CA2555509A1

CA2555509A1 - Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of lung cancer

Info

Publication number: CA2555509A1
Application number: CA002555509A
Authority: CA
Inventors: Sarah Pollock; Zurit Levine; Amit Novik; Dvir Dahary; Rotem Sorek; Amir Toporik; Shirley Sameah-Greenwald; Osnat Sella-Tavor; Alexander Diber; Gad S. Cojocaru; Michal Ayalon-Soffer; Shira Walach; Pinchas Akiva; Naomi Keren; Ronen Shemesh
Original assignee: Individual
Current assignee: Compugen USA Inc
Priority date: 2004-01-27
Filing date: 2005-01-27
Publication date: 2005-07-27
Also published as: EP1774046A2; AU2005320352A2; JP2008507261A; EP1774046A4; AU2005320352A8; AU2005320352A1; WO2006131783A2; WO2006131783A3

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.

Description

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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 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 f 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.

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 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 2.0 Array at www.affymetrix.com/products/arrays/specific/hgu133av2.affx; and Human Genome U133 Plus 2.0 Array at 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 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

>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 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";

"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 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 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 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 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.

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.

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.

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.

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.

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 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.

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 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 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.

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.

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.

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 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 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 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

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 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 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

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 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

YSPDCDSSAPKAAQAQEPQIDEYAPEDIIEYDYEYGEAEYKEAESVTEGPTVTEETIAQT
EANIVDDFQEYNYGTMESYQTEAPRHVSGTNEPNPVEEIFTEEYLTGEDYDSQRKNSED
TLYENKEIDGRDSDLLVDGDLGEYDFYEYKEYEDKPTSPPNEEFGPGVPAETDITETSIN
GHGAYGEKGQKGEPAVVEPGMLVEGPPGPAGPAGIMGPPGLQGPTGPPGDPGDRGPPG

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 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 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.

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.

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

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.

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.

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.

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

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.

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

NIRVVGGLLSAHLLSKKAGVEVEAGWPCSGPLLRMAEEAARKLLPAFQTPTGMPYGTV
NLLHGVNPGETPVTCTAGIGTFIVEFATLSSLTGDPVFEDVARVALMRLWESRSDIGLV
GNHIDVLTGKWVAQDAGIGAGVDSYFEYLVKGAILLQDKKLMAMFLEYNKAIRNYTR
FDDWYLWVQMYKGTVSMPVFQSLEAYWPGLQSLIGDIDNAMRTFLNYYTVWKQFGG

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

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.

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.

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 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

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

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 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 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, 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.

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

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 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

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.

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

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

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

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 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

RWCGGSRSGSCAHPHHQVVPFRCLPGEFVSEALLVPEGCRFLHQERMDQCESSTRRHQ
EAQEACSSQGLILHGSGMLLPCGSDRFRGVEYVCCPPPGTPDPSGTAVGDPSTRSWPPG
SRVEGAEDEEEEESFPQPVDDYFVEPPQAEEEEETVPPPSSHTLAVVGKVTPTPRPTDGV
DIYFGMPGEISEHEGFLRAKMDLEERRMRQINEVMREWAMADNQSKNLPKADRQALN

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, 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

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 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

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

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.

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 EAGKRIFGPRVGNELCEVKHVLDLCRIRESVSEELLQLEAKRQELNSEIAKLNLKIEACK
KSIENAKQDLLQLKNVISQTEHSYKELMAQNQPKLSLPIRLLPEKDDAGLPPPKATRGC
RLHNCFDYSRCPLTSGFPVYVYDSDQFVFGSYLDPLVKQAFQATARANVYVTENADIA
CLYVILVGEMQEPVVLRPAELEKQLYSLPHWRTDGHNHVIINLSRKSDTQNLLYNVSTG

RSSLQEARSFEEEMEGDPPADYDDRIIATLKAVQDSKLDQVLVEFTCKNQPKPSLPTEW
ALCGEREDRLELLKLSTFALIITPGDPRLVISSGCATRLFEALEVGAVPVVLGEQVQLPY
QDMLQWNEAALVVPKPRVTEVHFLLRSLSDSDLLAMRRQGRFLWETYFSTADSIFNTV
LAMIRTRIQIPAAPIREEAAAEIPHRSGKAAGTDPNMADNGDLDLGPVETEPPYASPRYL

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 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 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

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 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

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

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 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 EQVYNACAKQIVKDVLEGYNGTIFAYGQTSSGKTHTMEGKLHDPQLMGIIPRIAHI~IFD

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.

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

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

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

LLTYQLYGKFSEAMS VPGEEERLVRV corresponding to amino acids 1 - 443 of T08446 PEA 1 P18, a second amino acid sequence being at least 90 % homologous to HDVIQQLPPPHYRTLEYLLRHLA,RMARHSANTSI4gL~RNLAIVWAPNLLRSMELESVG
MGGAAAFREVRVQSVVVEFLLTHVDVLFSDTFTSAGLDPAGRCLLPRPKSLAGSCPSTR
LLTLEEAQARTQGRLGTPTEPTTPKAPASPAERRKGERGEKQRKPGGSSWKTFFALGRG

SSDAFPVGPAPAGSCESLSSSSSSESSSSESSSSSSESSAAGLGALSGSPSHRTSAWLDDG
DELDFSPPRCLEGLRGLDFDPLTFRCSSPTPGDPAPPASPAPPAPASAFPPRVTPQAISPRG
PTSPASPAALDISEPLAVSVPPAVLELLGAGGAPASATPTPALSPGRSLRPHLIPLLLRGA
EAPLTDACQQEMCSKLRGAQGPLGPDMESPLPPPPLSLLRPGGAPPPPPKNPARLMALA

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

GPVLTWMELDNHGRRLLLSEEASLNIPAVAAAHVIKRYTAQAPDELSFEVGDIVSVIDM

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

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

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

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 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 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 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 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.

-.

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 r 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%, 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 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

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 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.

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 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

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 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.

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 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 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 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

PTISPLNTSYRSGENLNLSCHAASNPPAQYSWFVNGTFQQSTQELFIPNITVNNSGSYTC
QAHNSDTGLNRTTVTTITVYAEPPKPFITSNNSNPVEDEDAVALTCEPEIQNTTYLWWV
NNQSLPVSPRLQLSNDNRTLTLLSVTRNDVGPYECGIQNELSVDHSDPVILNVLYGPDD
PTISPSYTYYRPGVNLSLSCHAASNPPAQYSWLIDGNIQQHTQELFISNITEKNSGLYTCQ

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 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

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 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.

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 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 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 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.

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 -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.

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

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 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 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 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 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.

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.

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

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

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 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

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 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 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 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

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 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.

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%, 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.

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 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

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.

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

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 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 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 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 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.

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

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. , 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.

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.

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.

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.

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.

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.

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 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 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).

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).

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 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.

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 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.

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 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 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 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 (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.

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 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 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 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.

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 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 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, 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.

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 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 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.

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 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 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 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 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 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.

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 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 ~ ~ ~

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 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 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.

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 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 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 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 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 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.

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 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.

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 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 below. The cancer biomarkers selection engine and the following wet validation stages are schematically summarized in Figure 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 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.

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 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 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:

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.

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 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.

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.

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 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 Carcinoma Biochai 30-B-Small cell carci A501389 small cell 3 34 Biochai 31-B-Small cell carci A501390 small cell 3 /59 iochai 32-B-Small cell carci A501391 n small cell 3 M/30 iochai 33-B-Small cell carci A504115 small cell 3 BiochaiSmall Cell 86-B-Small cell carci 608032 Carcinoma 3 /52 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 91-B-N A607257 Biochaiormal (Pool ool 2) 2 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 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 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 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, 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

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

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

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

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.

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).

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:

(800299) HUMGRPSE
HUMODCA

The following clusters were found to be overexpressed in lung small cell cancer:

HLTMGRPSE

The following clusters were found to be overexpressed in lung adenocarcinoma:

The following clusters were found to be overexpressed in lung squamous cell:
HUMODCA

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. >~

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~

H.(>1??5node8 1S4 Hf>l nodet) t SS
??5 1~~161.775codeS l S6 2(>

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 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 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 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

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 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 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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Claims

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.

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.

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.