteroduplex analysis,
allele-specific
oligonucleotides, denaturing gradient gel electrophoresis, constant denaturant
gel
electrophoresis, temperature gradient gel electrophoresis and dideoxy
fingerprinting.
Detection may also optionally be performed with a chip or other such device.
The nucleic
acid sample which includes the candidate region to be analyzed is preferably
isolated, amplified
and labeled with a reporter group. This reporter group can be a fluorescent
group such as
phycoerythrin. The labeled nucleic acid is then incubated with the probes
immobilized on the
chip using a fluidics station. describe the fabrication of fluidics devices
and particularly
microcapillary devices, in silicon and glass substrates.
Once the reaction is completed, the chip is inserted into a scanner and
patterns of
hybridization are detected. The hybridization data is collected, as a signal
emitted from the
reporter groups already incorporated into the nucleic acid, which is now bound
to the probes

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attached to the chip. Since the sequence and position of each probe
immobilized on the chip is
known, the identity of the nucleic acid hybridized to a given probe can be
determined.
It will be appreciated that when utilized along with automated equipment, the
above
described detection methods can be used to screen multiple samples for a
disease and/or
pathological condition both rapidly and easily.
Amino acid sequences and peptides
The terms "polypeptide," "peptide" and "protein" are used interchangeably
herein to
refer to a polymer of amino acid residues. The terms apply to amino acid
polymers in which one
or more amino acid residue is an analog or mimetic of a corresponding
naturally occurnng
amino acid, as well as to naturally occurring amino acid polymers.
Polypeptides can be
modified, e.g., by the addition of carbohydrate residues to form
glycoproteins. The terms
"polypeptide," "peptide" and "protein" include glycoproteins, as well as non-
glycoproteins.
Polypeptide products can be biochemically synthesized such as by employing
standard
1 S solid phase techniques. Such methods include but are not limited to
exclusive solid phase
synthesis, partial solid phase synthesis methods, fragment condensation,
classical solution
synthesis. These methods are preferably used when the peptide is relatively
short (i.e., 10 kDa)
and/or when it cannot be produced by recombinant techniques (i.e., not encoded
by a nucleic
acid sequence) and therefore involves different chemistry.
Solid phase polypeptide synthesis procedures are well known in the art and
further
described by John Morrow Stewart and Janis Dillaha Young, Solid Phase Peptide
Syntheses (2nd
Ed., Pierce Chemical Company, 1984).
Synthetic polypeptides can optionally be purified by preparative high
performance liquid
chromatography [Creighton T. (1983) Proteins, structures and molecular
principles. WH
Freeman and Co. N.Y.J, after which their composition can be confirmed via
amino acid
sequencing.
In cases where large amounts of a polypeptide are desired, it can be generated
using
recombinant techniques such as described by Bitter et al., (1987) Methods in
Enzymol. 153:516-
544, Studier et al. (1990) Methods in Enzymol. 185:60-89, Brisson et al.
(1984) Nature 310:511-
514, Takamatsu et al. (1987) EMBO J. 6:307-311, Coruzzi et al. (1984) EMBO J.
3:1671-1680
and Brogli et al., (1984) Science 224:838-843, Gurley et al. (1986) Mol. Cell.
Biol. 6:559-565

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and Weissbach & Weissbach, 1988, Methods for Plant Molecular Biology, Academic
Press, NY,
Section VIII, pp 421-463.
The present invention also encompasses polypeptides encoded by the
polynucleotide
sequences of the present invention, as well as polypeptides according to the
amino acid
sequences described herein. The present invention also encompasses homologues
of these
polypeptides, such homologues can be at Least 50 %, at least 55 %, at least
60%, at least 65 %, at
least 70 %, at least 75 %, at least 80 %, at least 85 %, at least 95 % or more
say 100
homologous to the amino acid sequences set forth below, as can be determined
using BlastP
software of the National Center of Biotechnology Information (NCBI) using
default parameters,
optionally and preferably including the following: filtering on (this option
filters repetitive or
Low-complexity sequences from the query using the Seg (protein) program),
scoring matrix is
BLOSUM62 for proteins, word size is 3, E value is 10, gap costs are 11, 1
(initialization and
extension), and number of alignments shown is 50. Optionally, nucleic acid
sequence
identity/homology may be determined by using BlastN software of the National
Center of
1 S Biotechnology Information (NCBI) using default parameters, which
preferably include using the
DUST filter program, and also preferably include having an E value of 10,
filtering low
complexity sequences and a word size of 11. Finally, the present invention
also encompasses
fragments of the above described polypeptides and polypeptides having
mutations, such as
deletions, insertions or substitutions of one or more amino acids, either
naturally occurring or
artificially induced, either randomly or in a targeted fashion.
It will be appreciated that peptides identified according the present
invention may be
degradation products, synthetic peptides or recombinant peptides as well as
peptidomimetics,
typically, synthetic peptides and peptoids and semipeptoids which are peptide
analogs, which
may have, for example, modifications rendering the peptides more stable while
in a body or
more capable of penetrating into cells. Such modifications include, but are
not limited to N
terminus modification, C terminus modification, peptide bond modification,
including, but not
limited to, CH2-NH, CH2-S, CH2-S=O, O=C-NH, CH2-O, CH2-CH2, S=C-NH, CH=CH or
CF=CH, backbone modifications, and residue modification. Methods for preparing
peptidomimetic compounds are well known in the art and are specified. Further
details in this
respect are provided hereinunder.

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Peptide bonds (-CO-NH-) within the peptide may be substituted, for example, by
N-
methylated bonds (-N(CH3)-CO-), ester bonds (-C(R)H-C-O-O-C(R)-N-),
ketomethylen bonds
(-CO-CH2-), a-aza bonds (-NH-N(R)-CO-), wherein R is any alkyl, e.g., methyl,
carba bonds (-
CH2-NH-), hydroxyethylene bonds (-CH(OH)-CH2-), thioamide bonds (-CS-NH-),
olefinic
S double bonds (-CH=CH-), retro amide bonds (-NH-CO-), peptide derivatives (-
N(R)-CH2-CO-),
wherein R is the "normal" side chain, naturally presented on the carbon atom.
These modifications can occur at any of the bonds along the peptide chain and
even at
several (2-3) at the same time.
Natural aromatic amino acids, Trp, Tyr and Phe, may be substituted for
synthetic non-
natural acid such as Phenylglycine, TIC, naphthylelanine (Nol), ring-
methylated derivatives of
Phe, halogenated derivatives of Phe or o-methyl-Tyr.
In addition to the above, the peptides of the present invention may also
include one or
more modified amino acids or one or more non-amino acid monomers (e.g. fatty
acids, complex
carbohydrates etc).
As used herein in the specification and in the claims section below the term
"amino acid"
or "amino acids" is understood to include the 20 naturally occurring amino
acids; those amino
acids often modified post-translationally in vivo, including, for example,
hydroxyproline,
phosphoserine and phosphothreonine; and other unusual amino acids including,
but not limited
to, 2-aminoadipic acid, hydroxylysine, isodesmosine, nor-valine, nor-leucine
and ornithine.
Furthermore, the term "amino acid" includes both D- and L-amino acids.
Table 1 non-conventional or modified amino acids which can be used with the
present
invention.
Table 1
Non-conventional Code Non-conventional aminoCode
amino acid


acid


a-aminobutyric acidAbu L-N-methylalanine Nmala



a-amino-a-methylbutyrateMgabu L-N-methylarginine Nmarg


aminocyclopropane- Cpro L-N-methylasparagine Nmasn



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Carboxylate ~ L-N-methylaspartic Nmasp
acid


Aminoisobutyric Aib L-N-methylcysteine Nmcys
acid


aminonorbornyl- Norb L-N-methylglutamine Nmgin


Carboxylate L-N-methylglutamic Nmglu
acid


Cyclohexylalanine Chexa L-N-methylhistidine Nmhis


Cyclopentylalanine Cpen L-N-methylisolleucineNmile


D-alanine Dal L-N-methylleucine Nmleu


D-arginine Darg L-N-methyllysine Nmlys


D-aspartic acid Dasp L-N-methylmethionine Nmmet


D-cysteine Dcys L-N-methylnorleucine Nmnle


D-glutamine Dgln L-N-methylnorvaline Nmnva


D-glutamic acid Dglu L-N-methylornithine Nmorn


D-histidine Dhis L-N-methylphenylalanineNmphe


D-isoleucine Dile L-N-methylproline Nmpro


D-leucine Dleu L-N-methylserine Nmser


D-lysine Dlys L-N-methylthxeonine Nmthr


D-methionine Dmet L-N-methyltryptophan Nmtrp


D-ornithine Dorn L-N-methyltyrosine Nmtyr


D-phenylalanine Dphe L-N-methylvaline Nmval


D-proline Dpro L-N-methylethylglycineNmetg


D-serine Dser L-N-methyl-t-butylglycineNmtbug


D-threonine Dthr L-norleucine Nle


D-tryptophan Dtrp L-norvaline Nva


D-tyrosine Dtyr a-methyl-aminoisobutyrateMaib


D-valine Dval a-methyl-y-aminobutyrateMgabu


D-a-methylalanine Dmala a-methylcyclohexylalanineMchexa


D-a-methylarginine Dmarg a-methylcyclopentylalanineMcpen


D-a-methylasparagineDmasn a-methyl-a-napthylalanineManap


~D-a-methylaspartateDmasp a- methylpenicillamineMpen
~ ~ ~



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D-a-methylcysteine Dmcys N-(4-aminobutyl)glycineNglu


D-a-methylglutamineDmgln N-(2-aminoethyl)glycineNaeg


D-a-methylhistidineDmhis N-(3-aminopropyl)glycineNorn


D-a-methylisoleucineDmile N- amino-a-methylbutyrateNmaabu


D-a-methylleucine Dmleu a-napthylalanine Anap


D-a-methyllysine Dmlys N-benzylglycine Nphe


D-a-methylmethionineDmmet N-(2-carbamylethyl)glycineNgln


D-a-methylornithineDmorn N-(carbamylmethyl)glycineNasn


D-a-methylphenylalanineDmphe N-(2-carboxyethyl)glycineNglu


D-a-methylproline Dmpro N-(carboxymethyl)glycineNasp


D-a-methylserine Dmser N-cyclobutylglycine Ncbut


D-a-methylthreonineDmthr N-cycloheptylglycine Nchep


D-a-methyltryptophanDmtrp N-cyclohexylglycine Nchex


D-a-methyltyrosine Dmty N-cyclodecylglycine Ncdec


D-a-methylvaline Drrival N-cyclododeclglycine Ncdod


D-a-methylalnine Dnmala N-cyclooctylglycine Ncoct


D-a-methylarginine Dnmarg N-cyclopropylglycine Ncpro


D-a-methylasparagineDnmasn N-cycloundecylglycineNcund


D-a-methylasparatateDnmasp N-(2,2-diphenylethyl)glycineNbhm


D-a-methylcysteine Dnmcys N-(3,3- Nbhe
diphenylpropyl)glycine


D-N-methylleucine Dnmleu N-(3-indolylyethyl) Nhtrp
glycine


D-N-methyllysine Dnmlys N-methyl-y-aminobutyrateNmgabu


N- Nmchexa D-N-methylmethionine Dnmmet
methylcyclohexylalanine


D-N-methylornithineDnmorn N-methylcyclopentylalanineNmcpen


N-methylglycine Nala D-N-methylphenylalanineDnmphe


N-methylaminoisobutyrateNmaib D-N-methylproline Dnmpro


N-(1-methylpropyl)glycineNile D-N-methylserine Dnmser



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N-(2-methylpropyl)glycineNile D-N-methylserine Dnmser


N-(2-methylpropyl)glycineNleu D-N-methylthreonine Dnmthr


D-N-methyltryptophanDnmtrp N-(1-methylethyl)glycineNva


D-N-methyltyrosine Dnmtyr N-methyla-napthylalanineNmanap


D-N-methylvaline Dnmval N-methylpenicillamine Nmpen


y-aminobutyric acidGabu N-(p-hydroxyphenyl)glycineNhtyr


L-t-butylglycine Tbug N-(thiomethyl)glycine Ncys


L-ethylglycine Etg penicillamine Pen


L-homophenylalanineHphe L-a-methylalanine Mala


L-a-methylarginine Marg L-a-methylasparagine Masn


L-a-methylaspartateMasp L-a-methyl-t-butylglycineMtbug


L-a-methylcysteine Mcys L-methylethylglycine Metg


L-a-methylglutamineMgln L-a-methylglutamate Mglu


L-a-methylhistidineMhis L-a-methylhomo Mhphe


phenylalanine


L-a-methylisoleucineMile N-(2-methylthioethyl)glycineNmet


D-N-methylglutamineDnmgln N-(3- Narg


guanidinopropyl)glycine


D-N-methylglutamateDnmglu N-(1-hydroxyethyl)glycineNthr


D-N-methylhistidineDnmhis N-(hydroxyethyl)glycineNser


D-N-methylisoleucineDnmile N-(imidazolylethyl)glycineNhis


D-N-methylleucine Dnmleu N-(3-indolylyethyl)glycineNhtrp


D-N-methyllysine Dnmlys N-methyl-y-aminobutyrateNmgabu


N- Nmchexa D-N-methylmethionine Dnmmet


methylcyclohexylalanine


D-N-methylornithineDnmorn N-methylcyclopentylalanineNmcpen


N-methylglycine Nala D-N-methylphenylalanineDnmphe


N-methylaminoisobutyrateNmaib D-N-methylproline Dnmpro


N-(1-methylpropyl)glycineNile D-N-methylserine Dnmser



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N-(2-methylpropyl)glycineNleu D-N-methylthreonine Dnmthr


D-N-methyltryptophanDnmtrp N-( 1-methylethyl)glycineNval


D-N-methyltyrosine Dnmtyr N-methyla-napthylalanineNmanap


D-N-methylvaline Dnmval N-methylpenicillamineNmpen


y-aminobutyric acidGabu N-(p-hydroxyphenyl)glycineNhtyr


L-t-butylglycine Tbug N-(thiomethyl)glycineNcys


L-ethylglycine Etg penicillamine Pen


L-homophenylalanineHphe L-a-methylalanine Mala


L-a-methylarginine Marg L-a-methylasparagine Masn


L-a-methylaspartateMasp L-a-methyl-t-butylglycineMtbug


L-a-methylcysteine Mcys L-methylethylglycine Metg


L-a-methylglutamineMgln L-a-methylglutamate Mglu


L-a-methylhistidineMhis L-a- Mhphe
methylhomophenylalanine


L-a-methylisoleucineMile N-(2-methylthioethyl)glycineNmet


L-a-methylleucine Mleu L-a-methyllysine Mlys


L-a-methylmethionineMmet L-a-methylnorleucine Mnle


L-a-methylnorvalineMnva L-a-methylornithine Morn


L-a-methylphenylalanineMphe L-a-methylproline Mpro


L-a-methylserine mser L-a-methylthreonine Mthr


L-a-methylvaline Mtrp L-a-methyltyrosine Mtyr


L-a-methylleucine Mval L-N- Nmhphe
Nnbhm methylhomophenylalanine


N-(N-(2,2-diphenylethyl) N-(N-(3,3-diphenylpropyl)


carbamylmethyl-glycineNnbhm carbamylmethyl(1)glycineNnbhe


1-carboxy-1-(2,2-diphenylNmbc
ethylamino)cyclopropane


Table 1 Cont.

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Since the peptides of the present invention are preferably utilized in
diagnostics which
require the peptides to be in soluble form, the peptides of the present
invention preferably
include one or more non-natural or natural polar amino acids, including but
not limited to serine
and threonine which are capable of increasing peptide solubility due to their
hydroxyl-containing
side chain.
The peptides of the present invention are preferably utilized in a linear
form, although it
will be appreciated that in cases where cyclicization does not severely
interfere with peptide
characteristics, cyclic forms of the peptide can also be utilized.
The peptides of present invention can be biochemically synthesized such as by
using
standard solid phase techniques. These methods include exclusive solid phase
synthesis well
known in the art, partial solid phase synthesis methods, fragment
condensation, classical solution
synthesis. These methods are preferably used when the peptide is relatively
short (i.e., 10 kDa)
and/or when it cannot be produced by recombinant techniques (i.e., not encoded
by a nucleic
acid sequence) and therefore involves different chemistry.
Synthetic peptides can be purified by preparative high performance liquid
chromatography and the composition of which can be confirmed via amino acid
sequencing.
In cases where large amounts of the peptides of the present invention are
desired, the
peptides of the present invention can be generated using recombinant
techniques such as
described by Bitter et al., (1987) Methods in Enzymol. 153:516-544, Studier et
al. (1990)
Methods in Enzymol. 185:60-89, Brisson et al. (1984) Nature 310:511-514,
Takamatsu et al.
(1987) EMBO J. 6:307-311, Coruzzi et al. (1984) EMBO J. 3:1671-1680 and Brogli
et al.,
(1984) Science 224:838-843, Gurley et al. (1986) Mol. Cell. Biol. 6:559-565
and Weissbach &
Weissbach, 1988, Methods for Plant Molecular Biology, Academic Press, NY,
Section VIII, pp
421-463 and also as described above.
Antibodies
"Antibody" refers to a polypeptide ligand that is preferably substantially
encoded by an
immunoglobulin gene or immunoglobulin genes, or fragments thereof, which
specifically binds
and recognizes an epitope (e.g., an antigen). The recognized immunoglobulin
genes include the
kappa and lambda light chain constant region genes, the alpha, gamma, delta,
epsilon and mu

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heavy chain constant region genes, and the myriad-immunoglobulin variable
region genes.
Antibodies exist, e.g., as intact immunoglobulins or as a number of well
characterized fragments
produced by digestion with various peptidases. This includes, e.g., Fab' and
F(ab)'2 fragments.
The term "antibody," as used herein, also includes antibody fragments either
produced by the
modification of whole antibodies or those synthesized de novo using
recombinant DNA
methodologies. It also includes polyclonal antibodies, monoclonal antibodies,
chimeric
antibodies, humanized antibodies, or single chain antibodies. "Fc" portion of
an antibody refers
to that portion of an immunoglobulin heavy chain that comprises one or more
heavy chain
constant region domains, CH1, CH2 and CH3, but does not include the heavy
chain variable
region.
The functional fragments of antibodies, such as Fab, F(ab')2, and Fv that are
capable of
binding to macrophages, are described as follows: ( 1 ) Fab, the fragment
which contains a
monovalent antigen-binding fragment of an antibody molecule, can be produced
by digestion of
whole antibody with the enzyme papain to yield an intact light chain and a
portion of one heavy
chain; (2) Fab', the fragment of an antibody molecule that can be obtained by
treating whole
antibody with pepsin, followed by reduction, to yield an intact light chain
and a portion of the
heavy chain; two Fab' fragments are obtained per antibody molecule; (3)
(Fab')2, the fragment
of the antibody that can be obtained by treating whole antibody with the
enzyme pepsin without
subsequent reduction; F(ab')2 is a dimer of two Fab' fragments held together
by two disulfide
bonds; (4) Fv, defined as a genetically engineered fragment containing the
variable region of the
light chain and the variable region of the heavy chain expressed as two
chains; and (5) Single
chain antibody ("SCA"), a genetically engineered molecule containing the
variable region of the
light chain and the variable region of the heavy chain, linked by a suitable
polypeptide linker as
a genetically fused single chain molecule.
Methods of producing polyclonal and monoclonal antibodies as well as fragments
thereof are well known in the art (See for example, Harlow and Lane,
Antibodies: A Laboratory
Manual, Cold Spring Harbor Laboratory, New York, 1988, incorporated herein by
reference).
Antibody fragments according to the present invention can be prepared by
proteolytic
hydrolysis of the antibody or by expression in E. coli or mammalian cells
(e.g. Chinese hamster
ovary cell culture or other protein expression systems) of DNA encoding the
fragment.
Antibody fragments can be obtained by pepsin or papain digestion of whole
antibodies by

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conventional methods. For example, antibody fragments can be produced by
enzymatic
cleavage of antibodies with pepsin to provide a SS fragment denoted F(ab')2.
This fragment can
be further cleaved using a thiol reducing agent, and optionally a blocking
group for the
sulfhydryl groups resulting from cleavage of disulfide linkages, to produce
3.5S Fab'
monovalent fragments. Alternatively, an enzymatic cleavage using pepsin
produces two
monovalent Fab' fragments and an Fc fragment directly. These methods are
described, for
example, by Goldenberg, U.S. Pat. Nos. 4,036,945 and 4,331,647, and references
contained
therein, which patents are hereby incorporated by reference in their entirety.
See also Porter, R.
R. [Biochem. J. 73: 119-126 (1959)]. Other methods of cleaving antibodies,
such as separation
of heavy chains to form monovalent light-heavy chain fragments, further
cleavage of fragments,
or other enzymatic, chemical, or genetic techniques may also be used, so long
as the fragments
bind to the antigen that is recognized by the intact antibody.
Fv fragments comprise an association of VH and VL chains. This association may
be
noncovalent, as described in mbar et al. [Proc. Nat'1 Acad. Sci. USA 69:2659-
62 (19720].
Alternatively, the variable chains can be linked by an intermolecular
disulfide bond or cross
linked by chemicals such as glutaraldehyde. Preferably, the Fv fragments
comprise VH and VL
chains connected by a peptide linker. These single-chain antigen binding
proteins (sFv) are
prepared by constructing a structural gene comprising DNA sequences encoding
the VH and VL
domains connected by an oligonucleotide. The structural gene is inserted into
an expression
vector, which is subsequently introduced into a host cell such as E. coli. The
recombinant host
cells synthesize a single polypeptide chain with a linker peptide bridging the
two V domains.
Methods for producing sFvs are described, for example, by [Whitlow and
Filpula, Methods 2:
97-105 (1991); Bird et al., Science 242:423-426 (1988); Pack et al.,
Bio/Technology 11:1271-77
(1993); and U.S. Pat. No. 4,946,778, which is hereby incorporated by reference
in its entirety.
Another form of an antibody fragment is a peptide coding for a single
complementarity-
determining region (CDR). CDR peptides ("minimal recognition units") can be
obtained by
constructing genes encoding the CDR of an antibody of interest. Such genes are
prepared, for
example, by using the polymerase chain reaction to synthesize the variable
region from RNA of
antibody-producing cells. See, for example, Larrick and Fry [Methods, 2: 106-
10 (1991)].
Humanized forms of non-human (e.g., marine) antibodies are chimeric molecules
of
immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab,
Fab', F(ab') or

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other antigen-binding subsequences of antibodies) which contain minimal
sequence derived
from non-human immunoglobulin. Humanized antibodies include human
immunoglobulins
(recipient antibody) in which residues from a complementary determining region
(CDR) of the
recipient are replaced by residues from a CDR of a non-human species (donor
antibody) such as
S mouse, rat or rabbit having the desired specificity, affinity and capacity.
In some instances, Fv
framework residues of the human immunoglobulin are replaced by corresponding
non-human
residues. Humanized antibodies may also comprise residues which are found
neither in the
recipient antibody nor in the imported CDR or framework sequences. In general,
the humanized
antibody will comprise substantially all of at least one, and typically two,
variable domains, in
which all or substantially all of the CDR regions correspond to those of a non-
human
immunoglobulin and all or substantially all of the FR regions are those of a
human
immunoglobulin consensus sequence. The humanized antibody optimally also will
comprise at
least a portion of an immunoglobulin constant region (Fc), typically that of a
human
immunoglobulin [Jones et al., Nature, 321:522-S2S (1986); Riechmann et al.,
Nature, 332:323
329 (1988); and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)].
Methods for humanizing non-human antibodies are well known in the art.
Generally, a
humanized antibody has one or more amino acid residues introduced into it from
a source which
is non-human. These non-human amino acid residues are often referred to as
import residues,
which are typically taken from an import variable domain. Humanization can be
essentially
performed following the method of Winter and co-workers [Jones et al., Nature,
321:522-S2S
(1986); Riechmann et al., Nature 332:323-327 (1988); Verhoeyen et al.,
Science, 239:1534-
1536 (1988)], by substituting rodent CDRs or CDR sequences for the
corresponding sequences
of a human antibody. Accordingly, such humanized antibodies are chimeric
antibodies (LJ.S.
Pat. No. 4,816,567), wherein substantially less than an intact human variable
domain has been
substituted by the corresponding sequence from a non-human species. In
practice, humanized
antibodies are typically human antibodies in which some CDR residues and
possibly some FR
residues are substituted by residues from analogous sites in rodent
antibodies.
Human antibodies can also be produced using various techniques known in the
art,
including phage display libraries [Hoogenboom and Winter, J. Mol. Biol.,
227:381 (1991);
Marks et al., J. Mol. Biol., 222:581 (1991)]. The techniques of Cole et al.
and Boerner et al. are
also available for the preparation of human monoclonal antibodies (Cole et
al., Monoclonal

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Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boerner et al.,
J. Immunol.,
147(1):86-95 (1991)]. Similarly, human antibodies can be made by introduction
of human
immunoglobulin loci into transgenic animals, e.g., mice in which the
endogenous
immunoglobulin genes have been partially or completely inactivated. Upon
challenge, human
antibody production is observed, which closely resembles that seen in humans
in all respects,
including gene rearrangement, assembly, and antibody repertoire. This approach
is described,
for example, in U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126;
5,633,425;
5,661,016, and in the following scientific publications: Marks et al.,
Bio/Technology 10,: 779-
783 (1992); Lonberg et al., Nature 368: 856-859 (1994); Morrison, Nature 368
812-13 (1994);
Fishwild et al., Nature Biotechnology 14, 845-S1 (1996); Neuberger, Nature
Biotechnology 14:
826 (1996); and Lonberg and Huszar, Intern. Rev. Immunol. 13, 65-93 (1995).
Preferably, the antibody of this aspect of the present invention specifically
binds at least
one epitope of the polypeptide variants of the present invention. As used
herein, the term
"epitope" refers to any antigenic determinant on an antigen to which the
paratope of an antibody
binds.
Epitopic determinants usually consist of chemically active surface groupings
of
molecules such as amino acids or carbohydrate side chains and usually have
specific three
dimensional structural characteristics, as well as specific charge
characteristics.
Optionally, a unique epitope may be created in a variant due to a change in
one or more
post-translational modifications, including but not limited to glycosylation
and/or
phosphorylation, as described below. Such a change may also cause a new
epitope to be
created, for example through removal of glycosylation at a particular site.
An epitope according to the present invention may also optionally comprise
part or all of
a unique sequence portion of a variant according to the present invention in
combination with at
least one other portion of the variant which is not contiguous to the unique
sequence portion in
the linear polypeptide itself, yet which are able to form an epitope in
combination. One or more
unique sequence portions may optionally combine with one or more other non-
contiguous
portions of the variant (including a portion which may have high homology to a
portion of the
known protein) to form an epitope.
Immunoassays

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In another embodiment of the present invention, an immunoassay can be used to
qualitatively or quantitatively detect and analyze markers in a sample. This
method comprises:
providing an antibody that specifically binds to a marker; contacting a sample
with the antibody;
and detecting the presence of a complex of the antibody bound to the marker in
the sample.
To prepare an antibody that specifically binds to a marker, purified protein
markers can
be used. Antibodies that specifically bind to a protein marker can be prepared
using any suitable
methods known in the art.
After the antibody is provided, a marker can be detected and/or quantified
using any of a
number of well recognized immunological binding assays. Useful assays include,
for example,
an enzyme immune assay (EIA) such as enzyme-linked immunosorbent assay
(ELISA), a
radioimmune assay (RIA), a Western blot assay, or a slot blot assay see, e.g.,
U.S. Pat. Nos.
4,366,241; 4,376,110; 4,517,288; and 4,837,168). Generally, a sample obtained
from a subject
can be contacted with the antibody that specifically binds the marker.
Optionally, the antibody can be fixed to a solid support to facilitate washing
and
subsequent isolation of the complex, prior to contacting the antibody with a
sample. Examples
of solid supports include but are not limited to glass or plastic in the form
of, e.g., a microtiter
plate, a stick, a bead, or a microbead. Antibodies can also be attached to a
solid support.
After incubating the sample with antibodies, the mixture is washed and the
antibody
marker complex formed can be detected. This can be accomplished by incubating
the washed
mixture with a detection reagent. Alternatively, the marker in the sample can
be detected using
an indirect assay, wherein, for example, a second, labeled antibody is used to
detect bound
marker-specific antibody, and/or in a competition or inhibition assay wherein,
for example, a
monoclonal antibody which binds to a distinct epitope of the marker are
incubated
simultaneously with the mixture.
Throughout the assays, incubation and/or washing steps may be required after
each
combination of reagents. Incubation steps can vary from about 5 seconds to
several hours,
preferably from about 5 minutes to about 24 hours. However, the incubation
time will depend
upon the assay format, marker, volume of solution, concentrations and the
like. Usually the
assays will be carried out at ambient temperature, although they can be
conducted over a range
of temperatures, such as 10 °C to 40 °C.

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The immunoassay can be used to determine a test amount of a marker in a sample
from a
subject. First, a test amount of a marker in a sample can be detected using
the immunoassay
methods described above. If a marker is present in the sample, it will form an
antibody-marker
complex with an antibody that specifically binds the marker under suitable
incubation
conditions described above. The amount of an antibody-marker complex can
optionally be
determined by comparing to a standard. As noted above, the test amount of
marker need not be
measured in absolute units, as long as the unit of measurement can be compared
to a control
amount and/or signal.
Preferably used are antibodies which specifically interact with the
polypeptides of the
present invention and not with wild type proteins or other isoforms thereof,
for example. Such
antibodies are directed, for example, to the unique sequence portions of the
polypeptide variants
of the present invention, including but not limited to bridges, heads, tails
and insertions described
in greater detail below. Preferred embodiments of antibodies according to the
present invention
are described in greater detail with regard to the section entitled
"Antibodies".
Radio-immunoassay (RIA): In one version, this method involves precipitation of
the
desired substrate and in the methods detailed hereinbelow, with a specific
antibody and
radiolabelled antibody binding protein (e.g., protein A labeled with 1125)
immobilized on a
precipitable carrier such as agarase beads. The number of counts in the
precipitated pellet is
proportional to the amount of substrate.
In an alternate version of the RIA, a labeled substrate and an unlabelled
antibody binding
protein are employed. A sample containing an unknown amount of substrate is
added in varying
amounts. The decrease in precipitated counts from the labeled substrate is
proportional to the
amount of substrate in the added sample.
Enzyme linked immunosorbent assay (ELISA): This method involves fixation of a
sample
(e.g., fixed cells or a proteinaceous solution) containing a protein substrate
to a surface such as a
well of a microtiter plate. A substrate specific antibody coupled to an enzyme
is applied and
allowed to bind to the substrate. Presence of the antibody is then detected
and quantitated by a
colorimetric reaction employing the enzyme coupled to the antibody. Enzymes
commonly
employed in this method include horseradish peroxidase and alkaline
phosphatase. If well
calibrated and within the linear range of response, the amount of substrate
present in the sample

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is proportional to the amount of color produced. A substrate standard is
generally employed to
improve quantitative accuracy.
Western blot: This method involves separation of a substrate from other
protein by means
of an acrylamide gel followed by transfer of the substrate to a membrane
(e.g., nylon or PVDF).
Presence of the substrate is then detected by antibodies specific to the
substrate, which are in turn
detected by antibody binding reagents. Antibody binding reagents may be, for
example, protein
A, or other antibodies. Antibody binding reagents may be radiolabelled or
enzyme linked as
described hereinabove. Detection may be by autoradiography, colorimetric
reaction or
chemiluminescence. This method allows both quantitation of an amount of
substrate and
determination of its identity by a relative position on the membrane which is
indicative of a
migration distance in the acrylamide gel during electrophoresis.
Immunohistochemical analysis: This method involves detection of a substrate in
situ in
fixed cells by substrate specific antibodies. The substrate specific
antibodies may be enzyme
linked or linked to fluorophores. Detection is by microscopy and subjective
evaluation. If
enzyme linked antibodies are employed, a colorimetric reaction may be
required.
Fluorescence activated cell sorting (FACS): This method involves detection of
a
substrate in situ in cells by substrate specific antibodies. The substrate
specific antibodies are
linked to fluorophores. Detection is by means of a cell sorting machine which
reads the
wavelength of light emitted from each cell as it passes through a light beam.
This method may
employ two or more antibodies simultaneously.
Radio-imaging Methods
These methods include but are not limited to, positron emission tomography
(PET)
single photon emission computed tomography (SPELT). Both of these techniques
are non-
invasive, and can be used to detect and/or measure a wide variety of tissue
events and/or
functions, such as detecting cancerous cells for example. Unlike PET, SPELT
can optionally be
used with two labels simultaneously. SPELT has some other advantages as well,
for example
with regard to cost and the types of labels that can be used. For example, US
Patent No.
6,696,686 describes the use of SPELT for detection of breast cancer, and is
hereby incorporated
by reference as if fully set forth herein.

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Display Libraries
According to still another aspect of the present invention there is provided a
display
library comprising a plurality of display vehicles (such as phages, viruses or
bacteria) each
displaying at least 6, at least 7, at least 8, at least 9, at least 10, 10-15,
12-17, 15-20, 15-30 or 20-
50 consecutive amino acids derived from the polypeptide sequences of the
present invention.
Methods of constructing such display libraries are well known in the art. Such
methods
are described in, for example, Young AC, et al., "The three-dimensional
structures of a
polysaccharide binding antibody to Cryptococcus neoformans and its complex
with a peptide
from a phage display library: implications for the identification of peptide
mimotopes" J Mol
Biol 1997 Dec 12;274(4):622-34; Giebel LB et al. "Screening of cyclic peptide
phage libraries
identifies ligands that bind streptavidin with high affinities" Biochemistry
1995 Nov
28;34(47):15430-5; Davies EL et al., "Selection of specific phage-display
antibodies using
libraries derived from chicken immunoglobulin genes" J Immunol Methods 1995
Oct
12;186(1):125-35; Jones C RT al. "Current trends in molecular recognition and
bioseparation" J
Chromatogr A 1995 Jul 14;707(1):3-22; Deng SJ et al. "Basis for selection of
improved
carbohydrate-binding single-chain antibodies from synthetic gene libraries"
Proc Natl Acad Sci
U S A 1995 May 23;92(11):4992-6; and Deng SJ et al. "Selection of antibody
single-chain
variable fragments with improved carbohydrate binding by phage display" J Biol
Chem 1994
Apr 1;269(13):9533-8, which are incorporated herein by reference.
The following sections relate to Candidate Marker Examples (first section) and
to
Experimental Data for these Marker Examples (second section).
CANDIDATE MARKER EXAMPLES SECTION
This Section relates to Examples of sequences according to the present
invention,
including illustrative methods of selection thereof.
Description of the methodology undertaken to uncover the biomolecular
sequences of
the present invention
Human ESTs and cDNAs were obtained from GenBank versions 136 (June 15, 2003
ftp.ncbi.nih.gov/genbank/release.notes/gb136.release.notes); NCBI genome
assembly of April
2003; Refseq sequences from June 2003; Genbank version 139 (December 2003);
Human

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Genome from NCBI (Build 34) (from Oct 2003); and RefSeq sequences from
December 2003;
and from the LifeSeq library of Incyte Corporation (ESTs only; Wilmington, DE,
USA). With
regard to GenBank sequences, the human EST sequences from the EST (GBEST)
section and
the human mRNA sequences from the primate (GBPRI) section were used; also the
human
nucleotide RefSeq mRNA sequences were used (see for example
www.ncbi.nlm.nih.gov/Genbank/GenbankOverview.html and for a reference to the
EST section,
see www.ncbi.nlm.nih.gov/dbEST/; a general reference to dbEST, the EST
database in
GenBank, may be found in Boguski et al, Nat Genet. 1993 Aug;4(4):332-3; all of
which are
hereby incorporated by reference as if fully set forth herein).
Novel splice variants were predicted using the LEADS clustering and assembly
system
as described in Sorek, R., Ast, G. & Graur, D. Alu-containing exons are
alternatively spliced.
Genome Res 12, 1060-7 (2002); US patent No: 6,625,545; and U.S. Pat. Appl. No.
10/426,002,
published as US20040101876 on May 27 2004; all of which are hereby
incorporated by
reference as if fully set forth herein. Briefly, the software cleans the
expressed sequences from
repeats, vectors and immunoglobulins. It then aligns the expressed sequences
to the genome
taking alternatively splicing into account and clusters overlapping expressed
sequences into
"clusters" that represent genes or partial genes.
These were annotated using the GeneCarta (Compugen, Tel-Aviv, Israel)
platform. The
GeneCarta platform includes a rich pool of annotations, sequence information
(particularly of
spliced sequences), chromosomal information, alignments, and additional
information such as
SNPs, gene ontology terms, expression profiles, functional analyses, detailed
domain structures,
known and predicted proteins and detailed homology reports.
A brief explanation is provided with regard to the method of selecting the
candidates.
However, it should noted that this explanation is provided for descriptive
purposes only, and is
not intended to be limiting in any way. The potential markers were identified
by a computational
process that was designed to find genes and/or their splice variants that are
over-expressed in
tumor tissues, by using databases of expressed sequences. Various parameters
related to the
information in the EST libraries, determined according to a manual
classification process, were
used to assist in locating genes and/or splice variants thereof that are over-
expressed in
cancerous tissues. The detailed description of the selection method is
presented in Example 1

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below. The cancer biomarkers selection engine and the following wet validation
stages are
schematically summarized in Figure 1.
EXAMPLE 1
Identification of differentially expressed gene products - Algorithm
In order to distinguish between differentially expressed gene products and
constitutively
expressed genes (i.e., house keeping genes ) an algorithm based on an analysis
of frequencies was
configured. A specific algorithm for identification of transcripts over
expressed in cancer is
described hereinbelow.
Dry analysis
Library annotation - EST libraries are manually classified according to:
~ Tissue origin
~ Biological source - Examples of frequently used biological sources for
construction of EST libraries include cancer cell-lines; normal tissues;
1 S cancer tissues; fetal tissues; and others such as normal cell lines and
pools
of normal cell-lines, cancer cell-lines and combinations thereof. A
specific description of abbreviations used below with regard to these
tissues/cell lines etc is given above.
~ Protocol of library construction - various methods are known in
the art for library construction including normalized library construction;
non-normalized library construction; subtracted libraries; ORESTES and
others. It will be appreciated that at times the protocol of library
construction is not indicated.
The following rules are followed:
EST libraries originating from identical biological samples are considered as
a single
library.
EST libraries which included above-average levels of contamination, such as
DNA
contamination for example, were eliminated. The presence of such contamination
was determined
as follows. For each library, the number of unspliced ESTs that are not fully
contained within
other spliced sequences was counted. If the percentage of such sequences (as
compared to all
other sequences) was at least 4 standard deviations above the average for all
libraries being

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analyzed, this library was tagged as being contaminated and was eliminated
from further
consideration in the below analysis (see also Sorek, R. & Safer, H.M. A novel
algorithm for
computational identification of contaminated EST libraries. Nucleic Acids Res
31, 1067-74
(2003)for further details).
Clusters (genes) having at least five sequences including at least two
sequences from the
tissue of interest were analyzed. Splice variants were identified by using the
LEADS software
package as described above.
EXAMPLE 2
Identification of genes over expressed in cancer.
Two different scoring algorithms were developed.
Libraries score -candidate sequences which are supported by a number of cancer
libraries,
are more likely to serve as specific and effective diagnostic markers.
The basic algorithm - for each cluster the number of cancer and normal
libraries
contributing sequences to the cluster was counted. Fisher exact test was used
to check if cancer
libraries are significantly over-represented in the cluster as compared to the
total number of
cancer and normal libraries.
Library counting: Small libraries (e.g., less than 1000 sequences) were
excluded from
consideration unless they participate in the cluster. For this reason, the
total number of libraries is
actually adjusted for each cluster.
Clones no. score - Generally, when the number of ESTs is much higher in the
cancer
libraries relative to the normal libraries it might indicate actual over-
expression.
The algorithm -
Clone counting: For counting EST clones each library protocol class was given
a weight
based on our belief of how much the protocol reflects actual expression
levels:
(i) non-normalized : 1
(ii) normalized : 0.2
(iii) all other classes : 0.1
Clones number score - The total weighted number of EST clones from cancer
libraries
was compared to the EST clones from normal libraries. To avoid cases where one
library

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contributes to the majority of the score, the contribution of the library that
gives most clones for a
given cluster was limited to 2 clones.
The score was computed as
c+1
n+1
N
where:
c - weighted number of "cancer" clones in the cluster.
C- weighted number of clones in all "cancer" libraries.
n - weighted number of "normal" clones in the cluster.
N- weighted number of clones in all "normal" libraries.
Clones number score significance - Fisher exact test was used to check if EST
clones from
cancer libraries are significantly over-represented in the cluster as compared
to the total number
of EST clones from cancer and normal libraries.
Two search approaches were used to find either general cancer-specific
candidates or
tumor specific candidates.
~ Libraries/sequences originating from tumor tissues are counted as well as
libraries originating from cancer cell-lines ("normal" cell-lines were
ignored).
~ Only libraries/sequences originating from tumor tissues are counted
EXAMPLE 3
Identification of tissue specific genes
For detection of tissue specific clusters, tissue libraries/sequences were
compared to the
total number of libraries/sequences in cluster. Similar statistical tools to
those described in above
were employed to identify tissue specific genes. Tissue abbreviations are the
same as for
cancerous tissues, but are indicated with the header "normal tissue".
The algorithm - for each tested tissue T and for each tested cluster the
following were
examined:

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1. Each cluster includes at least 2 libraries from the tissue T. At least 3
clones
(weighed - as described above) from tissue T in the cluster; and
2. Clones from the tissue T are at least 40 % from all the clones
participating in the
tested cluster
Fisher exact test P-values were computed both for library and weighted clone
counts to
check that the counts are statistically significant.
EXAMPLE 4
Identification of splice variants over expressed in cancer of clusters which
are not over
expressedin cancer
Cancer-specific splice variants containing a unique region were identified.
Identification of unique sequence regions in splice variants
A Region is defined as a group of adjacent exons that always appear or do not
appear
together in each splice variant.
A "segment" (sometimes referred also as "seg" or "node") is defined as the
shortest
contiguous transcribed region without known splicing inside.
Only reliable ESTs were considered for region and segment analysis. An EST was
defined as unreliable i~
(i) Unspliced;
(ii) Not covered by RNA;
(iii) Not covered by spliced ESTs; and
(iv) Alignment to the genome ends in proximity of long poly-A stretch or
starts in
proximity of long poly-T stretch.
Only reliable regions were selected for further scoring. Unique sequence
regions were
considered reliable if:
(i) Aligned to the genome; and
(ii) Regions supported by more than 2 ESTs.
The algorithm
Each unique sequence region divides the set of transcripts into 2 groups:
(i) Transcripts containing this region (group TA).
(ii) Transcripts not containing this region (group TB).

.r
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The set of EST clones of every cluster is divided into 3 groups:
(i) Supporting (originating from) transcripts of group TA (S1).
(ii) Supporting transcripts of group TB (S2).
(iii) Supporting transcripts from both groups (S3).
Library and clones number scores described above were given to S 1 group.
Fisher Exact Test P-values were used to check if
S1 is significantly enriched by cancer EST clones compared to S2; and
S 1 is significantly enriched by cancer EST clones compared to cluster
background
(S1+S2+S3).
Identification of unique sequence regions and division of the group of
transcripts
accordingly is illustrated in Figure 2. Each of these unique sequence regions
corresponds to a
segment, also termed herein a "node".
Region 1: common to all transcripts, thus it is not considered for detecting
variants;
Region 2: specific to Transcript 1; Region 3: specific to Transcripts 2 and 3;
Region 4: specific
to Transcript 3; Region 5: specific to Transcript 1 and 2; Region 6: specific
to Transcript 1.
EXAMPLE 5
Identification of cancer specific splice variants of genes over expressed in
cancer
A search for EST supported (no mRNA) regions for genes of
(i) known cancer markers
(ii) Genes shown to be over-expressed in cancer in published micro-array
experiments.
Reliable EST supported-regions were defined as supported by minimum of one of
the
following:
(i) 3 spliced ESTs; or
(ii) 2 spliced ESTs from 2 libraries;
(iii) 10 unspliced ESTs from 2 libraries, or
(iv) 3libraries.

CA 02555509 2006-07-26
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Actual Marker Examples
The following examples relate to specific actual marker examples.
EXPERIMENTAL EXAMPLES SECTION
This Section relates to Examples describing experiments involving these
sequences, and
illustrative, non-limiting examples of methods, assays and uses thereof. The
materials and
experimental procedures are explained first, as all experiments used them as a
basis for the work
that was performed.
The markers of the present invention were tested with regaxd to their
expression in
various cancerous and non-cancerous tissue samples. A description of the
samples used in the
panel is provided in Table 2 below. A description of the samples used in the
normal tissue panel
is provided in Table 3 below. Tests were then performed as described in the
"Materials and
Experimental Procedures" sectionbelow.
Table 2: Tissue samples in testin~panel
eg nder/a$


sam 1e rename Lot No. sourceatholo Gradea


BiochaiAdenocarcinom
1-B-Adeno G1 A504117 a 1 F/29


BiochaiAdenocarcinom
2-B-Adeno G1 A504118 n a 1 M/64


BiochaiAdenocarcinom
95-B-Adeno G1 A610063 a 1 F/54


BiochaiAdenocarcinom
12-B-Adeno G2 A504119 n a 2 F/74


BiochaiAdenocarcinom
75-B-Adeno G2 A609217 n a 2 M/65


77-B-Adeno G2 A608301 BiochaiAdenocarcinom2 M/44



Image

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180
BiochaiSquamous
Cell


80-B-Squamous G2 A609I63 Carcinoma 2 74


iochaiSquamous
Cell


18-B-Squamous G2-3 A503387 n Carcinoma 2-3 M/63


iochaiSquamous


81-B-Squamous G3 609076 n Carcinoma 3 53


BiochaiSquamous
Cell


79-B-Squamous G3 609018 Carcinoma 3 67


BiochaiSquamous


20-B-Squamous A501121 Carcinoma 64


iochaiSquamous


22-B-Squamous A503386 n Carcinoma M/48


iochaiSquamous
Cell


88-B-Squamous A609219 Carcinoma 64


BiochaiSquamous


100-B-Squamous 409017 Carcinoma 64


Squamous


23-CG-Squamous CG-109 IchilovCarcinoma 65
(1)


Squamous


24-CG-Squamous CG-123 IchilovCarcinoma M/76


Squamous


25-CG-Squamous CG-204 IchilovCarcinoma M/72


iochaiLarge Cell


87-B-Large cell G3 A609165 Carcinoma 3 F/47


Biochai


38-B-Large cell A504113 Large cell 58


Biochai


39-B-Large cell A504114 n Large cell F/35


iochaiurge Cell


82-B-Large cell A609170 n euroendocrine M/68



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Carcinoma


Biochai


30-B-Small cell carci A501389 small cell 3 34
G3


Biochai


31-B-Small cell carci A501390 small cell 3 /59
G3


iochai


32-B-Small cell carci A501391 n small cell 3 M/30
G3


iochai


33-B-Small cell carci A504115 small cell 3
G3


BiochaiSmall Cell


86-B-Small cell carci 608032 Carcinoma 3 /52
G3


BiochaiSmall Cell


83-B-Small cell carci A609162 Carcinoma /47


iochaiSmall Cell


84-B-Small cell carci A609167 n Carcinoma F/59


iochaiSmall Cell


85-B-Small cell carci A609169 Carcinoma M/66


iochai


6-B-N M44 A501124 ormal M44 /61


Biochai


47-B-N 503205 ormal PM 26


Biochai


48-B-N A503206 ormal PM 44


iochai


49-B-N A503384 n ormal PM M/27


iochai


50-B-N A503385 n ormal PM M/28


iochaiormal (Pool
2)


90-B-N A608152 M ool
2


91-B-N A607257 Biochaiormal (Pool ool
2) 2



CA 02555509 2006-07-26
182
n M


iochai


92-B-N 503204 ormal PM 28


Ambio


93-Am-N 111P0103An ormal PM /61


Ambio


96-Am-N 36853 ormal PM /43


Ambio


97-Am-N 36854 ormal PM M/46


Ambio


98-Am-N 36855 n ormal PM F/72


bio


99-Am-N 36856 n ormal PM M/31


Table 3: Tissue samples in normal panel:
Lot no. Source Tissue Pathology Sex/Age


1-Am-Colon (C71 071P10B mbion Colon PM F/43
)


2-B-Coion (C69) 411078 BiochainColon PM-Pool M&F
of 10


3-CI-Colon (C70) 1110101 ClontechColon PM-Pool M&F
of 3


-Am-Small Intestine091P0201mbion Small IntestinePM M/75


5-B-Small IntestineA501158 BiochainSmall IntestinePM M/63


6-B-Rectum A605138 BiochainRectum PM M/25


7-B-Rectum A610297 BiochainRectum PM M/24


8-B-Rectum A610298 BiochainRectum PM M/27


9-Am-Stomach 110P04A mbion Stomach PM M/16


10-B-Stomach A501159 BiochainStomach PM M/24


11-B-Esophagus 603814 BiochainEsophagus PM M/26


12-B-Esophagus A603813 BiochainEsophagus PM M/41


13-Am-Pancreas 071P25C mbion Pancreas PM M/25


14-CG-Pancreas CG-255-2IchilovPancreas PM M/75



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15-B-Lung A409363 BiochainLung PM F/26


16-Am-Lung (L93) 111P0103Ambion Lung PM F/61


17-B-Lung (L92) A503204 BiochainLung PM M/28


18-Am-Ovary (047) 061P43A mbion Ovary PM F/16


19-B-Ovary (048) A504087 BiochainOvary PM F/51


20-B-Ovary (046) A504086 BiochainOvary PM F/41


21-Am-Cervix lOIPOIOIAmbion Cervix PM F/40


22-B-Cervix A408211 BiochainCervix PM F/36


23-B-Cervix A504089 BiochainCervix PM-Pool M&F
of 5


24-B-Uterus A411074 BiochainUterus PM-Pool M&F
of 10


25-B-Uterus A409248 BiochainUterus PM F/43


26-B-Uterus A504090 BiochainUterus PM-Pool M&F
of 5


27-B-Bladder A501157 BiochainBladder PM M/29


28-Am-Bladder 071P02C mbion Bladder PM M/20


29-B-Bladder A504088 BiochainBladder PM-Pool M&F
of 5


30-Am-Placenta 021P33A mbion Placenta PB F/33


31-B-Placenta A410165 BiochainPlacenta PB F/26


32-B-Placenta A411073 BiochainPlacenta PB-Pool M&F
of 5


33-B-Breast (B59) A607155 BiochainBreast PM F/36


34-Am-Breast (B63)26486 mbion Breast PM F/43


35-Am-Breast (B64)23036 mbion Breast PM F/57


36-CI-Prostate 1070317 ClontechProstate PB-Pool M&F
(P53) of 47


37-Am-Prostate 061P04A mbion Prostate PM M/47
(P42)


38-Am-Prostate 25955 mbion Prostate PM M/62
(P59)


39-Am-Testis 111P0104Ambion Testis PM M/25


0-B-Testis A411147 BiochainTestis PM M/74


41-CI-Testis 1110320 ClontechTestis PB-Pool M&F
of 45


42-CG-Adrenal CG-184-101chilovAdrenal PM F/81


43-B-Adrenal A610374 BiochainAdrenal PM F/83


4-B-Heart A411077 BiochainHeart PB-Pool M&F
of 5



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45-CG-Heart CG-255-9IchilovHeart PM M/75


6-CG-Heart CG-227-1IchilovHeart PM F/36


47-Am-Liver 081POlOlAmbion Liver PM M/64


48-CG-Liver CG-93-3 IchilovLiver PM F/19


9-CG-Liver CG-124-4IchilovLiver PM F/34


50-CI-BM 1110932 ClontechBone Marrow PM-Pool M&F
of 8


51-CGEN-Blood WBC#5 CGEN Blood M


52-CGEN-Blood WBC#4 CGEN Blood M


53-CGEN-Blood C#3 CGEN Blood M


54-CG-Spleen CG-267 IchilovSpleen PM F/25


55-CG-Spleen 111P0106Bmbion Spleen PM M/25


56-CG-Spleen A409246 BiochainSpleen PM F/12


56-CG-Thymus CG-98-7 IchilovThymus PM F/28


58-Am-Thymus lOIPOlOlAmbion hymns PM M/14


59-B-Thymus A409278 BiochainThymus PM M/28


60-B-Thyroid A610287 BiochainThyroid PM M/27


61-B-Thyroid A610286 BiochainThyroid PM M/24


62-CG-Thyroid CG-119-2Ichilovhyroid PM F/66


63-CI-Salivary 1070319 ClontechSalivary PM-Pool M&F
Gland Gland of 24


64-Am-Kidney 111PO1O1Bmbion Kidney PM-Pool M&F
of 14


65-CI-Kidney 1110970 ClontechKidney PM-Pool M&F
of 14


66-B-Kidney A411080 BiochainKidney PM-Pool M&F
of 5


67-CG-Cerebellum CG-183-5IchilovCerebellum PM M/74


68-CG-Cerebellum CG-212-5IchilovCerebellum PM M/54


69-B-Brain 411322 BiochainBrain PM M/28


70-CI-Brain 1120022 ClontechBrain PM-Pool M&F
of 2


71-B-Brain A411079 BiochainBrain PM-Pool M&F
of 2


72-CG-Brain CG-151-1IchilovBrain PM F/86


73-Am-Skeletal 1O1P013Ambion Skeletal PM F/28
Muscle Muscle


74-CI-Skeletal 1061038 ClontechSkeletal PM-Pool M&F
Muscle Muscle of 2



CA 02555509 2006-07-26
185
Materials and Experimental Procedures
RNA preparation - RNA was obtained from Clontech (Franklin Lakes, NJ USA
07417,
www.clontech.com), BioChain Inst. Inc. (Hayward, CA 94545 USA
www.biochain.com), ABS
(Wilmington, DE 19801, USA, http://www.absbioreagents.com) or Ambion (Austin,
TX 78744
USA, http://www.ambion.com). Alternatively, RNA was generated from tissue
samples using
TRI-Reagent (Molecular Research Center), according to Manufacturer's
instructions. Tissue and
RNA samples were obtained from patients or from postmortem. Total RNA samples
were
treated with DNaseI (Ambion) and purified using RNeasy columns (Qiagen).
RT PCR - Purified RNA (1 pg) was mixed with 150 ng Random Hexamer primers
(Invitrogen) and 500 pM dNTP in a total volume of 15.6 ~1. The mixture was
incubated for 5
min at 65 °C and then quickly chilled on ice. Thereafter, 5 ~1 of SX
SuperscriptII first strand
buffer (Invitrogen), 2.4p,1 O.1M DTT and 40 units RNasin (Promega) were added,
and the
mixture was incubated for 10 min at 25 °C, followed by further
incubation at 42 °C for 2 min.
Then, 1 p1 (200units) of SuperscriptII (Invitrogen) was added and the reaction
(final volume of
25p1) was incubated for 50 min at 42 °C and then inactivated at 70
°C for lSmin. The resulting
cDNA was diluted 1:20 in TE buffer (10 mM Tris pH=8, 1 mM EDTA pH=8).
Real-Time RT PCR analysis- cDNA (5 w1), prepared as described above, was used
as a
template in Real-Time PCR reactions using the SYBR Green I assay (PE Applied
Biosystem)
with specific primers and UNG Enzyme (Eurogentech or ABI or Roche). The
amplification was
effected as follows: 50 °C for 2 min, 95 °C for 10 min, and then
40 cycles of 95 °C for lSsec,
followed by 60 °C for 1 min. Detection was performed by using the PE
Applied Biosystem SDS
7000. The cycle in which the reactions achieved a threshold level (Ct) of
fluorescence was
registered and was used to calculate the relative transcript quantity in the
RT reactions. The
relative quantity was calculated using the equation Q=efficiency~-~t. The
efficiency of the PCR
reaction was calculated from a standard curve, created by using serial
dilutions of several
reverse transcription (RT) reactions. To minimize inherent differences in the
RT reaction, the
resulting relative quantities were normalized to the geometric mean of the
relative quantities of
several housekeeping (HSKP) genes. Schematic summary of quantitative real-time
PCR

CA 02555509 2006-07-26
186
analysis is presented in Figure 3. As shown, the x-axis shows the cycle
number. The CT =
Threshold Cycle point, which is the cycle that the amplification curve crosses
the fluorescence
threshold that was set in the experiment. This point is a calculated cycle
number in which PCR
product signal is above the background level (passive dye ROX) and still in
the
Geometric/Exponential phase (as shown, once the level of fluorescence crosses
the
measurement threshold, it has a geometrically increasing phase, during which
measurements are
most accurate, followed by a linear phase and a plateau phase; for
quantitative measurements,
the latter two phases do not provide accurate measurements). The y-axis shows
the normalized
reporter fluorescence. It should be noted that this type of analysis provides
relative
quantification.
The sequences of the housekeeping genes measured in all the examples in
testing panel were as
follows:
Ubiquitin (GenBank Accession No. BC000449)
Ubiquitin Forward primer (SEQ ID NO: 326): ATTTGGGTCGCGGTTCTTG
Ubiquitin Reverse primer (SEQ ID NO: 327): TGCCTTGACATTCTCGATGGT
Ubiquitin-amplicon (SEQ ID NO: 328)
ATTTGGGTCGCGGTTCTTGTTTGTGGATCGCTGTGATCGTCACTTGACAATGCAGAT
CTTCGTGAAGACTCTGACTGGTAAGACCATCACCCTCGAGG
TTGAGCCCAGTGACACCATCGAGAATGTCAAGGCA
SDHA (GenBank Accession No. NM 004168)
SDHA Forward primer (SEQ ID NO: 329): TGGGAACAAGAGGGCATCTG
SDHA Reverse primer (SEQ ID NO: 330): CCACCACTGCATCAAATTCATG
SDHA-amplicon (SEQ ID NO: 331):
TGGGAACAAGAGGGCATCTGCTAAAGTTTCAGATTCCATTTCTGCTCAGTATCCAGT
AGTGGATCATGAATTTGATGCAGTGGTGG
PBGD (GenBank Accession No. BC019323),
PBGD Forward primer (SEQ ID NO: 332): TGAGAGTGATTCGCGTGGG

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187
PBGD Reverse primer (SEQ ID NO: 333): CCAGGGTACGAGGCTTTCAAT
PBGD-amplicon (SEQ ID NO: 334):
TGAGAGTGATTCGCGTGGGTACCCGCAAGAGCCAGCTTGCTCGCATACAGACGGAC
AGTGTGGTGGCAACATTGAAAGCCTCGTACCCTGG
HPRT1 (GenBank Accession No. NM_000194),
HPRT1 Forward primer (SEQ ID NO: 1295): TGACACTGGCAAAACAATGCA
HPRT1 Reverse primer (SEQ ID NO: 1296): GGTCCTTTTCACCAGCAAGCT
HPRT1-amplicon (SEQ ID NO: 1297):
TGACACTGGCAAAACAATGCAGACTTTGCTTTCCTTGGTCAGGCAGTATAATCCAA
AGATGGTCAAGGTCGCAAGCTTGCTGGTGAAAAGGACC
The sequences of the housekeeping genes measured in all the examples on normal
tissue
samples panel were as follows:
RPL19 (GenBank Accession No. NM_000981),
RPL19 Forward primer (SEQ ID NO: 1298): TGGCAAGAAGAAGGTCTGGTTAG
RPL19 Reverse primer (SEQ ID NO: 1420): TGATCAGCCCATCTTTGATGAG
RPL19 -amplicon (SEQ ID NO: 1630):
TGGCAAGAAGAAGGTCTGGTTAGACCCCAATGAGACCAATGAAATCGCCAATGCCA
ACTCCCGTCAGCAGATCCGGAAGCTCATCAAAGATGGGCTGATCA
TATA box (GenBank Accession No. NM_003194),
TATA box Forward primer (SEQ ID NO: 1631) : CGGTTTGCTGCGGTAATCAT
TATA box Reverse primer (SEQ ID NO: 1632): TTTCTTGCTGCCAGTCTGGAC
TATA box -amplicon (SEQ ID NO: 1633):
CGGTTTGCTGCGGTAATCATGAGGATAAGAGAGCCACGAACCACGGCACTGATTTT
CAGTTCTGGGAAAATGGTGTGCACAGGAGCCAAGAGTGAAGAACAGTCCAGACTG
GCAGCAAGAAA
Ubiquitin (GenBank Accession No. BC000449)
Ubiquitin Forward primer (SEQ ID NO: 326): ATTTGGGTCGCGGTTCTTG
Ubiquitin Reverse primer (SEQ ID NO: 327): TGCCTTGACATTCTCGATGGT

CA 02555509 2006-07-26
188
Ubiquitin-amplicon (SEQ ID NO: 328)
ATTTGGGTCGCGGTTCTTGTTTGTGGATCGCTGTGATCGTCACTTGACAATGCAGAT
CTTCGTGAAGACTCTGACTGGTAAGACCATCACCCTCGAGG
TTGAGCCCAGTGACACCATCGAGAATGTCAAGGCA
S SDHA (GenBank Accession No. NM_004168)
SDHA Forward primer (SEQ ID NO: 329): TGGGAACAAGAGGGCATCTG
SDHA Reverse primer (SEQ ID NO: 330): CCACCACTGCATCAAATTCATG
SDHA-amplicon (SEQ ID NO: 331):
TGGGAACAAGAGGGCATCTGCTAAAGTTTCAGATTCCATTTCTGCTCAGTATCCAGT
AGTGGATCATGAATTTGATGCAGTGGTGG
Oligonucleotide-based micro-array experiment protocol-
1 S Microarray fabrication
Microarrays (chips) were printed by pin deposition using the MicroGrid II MGII
600
robot from BioRobotics Limited (Cambridge, UK). 50-mer oligonucleotides target
sequences
were designed by Compugen Ltd (Tel-Aviv, IL) as described by A. Shoshan et al,
"Optical
technologies and informatics", Proceedings of SPIE. Vol 4266, pp. 86-95
(2001). The designed
oligonucleotides were synthesized and purified by desalting with the Sigma-
Genosys system
(The Woodlands, T~, US) and all of the oligonucleotides were joined to a C6
amino-modified
linker at the S' end, or being attached directly to CodeLink slides (Cat #25-
6700-O1. Amersham
Bioscience, Piscataway, NJ, US). The 50-mer oligonucleotides, forming the
target sequences,
were first suspended in Ultra-pure DDW (Cat # Ol-866-lA Kibbutz Beit-Haemek,
Israel) to a
concentration of SO~,M. Before printing the slides, the oligonucleotides were
resuspended in
300mM sodium phosphate (pH 8.5) to final concentration of 150mM and printed at
35-40%
relative humidity at 21 °C.
Each slide contained a total of 9792 features in 32 subarrays. Of these
features, 4224
features were sequences of interest according to the present invention and
negative controls that
were printed in duplicate. An additional 288 features (96 target sequences
printed in triplicate)
contained housekeeping genes from Human Evaluation Library2, Compugen Ltd,
Israel.

CA 02555509 2006-07-26
189
Another 384 features are E.coli spikes 1-6, which are oligos to E-Coli genes
which are
commercially available in the Array Control product (Array control- sense
oligo spots, Ambion
Inc. Austin, TX. Cat #1781, Lot #112K06).
Post-couplin processing of printed slides
After the spotting of the oligonucleotides to the glass (CodeLink) slides, the
slides were
incubated for 24 hours in a sealed saturated NaCI humidification chamber
(relative humidity 70-
75%).
Slides were treated for blocking of the residual reactive groups by incubating
them in
blocking solution at 50°C for 15 minutes (lOml/slide of buffer
containing O.1M Tris, SOmM
ethanolamine, 0.1% SDS). The slides were then rinsed twice with Ultra-pure DDW
(double
distilled water). The slides were then washed with wash solution (lOml/slide.
4X SSC, 0.1%
SDS)) at 50°C for 30 minutes on the shaker. The slides were then rinsed
twice with Ultra-pure
DDW, followed by drying by centrifugation for 3 minutes at 800 rpm.
Next, in order to assist in automatic operation of the hybridization protocol,
the slides
were treated with Ventana Discovery hybridization station barcode adhesives.
The printed
slides were loaded on a Bio-Optica (Milan, Italy) hematology staining device
and were
incubated for 10 minutes in SOmI of 3-Aminopropyl Triethoxysilane (Sigma A3648
lot
#122K589). Excess fluid was dried and slides were then incubated for three
hours in 20 mm/Hg
in a dark vacuum desiccator (Pelco 2251, Ted Pella, Inc. Redding CA).
The following protocol was then followed with the Genisphere 900-RP (random
primer),
with mini elute columns on the Ventana Discovery HybStationTM, to perform the
microarray
experiments. Briefly, the protocol was performed as described with regard to
the instructions
and information provided with the device itself. The protocol included cDNA
synthesis and
labeling. cDNA concentration was measured with the TBS-380 (Turner Biosystems.
Sunnyvale, CA.) PicoFlour, which is used with the OliGreen ssDNA Quantitation
reagent and
kit.
Hybridization was performed with the Ventana Hybridization device, according
to the
provided protocols (Discovery Hybridization Station Tuscon AZ).

CA 02555509 2006-07-26
190
The slides were then scanned with GenePix 4000B dual laser scanner from Axon
Instruments Inc, and analyzed by GenePix Pro 5.0 software.
Schematic summary of the oligonucleotide based microarray fabrication and the
experimental flow is presented in Figures 4 and 5.
Briefly, as shown in Figure 4, DNA oligonucleotides at 25uM were deposited
(printed)
onto Amersham 'CodeLink' glass slides generating a well defined 'spot'. These
slides are
covered with a long-chain, hydrophilic polymer chemistry that creates an
active 3-D surface that
covalently binds the DNA oligonucleotides 5'-end via the
C6-amine modification. This binding ensures that the fill length of the DNA
oligonucleotides is
available for hybridization to the cDNA and also allows lower background, high
sensitivity and
reproducibility.
Figure 5 shows a schematic method for performing the microarray experiments.
It
should be noted that stages on the left-hand or right-hand side may optionally
be performed in
any order, including in parallel, until stage 4 (hybridization). Briefly, on
the left-hand side, the
target oligonucleotides are being spotted on a glass microscope slide
(although optionally other
materials could be used) to form a spotted slide (stage 1). On the right hand
side, control sample
RNA and cancer sample RNA are Cy3 and Cy5 labeled, respectively (stage 2), to
form labeled
probes. It should be noted that the control and cancer samples come from
corresponding tissues
(for example, normal prostate tissue and cancerous prostate tissue).
Furthermore, the tissue
from which the RNA was taken is indicated below in the specific examples of
data for particular
clusters, with regard to overexpression of an oligonucleotide from a "chip"
(microarray), as for
example "prostate" for chips in which prostate cancerous tissue and normal
tissue were tested as
described above. In stage 3, the probes are mixed. In stage 4, hybridization
is performed to
form a processed slide. In stage S, the slide is washed and scanned to form an
image file,
followed by data analysis in stage 6.
The following clusters were found to be overexpressed in lung cancer:
W60282 PEA 1
F05068 PEA 1
H38804 PEA 1
HSENA78

CA 02555509 2006-07-26
191
T39971
(800299)
H14624
241644 PEA 1
225299 PEA 2
HSSTROL3
HUMTREFAC PEA 2
HSS 1 OOPCB
HSU33147 PEA 1
HUMCA1XIA
H61775
HUMGRPSE
HUMODCA
AA161187
866178
D56406 PEA 1
M85491 PEA 1
221368 PEA 1
HUMCA 1 XIA
820779
838144 PEA 2
244808 PEA 1
HUMOSTRO PEA 1 PEA 1
811723 PEA 3
A1076020
T23580
M79217 PEA 1
M62096 PEA 1
M78076 PEA 1
T99080 PEA 4
T08446 PEA 1

CA 02555509 2006-07-26
192
816276 PEA 1
The following clusters were found to be overexpressed in lung small cell
cancer:
H61775


HLTMGRPSE


M85491 PEA 1


244808 PEA 1


AA161187


866178


HIJMPHOSLIP PEA 2


A1076020


T23580


M79217 PEA 1


M62096 PEA 1


M78076 PEA 1


T99080 PEA 4


T08446 PEA 1


The following clusters were found to be overexpressed in lung adenocarcinoma:
800299
M85491 PEA 1
221368 PEA 1
HLTMCA 1 XIA
AA161187
866178
T11628 PEA 1

CA 02555509 2006-07-26
193
The following clusters were found to be overexpressed in lung squamous cell:
HUMODCA
800299
D56406 PEA 1
S 244808 PEA 1
221368 PEA 1
HUMCA 1 XIA
AA161187
866178
HUMCEA PEA 1
lt3SI3? PEA 1 l'~,A 1 I'EA 1
D:ESCRIPT:I:ON FC):R. C,'LL,ISTER H6177S
Cluster .H(~l??S .features 2 transcripts) and (i sc~ment(s) of interest, the
names for which
1.S are; givc~t i~z Tab.les 4 and 5, respectively, the sequences themselves
are given at the end of the
application. The selected protein variaxits are gi~~n in table 6.
Tcthlee 4 - Tiwccrtscr-irJts c~f ir~t~~r~est
,v k ~ r

f YS . 1"A 7 +.a fit"-1"
a r'z~,~~'!~ '~~~ +': r ~f,.K~~
'~ ~
, ~
~~~ ~
~' ~~~
~


\ ". ,9,
~ -
f/ ~ :ai
p~ .:r.,.,a, a p, I, v
. ad ar",
, ~,: ~ : -L., a
,~e~ " ,;,~.. r ,Y .. F rm ,..,:a r 5dp;; '.
~' ~ ~ a a ,..: + E r
, , 3, ;n a t..~. " ,
I ,.....at ..I.
a, ,.. ~y r ~> ''r ,
d 2;$i "' :~-fX .a I '~
v., ~ d '.... F r Ir' I d4,.
,b~ ri' a:: ..,.;; ;', . ~~ i,~ $... t T
Yn,,a,:,: 1 a.r 1... ~e ...~ , y.. ,s, r .a
:"
V a,t .~- 1..
pr-~ Y ",. h'atl n...k --,~y
ya ..!ti. >~


H61775 T21 1


H6177S '1'2~ -. - 2 -


Tcxblo ~ - ;fegnterttr o f interest
...~..ry ~~3 ~ :.~ ~ , ~ ",


w,.s ~s- ,, ,~:
, ,,
~~


H61 node~ ~ a 1
??S


H6I??S node4 ISZ


??S code6 - _ l a~
I-I6 I


H.(>1??5node8 1S4


Hf>l nodet) t SS
??5


1~~161.775codeS l S6


2(>

CA 02555509 2006-07-26
194
Table 6 - Proteins of interest
,'>%' 3 '/7f:I," 9f. a~ '~'e'si,:, . /;7i
rev..:.., ,h~:: "~ , y~~~, ,~ , I"'.'~~ , ~~ ':I f ?s
' ~~~,y~. v~:, ~~ P ~ ~~ O ~ 'i~~~~I II ~~~~~~ ~!'
~ I II;;.k
I
~
'


i~l ~'' ;rIIrIII , ' ~ III a t ~ i'~ I
y
;~ t,,~ . ~~, ,
d, eat , 1i4 ~~ "i.,
~,
,, ~ , ,e~p r ,. . r
:. ~ v ~ ,I ' ,
~ s ~r
,. a ~ r ~;~ i ~. ,~:, f vV
,fir ~.,..~,s r. ,-;.e,, ,W :.Y.~~ t..,.. d ..~"
~. s ~~,:r. , f ~G~"~. ..~. "i:
~ h


H61775 P16 1281


H61775 P17 1282


Cluster H61775 can be used as a diagnostic marker according to overexpression
of
transcripts of this cluster in cancer. Expression of such transcripts in
normal tissues is also given
according to the previously described methods. The term "number" in the right
hand column of
the table and the numbers on the y-axis of figure 6 refer to weighted
expression of ESTs in each
category, as "parts per million" (ratio of the expression of ESTs for a
particular cluster to the
expression of all ESTs in that category, according to parts per million).
Overall, the following results were obtained as shown with regard to the
histograms in
Figure 6 and Table 7. This cluster is overexpressed (at least at a minimum
level) in the
following pathological conditions: brain malignant tumors and a mixture of
malignant tumors
from different tissues.
Table 7 - Normal tissue distribution
;, 'N' i~ ~ 'e ~u tHS ~
ea, '~...
~, , r

V , ~~1'.'.
y


~'v~~
S ~v.
a.,~,
~ a':,~~ ~~
A;


bladder 0


brain 0


colon 0


epithelial 10


general 3


breast 8


muscle 0


ovary 0


pancreas 0



CA 02555509 2006-07-26
195
prostate 0


uterus 0


Table 8 - P values and ratios for expression in cancerous tissue
~ ~ ~~,<::,
r~~.4, ~ a ,-
.. ~ . ~;:
~


bladder 3.1e-01 3.8e-013.2e-01 2.5 4.6e-011.9


brain 8.8e-02 6.5e-021 3.5 4.1e-045.8


colon 5.6e-01 6.4e-0 1 1.1 1 1.1
1


epithelial 3.0e-02 1.3e-012.3e-02 2.1 3.2e-011.2


general 1.3e-06 4.9e-051.0e-07 6.3 1.5e-064.3


breast 4.7e-01 3.7e-013.3e-01 2.0 4.6e-011.6


muscle 2.3e-01 2.9e-01l.Se-O1 6.8 3.9e-012.6


ovary 3.8e-01 4.2e-01l.Se-O1 2.4 2.6e-011.9


pancreas 3.3e-01 4.4e-014.2e-01 2.4 5.3e-011.9


prostate 7.3e-01 7.8e-016.7e-01 1.5 7.5e-011.3


uterus 1.0e-0 2.6e-0 2.9e-0 2.6 5.1 1.8
1 1 1 e-O1


As noted above, contig H61775 features 2 transcript(s), which were listed in
Table 3
above. A description of each variant protein according to the present
invention is now provided.
Variant protein H61775 P16 according to the present invention has an amino
acid
sequence as given at the end of the application; it is encoded by transcripts)
H61775 T21. One
or more alignments to one or more previously published protein sequences are
given at the end
of the application. A brief description of the relationship of the variant
protein according to the
present invention to each such aligned protein is as follows:
Comparison report between H61775 P16 and Q9P2J2 (SEQ ID N0:1694):
1.An isolated chimeric polypeptide encoding for H61775 P 16, comprising a
first amino
acid sequence being at least 90 % homologous to
MVWCLGLAVLSLVISQGADGRGKPEVVSVVGRAGESVVLGCDLLPPAGRPPLHVIEWL

CA 02555509 2006-07-26
196
RFGFLLPIFIQFGLYSPRIDPDYVG corresponding to amino acids 11 - 93 of Q9P2J2,
which
also corresponds to amino acids 1 - 83 of H61775 P16, and a second amino acid
sequence being
at least 70%, optionally at least 80%, preferably at least 85%, more
preferably at least 90% and
most preferably at least 95% homologous to a polypeptide having the sequence
DCGFPAFRELKRAETVSPVFFTRRCIWEDLKSTGFSPAGGGRPPGGGPRTQEDSGLPCW
RSSCSVTLQV corresponding to amino acids 84 - 152 of H61775 P16, wherein said
first and
second amino acid sequences are contiguous and in a sequential order.
2.An isolated polypeptide encoding for a tail of H61775 P16, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
DCGFPAFRELKRAETVSPVFFTRRCIWEDLKSTGFSPAGGGRPPGGGPRTQEDSGLPCW
RSSCSVTLQV in H61775 P16.
Comparison report between H61775 P16 and AAQ88495 (SEQ ID N0:1695):
1.An isolated chimeric polypeptide encoding for H61775 P 16, comprising a
first amino
acid sequence being at least 90 % homologous to
MVWCLGLAVLSLVISQGADGRGKPEVVSVVGRAGESWLGCDLLPPAGRPPLHVIEWL
RFGFLLPIFIQFGLYSPRIDPDYVG corresponding to amino acids 1 - 83 of AAQ88495,
which
also corresponds to amino acids 1 - 83 of H61775 P 16, and a second amino acid
sequence being
at least 70%, optionally at least 80%, preferably at least 85%, more
preferably at least 90% and
most preferably at least 95% homologous to a polypeptide having the sequence
DCGFPAFRELKRAETVSPVFFTRRCIWEDLKSTGFSPAGGGRPPGGGPRTQEDSGLPCW
RSSCSVTLQV corresponding to amino acids 84 - 152 of H61775 P16, wherein said
first and
second amino acid sequences are contiguous and in a sequential order.
2.An isolated polypeptide encoding for a tail of H61775 P16, comprising a
polypeptide
being at least 70%, optionally at least about 80%, preferably at least about
85%, more preferably
at least about 90% and most preferably at least about 95% homologous to the
sequence
DCGFPAFRELKRAETVSPVFFTRRCIWEDLKSTGFSPAGGGRPPGGGPRTQEDSGLPCW
RSSCSVTLQV in H61775 P16.
The location of the variant protein was determined according to results from a
number of
different software programs and analyses, including analyses from SignalP and
other specialized

CA 02555509 2006-07-26
197
programs. The variant protein is believed to be located as follows with regard
to the cell:
secreted. The protein localization is believed to be secreted because both
signal-peptide
prediction programs predict that this protein has a signal peptide, and
neither traps-membrane
region prediction program predicts that this protein has a traps-membrane
region..
Variant protein H61775 P 16 also has the following non-silent SNPs (Single
Nucleotide
Polymorphisms) as listed in Table 9, (given according to their positions) on
the amino acid
sequence, with the alternative amino acids) listed; the last column indicates
whether the SNP is
known or not; the presence of known SNPs in variant protein H61775 P16
sequence provides
support for the deduced sequence of this variant protein according to the
present invention).
Table9 - Amino acid mutations
s._
' ~"
'
~


w ~~:~ ~~,~
~ k M
'% - r~.E ~' ... ~'~.'o,~''
~ ~ i~,~,kEE~" 1
i


'..a ~wz,.~//%~
w .; ~,;~.... ~:vs
y
o i c.:. ...,.


14 I -> No
T


138 G->R No


34 G -> E Yes


48 G -> R No


91 R -> * Yes


Variant protein H61775 P16 is encoded by the following transcript(s): H61775
T21, for
which the sequences) is/are given at the end of the application. The coding
portion of transcript
H61775 T21 is shown in bold; this coding portion starts at position 261 and
ends at position
716. The transcript also has the following SNPs as listed in Table 10 (given
according to their
position on the nucleotide sequence, with the alternative nucleic acid listed;
the last column
indicates whether the SNP is known or not; the presence of known SNPs in
variant protein
H61775 P16 sequence provides support for the deduced sequence of this variant
protein
according to the present invention).
Table 10 - Nucleic acid SNPs

CA 02555509 2006-07-26
198
117 T -> C Yes


200 T -> C No


672 G -> C No


222 T -> C Yes


301 T -> C No


361 G -> A Yes


377 G -> A No


400 -> C No


402 G -> C No


531 C -> T Yes


566 T -> C No


Variant protein H61775 P 17 according to the present invention has an amino
acid
sequence as given at the end of the application; it is encoded by transcripts)
H61775 T22. One
or more alignments to one or more previously published protein sequences are
given at the end
of the application. A brief description of the relationship of the variant
protein according to the
present invention to each such aligned protein is as follows:
Comparison report between H61775 P 17 and Q9P2J2:
l.An isolated chimeric polypeptide encoding for H61775 P17, comprising a first
amino
acid sequence being at least 90 % homologous to
MVWCLGLAVLSLVISQGADGRGKPEVVSVVGRAGESVVLGCDLLPPAGRPPLHVIEWL
RFGFLLPIFIQFGLYSPRIDPDYVG corresponding to amino acids 11 - 93 of Q9P2J2,
which
also corresponds to amino acids 1 - 83 of H61775 P 17.
Comparison report between H61775 P17 and AAQ88495:
l.An isolated chimeric polypeptide encoding for H61775 P17, comprising a first
amino
acid sequence being at least 90 % homologous to
MVWCLGLAVLSLVISQGADGRGKPEVVSVVGRAGESVVLGCDLLPPAGRPPLHVIEWL




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