EP1721257A2 - Differentieller ausdruck von markierungen beim ovarialkrebs - Google Patents

Differentieller ausdruck von markierungen beim ovarialkrebs

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Publication number
EP1721257A2
EP1721257A2 EP05780004A EP05780004A EP1721257A2 EP 1721257 A2 EP1721257 A2 EP 1721257A2 EP 05780004 A EP05780004 A EP 05780004A EP 05780004 A EP05780004 A EP 05780004A EP 1721257 A2 EP1721257 A2 EP 1721257A2
Authority
EP
European Patent Office
Prior art keywords
pea
amino acid
amino acids
homologous
acid sequence
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP05780004A
Other languages
English (en)
French (fr)
Inventor
Gad S. Cojocaru
Sarah Pollock
Zurit Levine
Alexander Diber
Guy Kol
Amir Toporik
Rotem Sorek
Dvir Dahary
Michal Ayalon-Soffer
Pinchas Akiva
Amit Novik
Yossi Cohen
Osnat Sella-Tavor
Shira Walach
Shirley Sameah-Greenwald
Ronen Shemesh
Maxim Shklar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Compugen Ltd
Original Assignee
Compugen Ltd
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Filing date
Publication date
Application filed by Compugen Ltd filed Critical Compugen Ltd
Publication of EP1721257A2 publication Critical patent/EP1721257A2/de
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification

Definitions

  • the present invention is related to novel nucleotide and protein sequences that are diagnostic markers for ovarian cancer, and assays and methods of use thereof.
  • Ovarian cancer causes more deaths than any other cancer of the female reproductive system.
  • An estimated 25,580 new cases will be diagnosed during 2004 in the United States, and approximately 16,090 of these women will die of the disease.
  • 70% to 80% of patients will ultimately succumb to disease that is diagnosed in iate stages.
  • ovarian cancer is diagnosed in stage I, more than 90% of patients can be cured with conventional surgery and chemotherapy.
  • stage I Detection of a greater fraction of ovarian cancers at an early stage might significantly affect survival.
  • CA-125 is a member of the epithelial sialomucins markers group and is the most well documented and the best performing single marker from this group.
  • CA- 125 Another name for CA- 125 is mucin 16, and although it is a membrane protein, it can be found in the serum. Its greatest sensitivity is achieved for serous and emdometrioid ovarian tumors compared to mucinous or clear cell tumors. Other than diagnosis, it can be used for disease monitoring (Eur J Gynaecol Oncol. 2000;21(l):64-9). In about 70% of patients, a rising level of CA-125 may be the first indication of relapse, predating clinical relapse by a median of 4 months. The serum concentration of CA-125 is elevated by the vascular invasion, tissue destruction and inflammation associated with malignant disease and is elevated in over 90% of those women with advanced ovarian cancer.
  • CA-125 is not specific to ovarian cancer. It is elevated in 40% of all patients with advanced intra-abdominal malignancy. Levels can also be elevated during menstruation or pregnancy and in other benign conditions such as cndometriosis, peritonitis or cirrhosis, particularly with ascites. CA- 125 is not a marker that can be detected through use of urine samples due to a high molecular weight. There are other ovarian cancer markers originating from epithelial ucins but none can replace CA- 125, due to poorer specificity and sensitivity. These other markers may prove complementary to CA-125.
  • CA-50, CA 54-61 , C ⁇ -195 and CA 19-9 all appear to have greater sensitivity for detection of mucinous tumors while STN and TAG-72 have better sensitivity for detection of clear cell tumors (Dis Markers. 2004;20(2):53-70).
  • Kallikreins, a family of serine proteases, and other protease-related proteins are also potential markers for ovarian cancer. Indeed, the entire family of kallikreins map to a region on chromosome 19q which is shown to be amplified in ovarian cancers. In particular, kallikrein 6 (protease M) and kallilrein 10 have been reported to have sensitivity up to 75% and specificity up to 100%.
  • MMPs Matrix metalloproteinases
  • Cathepsin L a cystein protease
  • CA-125 a cystein protease
  • Hormones have a role in normal ovarian physiology. Therefore, it is not surprising that hormones, and growth and inhibition factors as well, are suitable for ovarian cancer detection. Measurements of fragments of gonadotropin in the urine were found to have sensitivity up to 83% and specificity up to 92% for detecting ovarian cancer. Inhibins, members of the Transforming Growth Factors (TGF) beta superfamily, have been shown to have a diagnostic value in the detection of granulosa cell tumor, a relatively uncommon type of ovarian cancer, associated with better prognosis overall.
  • TGF Transforming Growth Factors
  • Serum inhibin is an ovarian product which decreases to non detectable levels after menopause, however, certain ovarian cancers (mucinous carcinomas and sex cord stromal tumours such as granulosa cell tumours) continue to produce inhibin. Studies have shown that that inhibin assays which detect all inhibin forms (as opposed to test detecting specific members of the inhibins family) provide the highest sensitivity/specificity characteristics as an ovarian cancer diagnostic test (Mol Cell Endocrinol. 2002 May 31 ; 191 ( 1):97- 103). Measurement of serum TGF-alpha itself was found to have sensitivity up to 70% and specificity of 89% in early stage disease.
  • the growth factor Mesothelin was also found to have diagnostic value but only for late stage disease. Immunohistochemistry is frequently used to assess the origin of tumor and staging when a pathological tissue sample is available. A few molecular markers have been shown to have diagnostic value in Immunohistochemistry of ovarian cancer, among them Epidermal Growth Factor, p53 and HER-2. P53 expression is much lower at early stage than late stage disease. P53 high expression is more typical or characteristic of invasive serous tumors than of mucinous tumors. No benign tumors are stained with P53. HER-2 is found in less than 25% of newly diagnosed ovarian cancers.
  • Ovarian cancer of type granulosa cell tumor has in general better prognosis with late relapse and/or metastasis formation. However, about 50% of patients still die within 20 years of diagnosis.
  • immunohistochemistry staining of estrogen receptor beta (ERb) and proliferating cell nuclear antigen (PCNA) showed that loss of ERb expression and high PCNA expression, characterized a subgroup of granulosa cell tumors with a worse outcome (Histopathology. 2003 Sep;43(3):254-62).
  • Survivin expression was also shown to be correlated to tumor grade, histologic type and mutant p53 but actual correlation to survival is questionable (Mod Pathol.
  • markers have been tested over the years for ovarian cancer detection. Some markers have shown only limited value while others are still under investigation. Among them are TPA and TPS, two cytokeratins whose inclusion in a panel with CA- 125 resulted in diagnoses with sensitivity up to 93% and specificity up to 98%. LPA - lysophosphatidic acid - was a very promising marker with one study demonstrating 98% sensitivity and 90% specificity. However, this marker is very unstable and requires quick processing and freezing of plasma, and therefore has limited usage. As previously described, no single marker has been shown to be sufficiently sensitive or specific to contribute to the diagnosis of ovarian cancer. Therefore combinations of markers in panel are being tested.
  • CA-125 is one of the panel members.
  • the best performing panel combinations so far have been CA-125 with CA 15-3 with sensitivity of 93% and specificity of 93%, CA-125 with CEA (which has very little sensitivity by itself) with specificity of 93% and specificity of 93%, and CA- 125 with TAG-72 and CA 15-3 where specificity becomes 95% but sensitivity is diminished (Dis Markers. 2004;20(2):53-70).
  • the background art does not teach or suggest markers for ovarian 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 ovarian cancer that are both sensitive and accurate. These markers are differentially expressed and preferably overexpressed in ovarian cancer specifically, as opposed to normal ovarian 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 ovarian cancer.
  • the markers of the present invention alone or in combination, show a high degree of differential detection between ovarian cancer and non-cancerous states.
  • 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, ovarian 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 female reproductive system), and also samples of in vivo cell culture constituents.
  • the biological sample comprises ovarian tissue and/or a serum sample and/or a urine sample and/or secretions or other samples from the female reproductive system 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.
  • 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.
  • T - > C means that the SNP results in a change at the position given in the table from T to C.
  • M - > Q 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 (*).
  • 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.
  • the header of the first column is "SNP position(s) 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.
  • the unabbreviated tissue name was used as the reference to the type of chip for which expression was measured.
  • 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.
  • the unabbreviated tissue name was used as the reference to the type of chip for which expression was measured.
  • the probe name begins with the name of the cluster (gene), followed by an identifying number. These probes are listed below with their respective sequences.
  • Genome U133 Plus 2.0 Array at www.affymetrix.com/products/arrays/specific/hgu l 33plus.affx).
  • the probe names follow the Affymetrix naming convention.
  • 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).
  • TAA histograms The following list of abbreviations for tissues was used in the TAA histograms.
  • TAA Tumor Associated Antigen
  • TAA histograms represent the cancerous tissue expression pattern as predicted by the biomarkers selection engine, as described in detail in examples 1-5 below (the first word is the abbreviation while the second word is the full name):
  • nucleic acid sequences of the present invention refer to portions of nucleic acid sequences that were shown to have one or more properties as described below. They are also the building blocks that were used to construct complete nucleic acid sequences as described in greater detail below.
  • 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.
  • ovarian cancer refers to cancers of the ovary including but not limited to Ovarian epithelial tumors (serous, mucinous, endometroid, clear cell, and Brenner tumor), ovarian germ-cell tumors, (teratoma, dysgerminoma, endodermal sinus tumor, and embryonal carcinoma) and ovarian stromal tumors (originating from granulosa, theca, Sertoli, Leydig, and collagen-producing stromal cells).
  • the tenn "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 ovarian cancer as compared to a comparable sample taken from subjects who do not have ovarian cancer.
  • the phrase "differentially present” refers to differences in the quantity of a marker present in a sample taken from patients having ovarian cancer as compared to a comparable sample taken from patients who do not have ovarian cancer.
  • 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.
  • diagnosis 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.
  • 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.
  • 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.
  • the term "level” refers to expression levels of RNA and/or protein or to DNA copy number of a marker of the present invention.
  • 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.
  • test amount refers to an amount of a marker in a subject's sample that is consistent with a diagnosis of ovarian cancer.
  • 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.
  • a control amount of a marker can be the amount of a marker in a patient with ovarian cancer or a person without ovarian cancer.
  • 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, immunochernical, or chemical means.
  • useful labels include 32 P, 35 S, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin- strep tavadin, 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 inco ⁇ orated in or attached to a primer or probe either covalently, or through ionic, van der Waals or hydrogen bonds, e.g., inco ⁇ oration 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.
  • 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 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.
  • 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 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.
  • 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 polymo ⁇ hic 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.
  • immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein.
  • 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).
  • a specific or selective reaction will be at least twice background signal or noise and more typically more than 10 to 100 times background.
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or:
  • nucleic acid sequence comprising a sequence in the table below:
  • an isolated polypeptide comprising an ammo acid sequence in the table below amino acid sequence comprising a sequence in the table below
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or
  • nucleic acid sequence compnsing a sequence in the table below:
  • an isolated polypeptide comprising an amino acid sequence in the table below
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or
  • HUMEDF PEA 2 T5 HUMEDF PEA 2 T10 HUMEDF PEA 2 Ti l a nucleic acid sequence comprising a sequence in the table below:
  • HUMEDF PEA . 2 . node .. 6 HUMEDF PEA . 2 . node . 1 1 HUMEDF PEA _2_ node . 18 HUMEDF . PEA . . 2 . node . . 19 HUMEDF . . PEA . . 2 . node . .22 HUMEDF . PEA . 2 . node . . 2 HUMEDF , PEA . . 2 . node . . 8 HUMEDF . PEA 2_ node . 20
  • an isolated polypeptide comprising an amino acid sequence in the table below:
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or:
  • HSAPHOL T9 a nucleic acid sequence comprising a sequence in the table below:
  • an isolated polypeptide comprising an amino acid sequence in the table below:
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or
  • nucleic acid sequence compnsing a sequence in the table below.
  • an isolated polypeptide comprising an ammo acid sequence in the table below
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and or
  • HSECADH node 52 HSECADH iode . .53 HSECADH_node_ .54 HSECADH_node_ . 57 HSECADH_node_ 60 HSECADH node 62 HSECADH_node_ 63 HSECADH node 1 HSECADH_node 1 HSECADH_node 11 HSECADH_node .
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or:
  • HUMGRP5E T4 HUMGRP5E T5 a nucleic acid sequence comprising a sequence in the table below:
  • an isolated polypeptide comprising an amino acid sequence in the table below: m ⁇ m aRliyBligii HUMGRP5E P4 HUMGRP5E P5
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or:
  • nucleic acid sequence compnsing a sequence in the table below:
  • an isolated polypeptide comprising an amino acid sequence in the table below:
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or:
  • nucleic acid sequence comprising a sequence in the table below: Segment Name D56406 PEA 1 node 0 D56406 PEA 1 node 13 D56406 PEA 1 node 1 1 D56406 PEA 1 node 2 D56406 PEA 1 node 3 D56406 PEA 1 node 5 D56406 PEA 1 node 6 D56406 PEA 1 node 7 D56406 PEA 1 node 8 D56406 PEA 1 node 9
  • an isolated polypeptide comprising an amino acid sequence in the table below
  • H53393 PEA 1 T10 H53393 PEA 1 Ti l H53393 PEA 1 T3 H53393 PEA 1 T9 27 a nucleic acid sequence comprising a sequence in the table below
  • H53393 PEA 1 P2 H53393 PEA 1 P3 H53393 PEA 1 P6 According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or:
  • nucleic acid sequence comprising a sequence in the table below:
  • an isolated polypeptide comprising an amino acid sequence in the table below:
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and or:
  • nucleic acid sequence comprising a sequence in the table below
  • an isolated polypeptide comprising an amino acid sequence m the table below. 2005/11685
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or
  • nucleic acid sequence comprising a sequence in the table below
  • an isolated polypeptide comprising an amino acid sequence in the table below:
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or:
  • T39971 T10 T39971 T12 T39971 T16 T39971 T5 a nucleic acid sequence comprising a sequence in the table below:
  • T39971 _node . . 29 T39971 node . 3 T39971 _node . 30 T39971 node . 34 T39971 _node . . 35 T39971 _node . . 36 T39971 node . 4 T39971 node . 5 T39971 node . 8 T39971 node . 9
  • an isolated polypeptide comprising an amino acid sequence in the table below:
  • an isolated polynucleotide comprising a nucleic acid sequence m the table below and/or
  • nucleic acid sequence comprising a sequence in the table below
  • an isolated polypeptide comprising an amino acid sequence in the table below:
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or:
  • an isolated polypeptide comprising an amino acid sequence in the table below:
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or:
  • nucleic acid sequence comprising a sequence in the table below:
  • an isolated polypeptide comprising an amino acid sequence in the table below:
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or:
  • nucleic acid sequence comprising a sequence in the table below:
  • an isolated polypeptide comprising an amino acid sequence in the table below:
  • nucleic acid sequence comprising a sequence in the table below:
  • T59832 node 1 T59832 node 7 T59832 node 29 T59832 node 39 T59832 node 2 T 9832 node 3 T59832 node 4 T59832 node 5 T59832 node 6 T59832 node 8 T59832 node 9 T59832 node 10 T59832 . node .. 11
  • an isolated polypeptide comprising an amino acid sequence in the table below:
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or:
  • an isolated polypeptide comprising an amino acid sequence in the table below:
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or:
  • nucleic acid sequence comprising a sequence in the table below:
  • HUMTEN PEA 1 P32 According to prefened embodiments of the present invention, there is provided an isolated polynucleotide compnsing a nucleic acid sequence in the table below and/or
  • nucleic acid sequence comprising a sequence in the table below
  • an isolated polypeptide comprising an amino acid sequence in the table below:
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or Transcnpt N me i T46984 PEA 1 T2 T46984 PEA 1 T3 T46984 PEA 1 T12 T46984 PEA 1 T13 T46984 PEA 1 T14 T46984 PEA 1 T15 T46984 PEA 1 T19 T46984 PEA 1 T23 T46984 PEA 1 T27 T46984 PEA 1 T32 T46984 PEA 1 T34 T46984 PEA 1 T35 T46984 PEA 1 T40 T46984 PEA 1 T42 T46984 PEA 1 T43 T46984 PEA 1 T46 T46984 PEA 1 T47 T46984 PEA 1 T48 T46984 PEA 1 T51
  • nucleic acid sequence compnsing a sequence in the table below.
  • an isolated polypeptide comprising an amino acid sequence in the table below: According to prefened embodiments of the present invention, there is provided an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or:
  • nucleic acid sequence compnsmg a sequence in the table below:
  • an isolated polypeptide comprising an amino acid sequence in the table below:
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or: iranscj ⁇ t ⁇ air ⁇ i I * T481 19 T2 a nucleic acid sequence comprising a sequence in the table below
  • an isolated polynucleotide comprising a nucleic acid sequence in the table below and/or:
  • nucleic acid sequence comprising a sequence in the table below:
  • an isolated polypeptide comprising an amino acid sequence in the table below:
  • an isolated chimeric polypeptide encoding for HSMUC1A_PEA_1_P63 comprising a first amino acid sequence being at least 90 % homologous to MTPGTQSPFFLLLLLTVLTVVTGSGHASSTPGGEKETSATQRSSV conesponding to amino acids 1 - 45 of MUC1 HUMAN, which also conesponds to amino acids 1 - 45 of HSMUC1A PEA J P63, and a second amino acid sequence being at feast 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 EEEVS ADQ VS VGASGVLGSFKEARNAPSFLSWSFSMGPSK conesponding to amino acids 46 - 85 of HSMUC 1 A PEAJ P63, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of HSMUC1A PEAJ P63 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 EEEVSADQVSVGASGVLGSFKEARNAPSFLSWSFSMGPSK in HSMUC 1A_PEA_1_P63.
  • an isolated chimeric polypeptide encoding for T46984 PEAJ P2 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for T46984_PEA J P10 comprising a first amino acid sequence being at least 90 %> homologous to
  • an isolated polypeptide encoding for a tail of T46984 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%> homolo gous to the sequence LMDQK in T46984_PEAJ_P10.
  • an isolated chimeric polypeptide encoding for T46984_PEAJ_P11 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of T46984_PEA_1_P12 comprising a polypeptide being at least 10%, 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 SQDLH in T46984_PEA_1_P12.
  • an isolated chimeric polypeptide encoding for T46984 PEAJ JP21 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 T46984_PEA_1_P21 , and a second amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for T46984 PEAJ P27 comprising a first amino acid sequence being at least 90 % homologous to MAPPGSSTVFLLALTIIASTWALTPTHYLTKHDVERLKASLDRPFTNLESAFYSIVGLSSL GAQVPDAKKACTYIRSNLDPSNVDSLFYAAQASQALSGCEISISNETKDLLLAAVSEDSS VTQIYHAVAALSGFGLPLASQEALSALTARLSKEETVLATVQALQTASHLSQQADLRSI VEEIEDLVARLDELGGVYLQFEEGLETTALFVAATYKLMDHVGTEPSIKEDQVIQLMNA IFSKKNFESLSEAFSVASAAAVLSHNRYHVPVVVVPEGSASDTHEQAILRLQVTNVLSQ PLTQATVKLEHAKSVASRATVLQKTSFTPVGDVFELNFMNVKFSSGYYDFLVEVEGDN RY
  • an isolated polypeptide encoding for a tail of T46984_PEAJ_P27 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 FGSGLVPMSPTSLLLLARLYFTWDMLLCWDSCMSTGLSSTCSRP in T46984_PEA_1_P27.
  • an isolated chimeric polypeptide encoding for T46984_PEA_1_P32 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of T46984 PEAJ P32 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 GQVRWLTPVIPALWEAKAGGSPEVRSSILAWPT in T46984_PEA_1_P32.
  • an isolated chimeric polypeptide encoding for T46984 PEAJ P34 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of T46984_PEAJ_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 GCVv SRQSREQHISSRRJKMEII TECQEKESRTIHSMRRKMEKK FI in T46984_PEA_1_P35.
  • an isolated chimeric polypeptide encoding for T46984_PEAJ JP38 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of T46984_PEA J_P38 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 MDPDWCQCLQLHFCS in T46984_PEAJ_P38.
  • an isolated chimeric polypeptide encoding for T46984 PEAJ P39 comprising a first amino acid sequence being at least 90 % homologous to MAPPGSSTVFLLALTIIASTWALTPTHYLTKHDVERLKASLDRPFTNLESAFYSIVGLSSL GAQVPDAKKACTYIRSNLDPSNVDSLFYAAQASQALSGCEISISNETKDLLLAAVSEDSS VTQIYHAVAALSGFGLPLASQEALSALTARLSKEETVLA conesponding to amino acids 1 - 160 of RIB2 HUMAN, which also conesponds to amino acids 1 - 160 of T46984_PEA_1_P39.
  • an isolated chimeric polypeptide encoding for T46984 PEA 1 P45 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of T46984 PEAJ P45 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 NSPGSADSIPPVPAG in T46984 PEA 1 P45.
  • an isolated chimeric polypeptide encoding for T46984 PEAJ P46 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of T46984 PEAJ P46 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 NSPGSADSIPPVPAG in T46984_PEAJ_P46.
  • an isolated chimeric polypeptide encoding for M78530_PEA_1_P15 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of M78530 PEAJ JP15 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 RKSWSSSRPITSMFLSPGSPEPASANTARS in M78530_PEA_1_P15.
  • an isolated chimeric polypeptide encoding for M78530 PEA 1 P15 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 MRLSPAPLKLSRTPALLALALPLAAALAFSDETLDKVPKSEGYCSRILRAQGTRREGYT EFSLRVEGDPDFYKPGTSYRVTLS conesponding to amino acids 1 - 83 of M78530_PEAJ_P15, a second amino acid sequence being at least 90 % homologous to AAPPSYFRGFTLIALRENREGDKEEDHAGTFQIIDEEETQFMSNCPVAVTESTPRRRTRJQ VFWIAPPAGTGCVILKASIVQKRIIYFQDEGSLTKKLCEQDSTFDGVTDKPILDCCACGT AKYRLTFYGNWSEKTHPKDYPR
  • an isolated polypeptide encoding for a head of M78530 PEA J 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 MRLSPAPLKLSRTPALLALALPLAAALAFSDETLDKVPKSEGYCSRILRAQGTRREGYT EFSLRVEGDPDFYKPGTSYRVTLS ofM78530_PEAJ_P15.
  • An isolated polypeptide encoding for a tail of M78530JPEAJ JP15 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 RKSWSSSRPITSMFLSPGSPEPASANTARS in M78530_PEA_1_P15.
  • an isolated chimeric polypeptide encoding for M78530_PEAJ_P16 comprising a first amino acid sequence being at least 90 % homologous to MRLSPAPLKLSRTPALLALALPLAAALAFSDETLDKVPKSEGYCSRILRAQGTRREGYT EFSLRVEGDPDFYKPGTSYRVTLSAAPPSYFRGFTLIALRENREGDKEEDHAGTFQIIDEE ETQFMSNCPVAVTESTPRRRTmQVFWIAPPAGTGCVILj ASIVQK-RIIYFQDEGSLTKKL CEQDSTFDGVTDKPILDCCACGTAKYRLTFYGNWSEKTHP DYPRRANHWSAIIGGSH SKNYVLWEYGGYASEGVKQVAELGSPVKMEEEIRQQSDEVLTVIKAKAQWPAWQPLN
  • an isolated chimeric polypeptide encoding for M78530_PEA_1_P16 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for M78530_PEA_1_P16 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 MRLSPAPLKLSRTPALLALALPLAAALAFSDETLDKVPKSEGYCSRILRAQGTRREGYT EFSLRVEGDPDFYKPGTSYRVTLS conesponding to amino acids 1 - 83 of
  • M78530 PEA 1 P16 and a second amino acid sequence being at least 90 % homologous to AAPPSYFRGFTLIALRENREGDKEEDHAGTFQIIDEEETQFMSNCPVAVTESTPRRRTRIQ VFWIAPPAGTGCVILKASIVQKRIIYFQDEGSLTKKLCEQDSTFDGVTDKPILDCCACGT AKYI ⁇ TFYGNWSEKTHPKDYPRRANHWSAIIGGSHSKNYVLWEYGGYASEGVKQVAE LGSPVKMEEEIRQQSDEVLTVIKAKAQWPAWQPLNV conesponding to amino acids 1 - 214 of 094862, which also conesponds to amino acids 84 - 297 of M78530_PEA_1_P16, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a head of M78530_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 MRLSPAPLKLSRTPALLALALPLAAALAFSDETLDKVPKSEGYCSRILRAQGTRREGYT EFSLRVEGDPDFYKPGTSYRVTLS of M78530_PEA_1_P 16.
  • an isolated chimeric polypeptide encoding for M78530_PEA_1_P17 comprising a first amino acid sequence being at least 90 % homologous to
  • M78530_PEAJ_P17 wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of M78530_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 VRQKNHRMTK in M78530_PEA_1_P17.
  • an isolated chimeric polypeptide encoding for M78530_PEA_1_P17 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of M78530_PEAJ_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 VRQKNHRMTK in M78530_PEA_1_P17.
  • an isolated chimeric polypeptide encoding for M78530_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 MRLSPAPLKLSRTP ALLALALPLAAALAFSDETLDKVPKSEG YCSRILRAQGTRREGYT EFSLRVEGDPDFYKPGTSYRVTLS conesponding to amino acids 1 - 83 of M78530_PEAJ_P17, a second amino acid sequence being at least 90 % homologous to AAPPSYFRGFTLIALRENREGDKEEDHAGTFQIIDEEETQFMSNCPVAVTESTPRRRTRIQ VFWIAPPAGTGCVILKASIVQKJIIIYFQDEGSLTKKLCEQDSTFDGVTDKPILDCCACGT AKYRLTFYGNWSEKTH
  • an isolated polypeptide encoding for a headofM78530_PEA_l_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
  • an isolated polypeptide encoding for a tail of M78530_PEA_1_P17 comprising a polypeptide being at least 1(1%, 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 VRQKNHRMTK in M78530_PEA_1_P17.
  • an isolated chimeric polypeptide encoding for T48119_P2 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for T48119_P2 comprising a first amino acid sequence being at least 90 %> homologous to
  • an isolated chimeric polypeptide encoding for T39971 JP6, 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%
  • 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 TQGWGD in T39971_P6.
  • an isolated chimeric polypeptide encoding for T39971_P9 comprising a first amino acid sequence being at least 90 % homologous to
  • 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.
  • an isolated chimeric polypeptide encoding for T39971 P1 1 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for an edge portion of T39971_P 1 1 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.
  • an isolated chimeric polypeptide encoding for T39971 J? l 1 comprising a first amino acid sequence being at least 90 %> homologous to
  • DKYYRVNLRTRRVDTVDPPYPRSIAQYWLGCPAPGHL conesponding to amino acids 442 - 478 of Q9BSH7, which also conesponds to amino acids 327 - 363 of T39971 P11, wherein said first and second amino acid sequences are contiguous and in a sequential order.
  • 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.
  • an isolated chimeric polypeptide encoding for T39971 P12 comprising a first amino acid sequence being at least 90 % homologous to
  • 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 JP12.
  • an isolated chimeric polypeptide encoding for T39971_P12 comprising a first amino acid sequence being at least 90 % homologous to
  • 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.
  • an isolated chimeric polypeptide encoding for Z44808_PEA_1_P5 comprising a first amino acid sequence being at least 90 % homologous to MLLPQLCWLPLLAGLLPPVPAQKFSALTFLRVDQDKDKDCSLDCAGSPQKPLCASDGR TFLSRCEFQRAKCKDPQLEIAYRGNCKDVSRCVAERKYTQEQARKEFQQVFIPECNDD GTYSQVQCHSYTGYCWCVTPNGRPISGTAVAHKTPRCPGSVNEKLPQREGTGKTDDAA APALETQPQGDEEDIASRYPTLWTEQVKSRQNKTNKNSVSSCDQEHQSALEEAKQPKN DNWIPECAHGGLYKPVQCHPSTGYCWCVLVDTGRPIPGTSTRYEQPKCDNTARAHPA KARDLYKGRQLQGCPGAKKHEFLTSVLDALSTDMVHAASDPSS
  • ELMGCLGVAKEDGKADTKKRHTPRGHAESTSNRQ conesponding to amino acids 1 - 441 of SM02_HUMAN which also conesponds to amino acids 1 - 441 of Z44808_PEA_1_P5, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%o, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DAMVVSSRPKATTHRKSRTLSRR conesponding to amino acids 442 - 464 of Z44808_PEA_1_P5, wherein said first and second amino acid sequences are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of Z44808 PEAJ 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 Z44808_PEA_1_P5.
  • an isolated chimeric polypeptide encoding for Z44808 PEA J_P6 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for Z44808 PEAJ P7 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of Z44808_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 Z44808_PEA_1_P7.
  • an isolated chimeric polypeptide encoding for Z44808 PEAJ P1 1 comprising a first amino acid sequence being at least 90 % homologous to
  • DGKADTKKRHTPRGHAESTSNRQPRKQG conesponding to amino acids 188 - 446 of SM02 HUMAN, which also conesponds to amino acids 171 - 429 of Z44808_PEA_1_P11, wherein said first and second amino acid sequences are contiguous and in a sequential order.
  • an isolated chimeric polypeptide encoding for an edge portion of Z44808 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 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 170-x to - 170; and ending at any of amino acid numbers 171+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated polypeptide encoding for a tail of S67314 PEA J_P4 comprising a polypeptide being at least 70%o, 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 VRWATLELYLIGYYYCSFSQACSKKPSPPLRAVEAGTREWLWVRVVSGGNFLCSGFGL TQAGTQILPYRLHDCGQITFSKCNCKTGINNTNLVGLLGSL in S67314 PEAJ P4.
  • an isolated chimeric polypeptide encoding for S67314_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 MVDAFLGTWKLVDSKNFDDYMKSLGVGFATRQVASMTKPTTIIEKNGDILTLKTHSTF KNTEISFKLGVEFDETTADDRKVKSIVTLDGGKLVHLQKWDGQETTLVRELIDGKLIL conesponding to amino acids 1 - 116 of FABH HUMAN, which also conesponds to amino acids 1 - 1 16 of S67314_PEA_1_P5, and a second amino acid sequence being at least 70%, optionally at least 80%o, preferably at least 85%, more preferably at least 90%> and most preferably at least 95% homolog
  • an isolated polypeptide encoding for a tail of S67314 PEA J 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 DVLTAWPSIYRRQVKVLREDEITILPWHLQWSREKATKLLRPTLPSYJ NHGWEELRVG KSIV in S67314_PEA_1_P5.
  • an isolated chimeric polypeptide encoding for S67314 PEAJ P5 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of S67314_PEA_1_P5 comprising a polypeptide being at least 70%>, optionally at least about 80%, preferably at least about 85%o, more preferably at least about 90%> and most preferably at least about 95% homologous to the sequence DVLTAWPSIYRRQVKVLREDEITILPWHLQWSREKATKLLRPTLPSY NHG WEELRVG KSIV in S67314_PEA_1_P5.
  • an isolated chimeric polypeptide encoding for S67314 PEAJ P6, comprising a first amino acid sequence being at least 70%, optionally at least 80%o, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MVDAFLGTWKLVDSKNFDDYMKSLGVGFATRQVASMTKPTTIIEKNGDILTLKTHSTF KNTEISFKLGVEFDETTADDRKVKSIVTLDGGKLVHLQKWDGQETTLVRELIDGKLIL conesponding to amino acids 1 - 116 of FABH HUMAN, which also conesponds to amino acids 1 - 116 of S67314 PEA J 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
  • an isolated polypeptide encoding for a tail of S67314_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 MEKLQLRNVK in S67314 PEA 1 P6.
  • an isolated chimeric polypeptide encoding for S67314 PEA J P7 comprising a first amino acid sequence being at least 90 % homologous to MVDAFLGTWKLVDSKNFDDYMKSL conesponding to amino acids 1 - 24 of FABH_HUMAN, which also conesponds to amino acids 1 - 24 of S67314 PEA J P7, 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 AHILITFPLPS conesponding to amino acids 25 - 35 of S67314 PEAJ P7, and a third amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for an edge portion of S67314_PEA_1_P7 comprising an amino acid sequence being at least 70%o, 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 AHILITFPLPS, conesponding to S67314JPEAJ P7.
  • an isolated chimeric polypeptide encoding for S67314_PEA_1_P7 comprising a first amino acid sequence being at least 90 % homologous to MVDAFLGTWKLVDSKNFDDYMKSL conesponding to amino acids 1 - 24 of AAP35373, which also conesponds to amino acids 1 - 24 of S67314_PEA_1_P7, 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 AHILITFPLPS conesponding to amino acids 25 - 35 of S67314_PEA_1_P7, and a third amino acid sequence being at least 90 %> homologous to
  • an isolated polypeptide encoding for an edge portion of S67314 PEAJ P7 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 AHILITFPLPS, conesponding to S67314_PEAJ_P7.
  • an isolated chimeric polypeptide encoding for Z39337 PEA 2 PEA J 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 MWLPLSGAA conesponding to amino acids 1 - 9 of Z39337J ⁇ A 2 PEA J P4, and a second amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a head of Z39337_PEA_2_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 MWLPLSGAA of Z39337_PEA_2_PEA_1_P4.
  • an isolated chimeric polypeptide encoding for Z39337_PEA_2_PEA_1_P9 comprising a first amino acid sequence being at least 90 % homologous to
  • Z39337_PEA_2_PEAJ_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 Q conesponding to amino acids 150 - 150 of Z39337_PEA_2_PEA_1_P9, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated chimeric polypeptide encoding for HUMPHOSLIP_PEA_2_P10 comprising a first amino acid sequence being at least 90 % homologous to MALFGALFLALLAGAHAEFPGCKIRVTSKALELVKQEGLRFLEQELETITIPDLRGKEGH FYYNISE conesponding to amino acids 1 - 67 of PLTP HUMAN, which also conesponds to amino acids 1 - 67 of HUMPHOSLIP PEA 2 P10, and a second amino acid sequence being at least 90 % homologous to
  • 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.
  • an isolated chimeric polypeptide encoding for HUMPHOSLIP PEA 2 P12 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of HUMPHOSLIP PEA 2 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 GKAGV in HUMPHOSLIP J > E A_2_P 12.
  • an isolated chimeric polypeptide encoding for HUMPHOSLIP PEA 2 P31 comprising a first amino acid sequence being at least 90 % homologous to MALFGALFLALLAGAHAEFPGCKIRVTSKALELVKQEGLRFLEQELETITIPDLRGKEGH FYYNISE conesponding to amino acids 1 - 67 of PLTP HUMAN, which also conesponds 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 conesponding to amino acids 68 - 98 of HUMPHOSLIP PEA 2 P31, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order
  • 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%>, more preferably at least about 90% and most preferably at least about 95%> homologous to the sequence PGLERGADKFPVVGGSSLFLALDLTLRPPVG in HUMPHOSLlT_PEA_2 J > 31.
  • an isolated chimeric polypeptide encoding for HUMPHOSLIP_PEA_2_P33 comprising a first amino acid sequence being at least 90 % homologous to MALFGALFLALLAGAHAEFPGCKIRVTSKALELVKQEGLRFLEQELETITIPDLRGKEGH FYYNISEVKVTELQLTSSELDFQPQQELMLQITNASLGLRFRRQLLYWFFYDGGYPNAS AEGVSIRTGLELSRDPAGRMKVSNVSCQASVSRMHAAFGGTFKKVYDFLSTFITSGMRF LLNQQ conesponding to amino acids 1 - 183 of PLTPJTUMAN, 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
  • 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 > EA_2_P33.
  • an isolated chimeric polypeptide encoding for HUMPHOSLIP PEA 2 P34 comprising a first amino acid sequence being at least 90 % homologous to
  • 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 conesponding to amino acids 206 - 217 of HUMPHOSLIP J ⁇ A_2_P34, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • 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 > EA_2 > 34.
  • an isolated chimeric polypeptide encoding for HUMPHOSLIP_PEA_2_P35 comprising a first amino acid sequence being at least 90 % homologous to
  • 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 50 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.
  • an isolated polypeptide encoding for a tail of HUMPHOSLIP PEA 2JP35 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 > EA_2J > 35.
  • an isolated chimeric polypeptide encoding for T59832_P7 comprising a first amino acid sequence being at least 90 %> homologous to
  • an isolated polypeptide encoding for a tail of T59832_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 VRIFLALSLTL ⁇ VPWSQGWTRQRDQR in T59832_P7.
  • an isolated chimeric polypeptide encoding for T59832_P9 comprising a first amino acid sequence being at least 90 % homologous to
  • GILT HUMAN which also conesponds to amino acids 1 - 203 of T59832 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 NPWKIRPSSLPLSASCTRARSRMSALPQPAPSGVFASSDGR conesponding to amino acids 204 - 244 of T59832 P9, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of T59832_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 NPWKIRPSSLPLSASCTRARSRMSALPQPAPSGVFASSDGR in T59832 P9.
  • an isolated chimeric polypeptide encoding for T59832_P12 comprising a first amino acid sequence being at least 90 % homologous to MTLSPLLLFLPPLLLLLDVPTAAVQASPLQALDFFGNGPPVNYKTGNLYLRGPLKKSNA PLVNVTLYYEALCGGCRAFLIRELFPTWLLVMEILNVTLVPYGNAQEQNVSGRWEFKC QHGEEECKFNKVE conesponding to amino acids 12 - 141 of GILT_HUMAN, which also conesponds to amino acids 1 - 130 of T59832 P12, and a second amino acid sequence being at least 90 % homologous to CLQLYAPGLSPDTIMECAMGDRGMQLMHANAQRTDALQPPHEYVPWVTVNGKPLED QTQLLTLVCQLYQGKKPDVCPSSTSSLRSVCFK conesponding to amino acids 173 - 261 of GILT_HUMAN,
  • an isolated chimeric polypeptide encoding for an edge portion of T59832 P12 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 EC, having a structure as follows: a sequence starting from any of amino acid numbers 130-x to 130; and ending at any of amino acid numbers 131+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for T59832 P18 comprising a first amino acid sequence being at least 90 % homologous to MTLSPLLLFLPPLLLLLDVPTAAVQASPLQALDFFGNGPPVNYK conesponding to amino acids 12 - 55 of GILT JIUMAN, which also conesponds to amino acids 1 - 44 of T59832_P18, and a second amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for an edge portion of T59832_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 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 KC, having a structure as follows: a sequence starting from any of amino acid numbers 44-x to 44; and ending at any of amino acid numbers 45+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HSCP2 PEAJ P4 comprising a first amino acid sequence being at least 90 %> homologous to
  • an isolated polypeptide encoding for a tail of HSCP2 PEAJ P4 comprising a polypeptide being at least 70%o, 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 GGTSM in HSCP2 PEA J P4.
  • an isolated chimeric polypeptide encoding for HSCP2 PEAJ P8 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of HSCP2 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 KCFQEHLEFGYSTAM in HSCP2_PEA_1_P8.
  • an isolated chimeric polypeptide encoding for HSCP2 PEAJ P14 comprising a first amino acid sequence being at least 90 %> homologous to MKILILGIFLFLCSTPAWAKEKHYYIGIIETTWDYASDHGEKKLISVDTEHSNIYLQNGPD RIGRLYKKALYLQYTDETFRTTIEKPVWLGFLGPIIKAETGDKVYVHLKNLASRPYTFHS HGITYYKEHEGAIYPDNTTDFQRADDKVYPGEQYTYMLLATEEQSPGEGDGNCVTRIY HSHIDAPKJJIASGLIGPL ⁇ CKKDSLDKEKEKHIDREFVVMFSVVDENFSWYLEDNIKTY CSEPEKVDKDNEDFQESNRMYSVNGYTFGSLPGLSMCAEDRVKWYLFGMGNEVDVH AAFFHGQALTNKNYRIDTINLFPATLFDAYMVAQNPGEWMLSC
  • an isolated polypeptide encoding for an edge portion of HSCP2 PEA _1_P14 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 HWT having a structure as follows (numbering according to HSCP2 PEAJ P14): a sequence starting from any of amino acid numbers 621-x to 621; and ending at any of amino acid numbers 623 + ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HSCP2 PEAJ P15 comprising a first amino acid sequence being at least 90 % homologous to MKILILGIFLFLCSTPAWAKEKHYYIGIIETTWDYASDHGEKKLISVDTEHSNIYLQNGPD RIGRLYKKALYLQYTDETFRTTIEKPVWLGFLGPIIKAETGDKVYVHLKNLASRPYTFHS HGITYYKEHEGAIYPDNTTDFQRADDKVYPGEQYTYMLLATEEQSPGEGDGNCVTRIY HSHIDAPKDIASGLIGPLIICKKDSLDK KEKHIDREFVVMFSVVDENFSWYLEDNIKTY CSEPEKVDKDNEDFQESNRMYSVNGYTFGSLPGLSMCAEDRVKWYLFGMGNEVDVH AAFFHGQALU KN ⁇ RIDTINLFPATLFDAYMVAQNPGEWMLSCQNL
  • an isolated chimeric polypeptide encoding for HSCP2 PEA J P2 comprising a first amino acid sequence being at least 90 %> homologous to
  • VHFHGHSFQYKH conesponding to amino acids 1 - 1007 of CERU_HUMAN which also conesponds to amino acids 1 - 1007 of HSCP2 PEAJ P16
  • a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%o, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence LLRLTGEYGM conesponding to amino acids 1008 - 1017 of HSCP2 PEAJ P16, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of HSCP2 PEAJ 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%o homologous to the sequence LLRLTGEYGM in HSCP2_PEA_1_P16.
  • an isolated chimeric polypeptide encoding for HSCP2 PEAJ P6 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for HSCP2 PEAJ P22 comprising a first amino acid sequence being at least 90 % homologous to MK1LILGIFLFLCSTPAWAKEKHYYIGIIETTWDYASDHGEKKLISVDTEHSNIYLQNGPD RIGRLYKKALYLQYTDETFRTTIEKPVWLGFLGPIIKAETGDKVYVHLKNLASRPYTFHS HGITYYKEHE conesponding to amino acids 1 - 131 of CERU_HUMAN, which also conesponds to amino acids 1 - 131 of HSCP2 PEA J P22, a second amino acid sequence bridging amino acid sequence comprising of A, and a third amino acid sequence being at least 90 % homologous to VNGYTFGSLPGLSMCAEDRVKWYLFGMGNEVDVHAAFFHGQALTNKNYRIDTINLFP ATLFDAYMVAQNPGEWMLSCQ
  • an isolated polypeptide encoding for an edge portion of HSCP2 PEA J P22 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 EAV having a structure as follows (numbering according to HSCP2 PEA _1_P22): a sequence starting from any of amino acid numbers 131-x to 131; and ending at any of amino acid numbers 133 + ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HSCP2 PEAJ P24 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 MPLTMGKRNLFLLTP conesponding to amino acids 1 - 15 of HSCP2_PEA_1_P24, and a second amino acid sequence being at least 90 % homologous to
  • DIFPGTYQTLEMFPRTPGIWLLHCHVTDHIHAGMETTYTVLQNEDTKSG conesponding to amino acids 262 - 1065 of CERU HUMAN, which also corresponds to amino acids 16 - 819 of HSCP2 PEA 1 P24, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a head of HSCP2 PEAJ 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 MPLTMGKRNLFLLTP of HSCP2 PEA J J > 24.
  • an isolated chimeric polypeptide encoding for HSCP2_PEA_1_P25 comprising a first amino acid sequence being at least 90 % homologous to MKILILGIFLFLCSTPAWAKEKHYYIGIIETTWDYASDHGEKKLISVDTEHSNIYLQNGPD RIGRLYKKALYLQYTDETFRTTIEKPVWLGFLGPIIKAETGDKVYVHLKNLASRPYTFHS HGITYYKEHEGAIYPDNTTDFQRADDKVYPGEQYTYMLLATEEQSPGEGDGNCVTRJY HSHIDAPKDIASGLIGPLIICKKDSLDKEKEKHIDREFVVMFSVVDENFSWYLEDNIKTY CSEPEKVDKDNEDFQESNRMYSVNGYTFGSLPGLSMCAEDRVKWYLFGMGNEVDVH AAFFHGQALTNKNYRIDTPNLFPATLFDAYMVAQNPGEWMLS
  • CERU HUMAN which also conesponds to amino acids 1 - 621 of HSCP2_PEAJ_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 CKYCIIHQSTKLF conesponding to amino acids 622 - 634 of HSCP2 PEAJ P25, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of HSCP2 PEA J 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 CKYCIIHQSTKLF in HSCP2 PEA 1 P25.
  • an isolated chimeric polypeptide encoding for HSCP2 PEA _1_P33 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of HSCP2 PEA J 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 GTSSPYCTCYMTKRQGQGSLSFKKKSSLLC in HSCP2_PEA_1_P33.
  • HUMTEN PEA J P5 wherein said first amino acid sequence, second amino acid sequence and third amino acid sequence are contiguous and in a sequential order.
  • an isolated polypeptide encoding for an edge portion of HUMTEN PEA J P5 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
  • HUMTEN_PEA_1_P5 an isolated chimeric polypeptide encoding for HUMTEN PEAJ P6, comprising a first amino acid sequence being at least 90 %> homologous to
  • an isolated chimeric polypeptide encoding for HUMTEN_PEA_1_P7 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of HUMTEN 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 GISNQVSHLFLFLVPFCVICLPDRHDFNIFVHIPYLIHKCSLLFHLLPTLPLVICT in HUMTEN_PEA_1_P7.
  • an isolated chimeric polypeptide encoding for HUMTEN PEAJ P8 comprising a first amino acid sequence being at least 90 %> homologous to
  • an isolated chimeric polypeptide encoding for an edge portion of HUMTEN_PEA J_P8, 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 TT, having a structure as follows: a sequence starting from any of amino acid numbers 1525-x to 1525; and ending at any of amino acid numbers 1526+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HUMTEN PEA J P10 comprising a first amino acid sequence being at least 90 %> homologous to MGAMTQLLAGVFLAFLALATEGGVLKKVIRHKRQSGVNATLPEENQPVVFNHVYNIK LPVGSQCSVDLESASGEKDLAPPSEPSESFQEHTVDGENQIVFTHPJNIPRRACGCAAAP DVKELLSRLEELENLVSSLREQCTAGAGCCLQPATGRLDTRPFCSGRGNFSTEGCGCVC EPGWKGPNCSEPECPGNCHLRGRCIDGQCICDDGFTGEDCSQLACPSDCNDQGKCVNG VCICFEGYAGADCSREICPVPCSEEHGTCVDGLCVCHDGFAGDDCNKPLCLNNCYNRG RCVENECVCDEGFTGEDCSELICPNDCFDRGRCINGTCYCEEGFTGEDCGKPTCPHACH TQGRCEEGQCVCD
  • an isolated chimeric polypeptide encoding for an edge portion of HUMTEN_PEA_1_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 LT, having a structure as follows: a sequence starting from any of amino acid numbers 1252-x to 1252; and ending at any of amino acid numbers 1253+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HUMTEN_PEA J P13 comprising a first amino acid sequence being at least 90 % homologous to MGAMTQLLAGVFLAFLALATEGGVLKKVIRHKRQSGVNATLPEENQPVVFNHVYNIK LPVGSQCSVDLESASGEKDLAPPSEPSESFQEHTVDGENQIVFTHRINIPRRACGCAAAP DVKELLSRLEELENLVSSLREQCTAGAGCCLQPATGRLDTRPFCSGRGNFSTEGCGCVC EPGWKGPNCSEPECPGNCHLRGRCIDGQCICDDGFTGEDCSQLACPSDCNDQGKCVNG VCICFEGYAGADCSREICPVPCSEEHGTCVDGLCVCHDGFAGDDCNKPLCLNNCYNRG RCVENECVCDEGFTGEDCSELICPNDCFDRGRCINGTCYCEEGFTGEDCGKPTCPHACH TQGRCEEGQCVCD
  • HUMTEN_PEA_1_P13 wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated chimeric polypeptide encoding for an edge portion of HUMTEN PEA 1 P13 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 VT, having a structure as follows: a sequence starting from any of amino acid numbers 1343-x to 1343; and ending at any of amino acid numbers 1344+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HUMTEN PEAJ P14 comprising a first amino acid sequence being at least 90 % homologous to MGAMTQLLAGVFLAFLALATEGGVLKKVIRHKRQSGVNATLPEENQPWFNHVYNIK LPVGSQCSVDLESASGEKDLAPPSEPSESFQEHTVDGENQIVFTHRTNIPRRACGCAAAP DVKELLSRLEELENLVSSLREQCTAGAGCCLQPATGRLDTRPFCSGRGNFSTEGCGCVC EPGWKGPNCSEPECPGNCHLRGRCIDGQCICDDGFTGEDCSQLACPSDCNDQGKCVNG VCICFEGYAGADCSREICPVPCSEEHGTCVDGLCVCHDGFAGDDCNKPLCLNNCYNRG RCVENECVCDEGFTGEDCSELICPNDCFDRGRCINGTCYCEEGFTGEDCGKPTCPHACH TQGRCEEGQCVCDEGFA
  • an isolated polypeptide encoding for a tail of HUMTEN_PEAJ_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 STTRDCRALRPRGRGRGQSRGGEEGDLLLMHSDTPMCEALQDSACHTEALRNSLLNKR MGNTLATF in HUMTEN PEA J P14.
  • an isolated chimeric polypeptide encoding for HUMTEN_PEA J P15 comprising a first amino acid sequence being at least 90 % homologous to MGAMTQLLAGVFLAFLALATEGGVLKKVIRHKRQSGVNATLPEENQPVVFNHVYNIK LPVGSQCSVDLESASGEKDLAPPSEPSESFQEHTVDGENQIVFTHRINIPRRACGCAAAP DVKELLSRLEELENLVSSLREQCTAGAGCCLQPATGRLDTRPFCSGRGNFSTEGCGCVC EPGWKGPNCSEPECPGNCHLRGRCIDGQCICDDGFTGEDCSQLACPSDCNDQGKCVNG VCICFEGYAGADCSREICPVPCSEEHGTCVDGLCVCHDGFAGDDCNKPLCLNNCYNRG RCVENECVCDEGFTGEDCSELICPNDCFDRGRCINGTCYCEEGFTGEDCGKPTCPHACH TQGRCEEGQCVCD
  • an isolated chimeric polypeptide encoding for an edge portion of HUMTEN_PEA_1_P15 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 ST, having a structure as follows: a sequence starting from any of amino acid numbers 1070-x to 1070; and ending at any of amino acid numbers 1071+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HUMTEN_PEA_1_P16 comprising a first amino acid sequence being at least 90 % homologous to MGAMTQLLAGVFLAFLALATEGGVLKKVIRHKRQSGVNATLPEENQPVVFNHVYNIK LPVGSQCSVDLESASGEKDLAPPSEPSESFQEHTVDGENQIVFTHRINIPRRACGCAAAP DVKELLSRLEELENLVSSLREQCTAGAGCCLQPATGRLDTRPFCSGRGNFSTEGCGCVC EPGWKGPNCSEPECPGNCHLRGRCIDGQCICDDGFTGEDCSQLACPSDCNDQGKCVNG VCICFEGYAGADCSREICPVPCSEEHGTCVDGLCVCHDGFAGDDCNKPLCLNNCYNRG RCVENECVCDEGFTGEDCSELICPNDCFDRGRCINGTCYCEEGFTGEDCGKPTCPHACH TQGRCEEGQC
  • an isolated chimeric polypeptide encoding for an edge portion of HUMTEN_PEAJ_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 ST, having a structure as follows: a sequence starting from any of amino acid numbers 1070-x to 1070; and ending at any of amino acid numbers 1071+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HUMTEN PEA _1_P17 comprising a first amino acid sequence being at least 90 % homologous to
  • HUMTEN PEAJ P17 and a second amino acid sequence being at least 70%, optionally at least 80%o, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence TPWPTTMADPSPPLTRTQIQPSPTVLCPTKGLSGTGTVTVST conesponding to amino acids 2026 - 2067 of HUMTEN PEAJ P17, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of HUMTEN PEAJ 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
  • an isolated chimeric polypeptide encoding for HUMTEN_PEA_1_P20 comprising a first amino acid sequence being at least 90 %> homologous to
  • an isolated polypeptide encoding for a tail of HUMTEN PEAJ P20 comprising a polypeptide being at least 10%, 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 NAALHVYI in HUMTEN_PEA_1_P20.
  • an isolated chimeric polypeptide encoding for HUMTEN_PEA_1_P26 comprising a first amino acid sequence being at least 90 %> homologous to
  • HUMTEN_PEAJ_P26 wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of HUMTEN PEAJ P26 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 GTVNKQERTEKSHDSGVFFSQG in HUMTENJ ⁇ AJ JP26.
  • an isolated chimeric polypeptide encoding for HUMTEN_PEAJ_P27 comprising a first amino acid sequence being at least 90 % homologous to
  • T conesponding to amino acids 1 - 1344 of TENA_HUMAN_V1 which also conesponds to amino acids 1 - 1344 of HUMTEN PEA J P27
  • 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 Gl conesponding to amino acids 1345 - 1346 of HUMTEN PEAJ P27, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated chimeric polypeptide encoding for HUMTEN PEAJ P28 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of HUMTEN PEA 1 P28 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 GILDEFTNSLPPLCLCSGGIKALSCFKLGSAPTTLGKYQ in HUMTEN .
  • an isolated chimeric polypeptide encoding for HUMTEN_PEA_1_P29 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of HUMTEN PEAJ P29 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 GESALSFLQTLG in HUMTEN_PEA_1_P29.
  • an isolated chimeric polypeptide encoding for HUMTEN_PEAJ_P30 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of HUMTEN 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 ELCISASLSQPALEGP in HUMTEN PEAJ J > 30.
  • an isolated chimeric polypeptide encoding for FIUMTEN_PEA_1_P31 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of HUMTEN_PEA_1_P31 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 EYHL in HUMTEN_PEA_1_P31.
  • an isolated chimeric polypeptide encoding for HUMTEN_PEAJ_P32 comprising a first amino acid sequence being at least 90 % homologous to MGAMTQLLAGVFLAFLALATEGGVLKKVIRHKRQSGVNATLPEENQPVVFNHVYNIK LPVGSQCSVDLESASGEKDLAPPSEPSESFQEHTVDGENQIVFTHRINIPRRACGCAAAP DVKELLSRLEELENLVSSLREQCTAGAGCCLQPATGRLDTRPFCSGRGNFSTEGCGCVC EPGWKGPNCSEPECPGNCHLRGRCIDGQCICDDGFTGEDCSQLACPSDCNDQGKCVNG VCICFEGYAGADCSREICPVPCSEEHGTCVDGLCVCHDGFAGDDCNKPLCLNNCYNRG RCVENECVCDEGFTGEDCSELICPNDCFDRGRCINGTCYCEEGFTGEDCGKPTCPHACH TQGRCEEGQCVCD
  • an isolated polypeptide encoding for a tail of HUMOSTRO PEA J_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 PEAJ PEA 1 P21.
  • an isolated chimeric polypeptide encoding for HUMOSTRO PEA J PEAJ P25 comprising a first amino acid sequence being at least 90 % homologous to
  • 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 conesponding to amino acids 32 - 32 of HUMOSTRO J > EAJ PEA J P25, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated chimeric polypeptide encoding for HUMOSTRO PEA _1_PEA_1_P30 comprising a first amino acid sequence being at least 90 % homologous to
  • HUMOSTRO_PEAJ_PEAJ_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 conesponding to amino acids 32 - 39 of HUMOSTRO_PEAJ_PEAJ_P30, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of HUMOSTRO_PEA_1_PEAJ_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_PEAJ_P30.
  • an isolated chimeric polypeptide encoding for H61775_P16 comprising a first amino acid sequence being at least 90 % homologous to
  • 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.
  • an isolated chimeric polypeptide encoding for H61775_P16 comprising a first amino acid sequence being at least 90 % homologous to
  • 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. According to prefened 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
  • an isolated chimeric polypeptide encoding for H61775_P17 comprising a first amino acid sequence being at least 90 % homologous to MVWCLGLAVLSLVISQGADGRGKPEVVSVVGRAGESVVLGCDLLPPAGRPPLHVIEWL
  • an isolated chimeric polypeptide encoding for HSAPHOL_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
  • PATPRPLSWLRAPTRLCLDGPSPVLCA conesponding to amino acids 1 - 27 of AAH21289, which also conesponds to amino acids 23 - 49 of HSAPHOL P2, and a third amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a head of HSAPHOL 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 PHSGPAAAFIRRRGWWPGPRCA of HSAPHOL J > 2.
  • an isolated chimeric polypeptide encoding for an edge portion of HSAPHOL 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 AE, having a structure as follows: a sequence starting from any of amino acid numbers 49-x to 50; and ending at any of amino acid numbers 50+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HSAPHOL 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 PHSGPAAAFIRRRGWWPGPRCAPATPRPLSWLRAPTRLCLDGPSPVLCA conesponding to amino acids 1 - 49 of HSAPHOL P2, second amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a head of HSAPHOL 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 PHSGPAAAFIRRRGWWPGPRCAPATPRPLSWLRAPTRLCLDGPSPVLCA of HSAPHOL_P2.
  • an isolated chimeric polypeptide encoding for an edge portion of HSAPHOL 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 AE, having a structure as follows: a sequence starting from any of amino acid numbers 49-x to 50; and ending at any of amino acid numbers 50+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HSAPHOL P3, comprising a first amino acid sequence being at least 90 %> homologous to MISPFLVLAIGTCLTNSLVP conesponding to amino acids 63 - 82 of AAH21289, which also conesponds to amino acids 1 - 20 of HSAPHOL P3, and a second amino acid sequence being at least 90 % homologous to GMGVSTVTAAPJLKGQLHHNPGEETRLEMDKFPFVALSKTYNTNAQVPDSAGTATAYL CGVKANEGTVGVSAATERSRCNTTQGNEVTSILRWAKDAGKSVGIVTTTRVNHATPSA AYAHSADRDWYSDNEMPPEALSQGCKDIAYQLMHNIRDIDVIMGGGRKYMYPKNKTD VEYESDEKARGTRLDGLDLVDTWKSFKPRYKHSHFIWNRTELLTLDPHNVDYLLGLFE PGDM
  • an isolated chimeric polypeptide encoding for an edge portion of HSAPHOL P3, 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 PG, having a structure as follows: a sequence starting from any of amino acid numbers 20-x to 20; and ending at any of amino acid numbers 21+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HSAPHOL_P3, comprising a first amino acid sequence being at least 90 % homologous to MISPFLVLAIGTCLTNSLVP conesponding to amino acids 1 - 20 of PPBT HUMAN, which also conesponds to amino acids 1 - 20 of HSAPHOL_P3, and a second amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for an edge portion of HSAPHOL P3, 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 PG, having a structure as follows: a sequence starting from any of amino acid numbers 20-x to 20; and ending at any of amino acid numbers 21+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HSAPHOLJM comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for HSAPHOL M comprising a first amino acid sequence being at least 90 % homologous to MGVSTVTAARJLKGQLHHNPGEETRLEMDKFPFVALSKTYNTNAQVPDSAGTATAYLC GVKANEGTVGVSAATERSRCNTTQGNEVTSILRWAKDAGKSVGIVTTTRVNHATPSAA YAHSADRDWYSDNEMPPEALSQGCKDIAYQLMHNIRDIDVIMGGGRKYMYPKNKTDV EYESDEKARGTRLDGLDLVDTWKSFKPRYlKHSHFIWNRTELLTLDPHNVDYLLGLFEP GDMQYELNR NVTDPSLSEMVVVAIQILRKNPKGFFLLVEGGRIDHGHHEGKAKQALH EAVEMDRAIGQAGSLTSSEDTLTVVTADHSHVFTFGGYTPRGNSIFGLAPMLSDTDKKP FTAIL
  • an isolated chimeric polypeptide encoding for an edge portion of HSAPHOL 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 MD, having a structure as follows: a sequence starting from any of amino acid numbers 355-x to 355; and ending at any of amino acid numbers 356+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HSAPHOL P5 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for an edge portion of HSAPHOL 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 MD, having a structure as follows: a sequence starting from any of amino acid numbers 355-x to 355; and ending at any of amino acid numbers 356+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HSAPHOL P6 comprising a first amino acid sequence being at least 90 %> homologous to
  • an isolated chimeric polypeptide encoding for an edge portion of HSAPHOL 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 LG, having a structure as follows: a sequence starting from any of amino acid numbers 287-x to 287; and ending at any of amino acid numbers 288+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HSAPHOL_P6 comprising a first amino acid sequence being at least 90 % homologous to MISPFLVLAIGTCLTNSLVPEKEKDPKYWRDQAQETLKYALELQKLNTNVAKNVIMFL GDGMGVSTVTAARILKGQLHHNPGEETRLEMDKFPFVALSKTYNTNAQVPDS AGTAT AYLCGVKANEGTVGVSAATERSRCNTTQGNEVTSILRWAKDAGKSVG1VTTTRVNHA TPSAAYAHSADRDWYSDNEMPPEALSQGCKDIAYQLMHNIRDIDVIMGGGRKYMYPK NKTDVEYESDEKARGTRLDGLDLVDTWKSFKPRYKHSHFIWNRTELLTLDPHNVDYLL conesponding to amino acids 1 - 287 of PPBT HUMAN, which also conesponds to amino acids 1 - 287 of H
  • an isolated chimeric polypeptide encoding for an edge portion of HSAPHOL_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 LG, having a structure as follows: a sequence starting from any of amino acid numbers 287-x to 287; and ending at any of amino acid numbers 288+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HSAPHOL_P7 comprising a first amino acid sequence being at least 90 %> homologous to
  • an isolated polypeptide encoding for a tail of HS APHOL 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
  • an isolated chimeric polypeptide encoding for HSAPHOL_P7 comprising a first amino acid sequence being at least 90 %> homologous to MISPFLVLAIGTCLTNSLVPEKEKDPKYWRDQAQETLKYALELQKLNTNVAKNVIMFL GDGMGVSTVTAARILKGQLHHNPGEETRLEMDKFPFVALSKTYNTNAQVPDSAGTAT AYLCGVKANEGTVGVSAATERSRCNTTQGNEVTSILRWAKDAGKSVGIVTTTRVNHA TPSAAYAHSADRDWYSDNEMPPEALSQGCKDIAYQLMHNIRDIDVIMGGGRKYMYPK NKTDVEYESDEKARGTRLDGLDLVDTWKSFKPRYK conesponding to amino acids 1 -
  • an isolated polypeptide encoding for a tail of HSAPHOL 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 LPPRCPLANRVDFSWAGREYRLQTFSKPLIFLANVFLQTQRP in HSAPHOL J > 7.
  • an isolated chimeric polypeptide encoding for HSAPHOL_P8 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of HSAPHOL 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 KWRGWRGGCMARSLVAGAACGQHLGTRP in HSAPHOLJP8.
  • an isolated chimeric polypeptide encoding for HSAPHOL P8 comprising a first amino acid sequence being at least 90 % homologous to MISPFLVLAIGTCLTNSLVPEKEKDPKYWRDQAQETLKYALELQKLNTNVAKNVIMFL GDGMGVSTVTAARILKGQLHHNPGEETRLEMDKFPFVALSKTYNTNAQVPDSAGTAT AYLCGVKANEGTVGVSAATERSRCNTTQGNEVTSILRWAKDAGKSVGIVTTTRVNHA TPSAAYAHSADRDWYSDNEMPPEALSQGCKDIAYQLMHNIRDIDVIMGGGRKYMYPK NKTDVEYESDEKARGTRLDGLDLVDTWKSFKPRYKHSHFIWNRTELLTLDPHNVDYLL G conesponding to amino acids 1 - 288 of PPBT HUMAN, which also conesponds to amino acids 1 - 288 of HSA
  • an isolated polypeptide encoding for a tail of HSAPHOL 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 KWRGWRGGCMARSLVAGAACGQHLGTRP in HSAPHOL P8.
  • an isolated chimeric polypeptide encoding for HSAPHOL P8 comprising a first amino acid sequence being at least 90 %> homologous to
  • an isolated chimeric polypeptide encoding for T10888 PEAJ P2 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of T10888 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 DWTRP in T10888_PEA_1_P2.
  • an isolated chimeric polypeptide encoding for T10888J ⁇ AJ JP4 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of T10888_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 LLLSSQLWPPSASRLECWPGWL in T10888 PEAJ P4.
  • an isolated chimeric polypeptide encoding for T10888_PEAJ_P4 comprising a first amino acid sequence being at least 90 % homologous to MGPPSAPPCRLHVPWKEVLLTASLLTFWNPPTTAKLTIESTPFNVAEGKEVLLLAHNLP QNRIG YS WYKGERVDGNSLIVGYVIGTQQATPGPAYSGRETIYPNASLLIQNVTQNDTG FYTLQVIKSDLVNEEATGQFHVYPELPKPSISSNNSNPVEDKDAVAFTCEPEVQNTTYL WWVNGQSLPVSPRLQLSNGNMTLTLLSVKRNDAGSYECEIQNPASANRSDPVTLNVL conesponding to amino acids 1 - 234 of Q 13774, which also conesponds to amino acids 1 - 234 of T10888 PEAJ P4, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at
  • an isolated polypeptide encoding for a tail of T10888_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 LLLSSQLWPPSASRLECWPGWL in T10888_PEA_1_P4.
  • an isolated chimeric polypeptide encoding for T10888 PEAJ P5 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of T10888_PEAJ_P5 comprising a polypeptide being at least 10%, 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 KWIHEALASHFQVESGSQRRARKKFSFPTCVQGAHANPKFSPEPSQFTSADSFPLVFLFF VVFCFLISHV in T10888_PEA_1_P5.
  • an isolated chimeric polypeptide encoding for T10888 PEAJ P6 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of T10888 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 REYFHMTSGCWGSVLLPTYGIVRPGLCLWPSLHYILYQGLD1 in T10888 PEA 1 P6.
  • an isolated chimeric polypeptide encoding for HSECADH P9 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of HSECADH 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 TACRSRIANSCHSGDSWRNSCFANSDSAALAVSSEESGGQRALTAPRG in HSECADH J > 9.
  • an isolated chimeric polypeptide encoding for HSECADH P9 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of HSECADH P9 comprising a polypeptide being at least 70%), optionally at least about 80%>, preferably at least about 85%o, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TACRSRIANSCHSGDSWRNSCFANSDSAALAVSSEESGGQRALTAPRG in HSECADH P9.
  • an isolated chimeric polypeptide encoding for HSECADH_P9 comprising a first amino acid sequence being at least 90 % homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEG conesponding to amino acids 1 - 274 of CADI HUMAN, which also conesponds to amino acids 1 - 274 of HSECADH P9, and a
  • an isolated polypeptide encoding for a tail of HSECADH 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 TACRSRIANSCHSGDSWRNSCFANSDSAALAVSSEESGGQRALTAPRG in HSECADH P9.
  • an isolated chimeric polypeptide encoding for HSECADH P13 comprising a first amino acid sequence being at least 90 %> homologous to
  • an isolated chimeric polypeptide encoding for HSECADHJP13 comprising a first amino acid sequence being at least 90 %> homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTAYFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNT YNAAIAYTILSQDPELPDKNMFTINRNTGVISVVTTGLDRESFPTYTLVVQAADLQGE
  • an isolated chimeric polypeptide encoding for HSECADH P14 comprising a first amino acid sequence being at least 90 % homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTA YFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNT YNAAIAYTILSQDPELPDKNMFTINRNTGVISVVTTGLDRE conesponding to amino acids 1 -
  • an isolated polypeptide encoding for a tail of HSECADH 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 VRGQEDPEGVEDKCVLAQSRGQSKILLGQLSVNTVMV in HSECADH . P14.
  • an isolated chimeric polypeptide encoding for HSECADH P14 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of HSECADH 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 VRGQEDPEGVEDKCVLAQSRGQSKILLGQLSVNTVMV in HSECADH .P14.
  • an isolated chimeric polypeptide encoding for HSECADH P14 comprising a first amino acid sequence being at least 90 % homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTA YFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYAWDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYTLFSHAVSSN GNAVEDPMEILITVTDQNDNKPEFTQEVFKGSVMEGALPGTSVMEVTATDADDDVNT YNAAIAYTILSQDPELPDKNMFTINRNTGVISWTTGLDRE conesponding to amino acids
  • an isolated polypeptide encoding for a tail of HSECADH P14 comprising a polypeptide being at least 70%), optionally at least about 80%, preferably at least about 85%, more preferably at least about 90%o and most preferably at least about 95% homologous to the sequence VRGQEDPEGVEDKCVLAQSRGQSKILLGQLSVNTVMV in HSECADH J> 14.
  • an isolated chimeric polypeptide encoding for HSECADH P15 comprising a first amino acid sequence being at least 90 % homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRT A YFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYA WDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYT conesponding to amino acids 1 - 229 of Q9UII7, which also conesponds to amino acids 1 - 229 of HSECADH P15, and a second amino acid sequence VSIS conesponding to amino acids 230 - 233 of HSECADH
  • an isolated chimeric polypeptide encoding for HSECADH P15 comprising a first amino acid sequence being at least 90 % homologous to MGPWSRSLSALLLLLQVSSWLCQEPEPCHPGFDAESYTFTVPRRHLERGRVLGRVNFED CTGRQRTA YFSLDTRFKVGTDGVITVKRPLRFHNPQIHFLVYA WDSTYRKFSTKVTLNT VGHHHRPPPHQASVSGIQAELLTFPNSSPGLRRQKRDWVIPPISCPENEKGPFPKNLVQI KSNKDKEGKVFYSITGQGADTPPVGVFIIERETGWLKVTEPLDRERIATYT conesponding to amino acids 1 - 229 of Q9UII8, which also conesponds to amino acids 1 - 229 of HSECADH J 5, and a second amino acid sequence VSIS conesponding to amino acids 230 - 233 of HSECADH J 5, wherein
  • MTLSPLLLFLPPLLLLLDVPTAAVQASPLQALDFFGNGPPVNYK conesponding to amino acids 12 - 55 of GILT HUMAN, which also conesponds to amino acids 1 - 44 of T59832 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
  • an isolated polypeptide encoding for a tail of T59832_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
  • an isolated chimeric polypeptide encoding for T59832_P7 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of T59832 P7 comprising a polypeptide being at least 10%, 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 VRIFLALSLTLIVPWSQGWTRQRDQR in T59832_P7.
  • an isolated chimeric polypeptide encoding for T59832 P7 comprising a first amino acid sequence being at least 90 % homologous to MTLSPLLLFLPPLLLLLDVPTAAVQASPLQALDFFGNGPPVNYKTGNLYLRGPLKKSNA PLVNVTLYYEALCGGCRAFLIRELFPTWLLVMEILNVTLVPYGNAQEQNVSGRWEFKC QHGEEECKFNKVEACVLDELDMELAFLTIVCMEEFEDMERSLPLCLQLYAPGLSPDTIM ECAMGDRGMQLMHANAQRTDALQPPHEYVPWVTVNG conesponding to amino acids 1 - 212 of BAC98466, which also conesponds to amino acids 1 - 212 of T59832 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
  • an isolated polypeptide encoding for a tail of T59832_P7 comprising a polypeptide being at least 70%o, 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 VRIFLALSLTLIVPWSQGWTRQRDQR in T59832_P7.
  • an isolated chimeric polypeptide encoding for T59832 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 MTLSPLLLFLPPLLLLLDVPTAAVQASPLQALDFFGNGPPVNYKTGNLYLRGPLKKSNA PLVNVTLYYEALCGGCRAFLIRELFPTWLLV conesponding to amino acids 1 - 90 of T59832 P7, and a second amino acid sequence being at least 90 %> homologous to MEILNVTLVPYGNAQEQNVSGRWEFKCQHGEEECKFNKVEACVLDELDMELAFLTIVC MEEFEDMERSLPLCLQLYAPGLSPDTIMECAMGDRGMQLMHANAQRTDALQPPHEYV PWVTVNGVRIFLALSLTLIVPWSQGWTR
  • an isolated polypeptide encoding for a head of T59832 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 MTLSPLLLFLPPLLLLLDVPTAAVQASPLQALDFFGNGPPVNYKTGNLYLRGPLKKSNA PLVNVTLYYEALCGGCRAFLIRELFPTWLLV of T59832_P7.
  • an isolated chimeric polypeptide encoding for T59832_P7 comprising a first amino acid sequence being at least 90 % homologous to MTLSPLLLFLPPLLLLLDVPTAAVQASPLQALDFFGNGPPVNYKTGNLYLRGPLKKSNA PLVNVTLYYEALCGGCRAFLIRELFPTWLLVMEILNVTLVPYGNAQEQNVSGRWEFKC QHGEEECKFNKVEACVLDELDMELAFLTIVCMEEFEDMERSLPLCLQLYAPGLSPDTIM ECAMGDRGMQLMHANAQRTDALQPPHEYVPWVTVNG conesponding to amino acids 1 - 212 of Q8WU77, which also corresponds to amino acids 1 - 212 of.T59832_P7, and a second amino acid sequence being at least 70%o, optionally at least 80%, preferably at least 85% > , more preferably at least 90% and most preferably at least 95% homo
  • an isolated polypeptide encoding for a tail of T59832_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 VRIFLALSLTLIVPWSQGWTRQRDQR in T59832_P7.
  • an isolated chimeric polypeptide encoding for T59832_P9 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of T59832 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 NPWKIRPSSLPLSASCTRARSRMSALPQPAPSGVFASSDGR in T59832_P9.
  • an isolated chimeric polypeptide encoding for T59832 P9 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of T59832 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 NPWKIRPSSLPLSASCTRARSRMSALPQPAPSGVFASSDGR in T59832JP9.
  • an isolated chimeric polypeptide encoding for T59832_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 MTLSPLLLFLPPLLLLLDVPTAAVQASPLQALDFFGNGPPVNYKTGNLYLRGPLKKSNA PLVNVTLYYEALCGGCRAFLIRELFPTWLLV conesponding to amino acids 1 - 90 of T59832_P9, second amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a head of T59832_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 MTLSPLLLFLPPLLLLLDVPTAAVQASPLQALDFFGNGPPVNYKTGNLYLRGPLKKSNA PLVNVTLYYEALCGGCRAFLIRELFPTWLLV of T59832_P9.
  • an isolated polypeptide encoding for a tail of T59832 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 NPWKIRPSSLPLSASCTRARSRMSALPQPAPSGVFASSDGR in T59832J 9.
  • an isolated chimeric polypeptide encoding for T59832_P9 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of T59832_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 NPWKIRPSSLPLSASCTRARSRMSALPQPAPSGVFASSDGR in T59832_P9.
  • an isolated chimeric polypeptide encoding for T59832_P12 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for an edge portion of T59832 P12 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 EC, having a structure as follows: a sequence starting from any of amino acid numbers 130-x to 130; and ending at any of amino acid numbers 131+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for T59832 P12 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 MTLSPLLLFLPPLLLLLDVPTAAVQASPLQALDFFGNGPPVNYKTGNLYLRGPLKKSNA PLVNVTLYYEALCGGCRAFLIRELFPTWLLV conesponding to amino acids 1 - 90 of T59832_P12, second amino acid sequence being at least 90 % homologous to MEILNVTLVPYGNAQEQNVSGRWEFKCQHGEEECKFNKVE conesponding to amino acids 1 - 40 of BAC85622, which also conesponds to amino acids 91 - 130 of T59832 P 12, third amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a head of T59832_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 MTLSPLLLFLPPLLLLLDVPTAAVQASPLQALDFFGNGPPVNYKTGNLYLRGPLKKSNA PLVNVTLYYEALCGGCRAFLIRELFPTWLLV of T59832 JP 12.
  • an isolated chimeric polypeptide encoding for an edge portion of T59832 P12 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 EC, having a structure as follows: a sequence starting from any of amino acid numbers 130-x to 130; and ending at any of amino acid numbers 131+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated polypeptide encoding for a tail of T59832 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 KPLEDQTQLLTLVCQLYQGKKPDVCPSSTSSLRSVCFK in T59832J 2.
  • an isolated chimeric polypeptide encoding for T59832_P12 comprising a first amino acid sequence being at least 90 %> homologous to MTLSPLLLFLPPLLLLLDVPTAAVQASPLQALDFFGNGPPVNYKTGNLYLRGPLKKSNA PLVNVTLYYEALCGGCRAFLIRELFPTWLLVMEILNVTLVPYGNAQEQNVSGRWEFKC QHGEEECKFNKVE conesponding to amino acids 1 - 130 of Q8WU77, which also conesponds to amino acids 1 - 130 of T59832_P12, and a second amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for an edge portion of T59832_P12 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 EC, having a structure as follows: a sequence starting from any of amino acid numbers 130-x to 130; and ending at any of amino acid numbers 131+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for T59832 P18 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for an edge portion of T59832JP18 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 KC, having a structure as follows: a sequence starting from any of amino acid numbers 44-x to 44; and ending at any of amino acid numbers 45+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for T59832_P18 comprising a first amino acid sequence being at least 90 %> homologous to
  • an isolated chimeric polypeptide encoding for an edge portion of T59832J 8 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 KC, having a structure as follows: a sequence starting from any of amino acid numbers 44-x to 44; and ending at any of amino acid numbers 45+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for T59832 P18 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for an edge portion of T59832_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 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 KC, having a structure as follows: a sequence starting from any of amino acid numbers 44-x to 44; and ending at any of amino acid numbers 45+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HUMGRP5E_P4 comprising a first amino acid sequence being at least 90 %> homologous to MRGSELPLVLLALVLCLAPRGRAVPLPAGGGTVLTKMYPRGNHWAVGHLMGKKSTG ESSSVSERGSLKQQLREYIRWEEAARNLLGLIEAKENRNHQPPQPKALGNQQPSWDSED SSNFKDVGSKGK conesponding to amino acids 1 - 127 of GRP_HUMAN, which also conesponds to amino acids 1 - 127 of HUMGRP5E_P4, and a second amino acid sequence being at least 90 % homologous to GSQREGRNPQLNQQ conesponding to amino acids 135 - 148 of GRP_HUMAN, which also conesponds to amino acids 128 - 141 of HUMGRP5E P4, wherein said first and second amino acid sequences are con
  • an isolated chimeric polypeptide encoding for an edge portion of HUMGRP5EJM 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.
  • an isolated chimeric polypeptide encoding for HUMGRP5E P5, comprising a first amino acid sequence being at least 90 % homologous to MRGSELPLVLLALVLCLAPRGRAVPLPAGGGTVLTKMYPRGNHWAVGHLMGKKSTG ESSSVSERGSLKQQLREYIRWEEAARNLLGLIEAKENRNHQPPQPKALGNQQPSWDSED SSNFKDVGSKGK conesponding to amino acids 1 - 127 of GRP_HUMAN, which also conesponds to amino acids 1 - 127 of HUMGRP5E 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%.
  • an isolated polypeptide encoding for a head of Rl 1723_PEAJ_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
  • Rl 1723_PEA_1_P6 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of Rl 1723 PEAJ 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 SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLVVGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPWLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ in R11723_PEA_1_P6.
  • an isolated chimeric polypeptide encoding for Rl 1723_PEA_1_P6 comprising a first amino acid sequence being at least 90 % homologous to
  • 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 SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLVVGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREG EEDHVRPEVGPRPV VLGFGRSHDPPNLVGHP AYGQ CHNNQPWADTSRRERQRKEKHSMRTQ in R1 1723_PEA_1_P6.
  • an isolated polypeptide encoding for a tail of Rl 1723 PEAJ 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 SPCRGLAPGREEQRALHKAGAVGGGVRMYAQALLVVGVLQRQAAAQHLHEHPPKLL RGHRVQERVDDRAEVEKRLREGEEDHVRPEVGPRPVVLGFGRSHDPPNLVGHPAYGQ CHNNQPWADTSRRERQRKEKHSMRTQ in R11723 PEAJ P6.
  • an isolated chimeric polypeptide encoding for Rl 1723_PEA_1_P7 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail 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 SHCVTRLECSGTISAHCNLCLPGSNDHPT in R11723_PEA_1_P7.
  • 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 conesponding to amino acids 1 - 64 of Q8N2G4, which also conesponds to amino acids 1 - 64 ofRl 1723_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 conesponding to amino acids 65 - 93 of
  • Rl 1723 PEAJ P7 wherein said first and second amino acid sequences are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of Rl 1723_PEAJ_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
  • 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%o homologous to a polypeptide having the sequence
  • Rl 1723_PEA_1_P7 64 of Rl 1723_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
  • 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
  • an isolated polypeptide encoding for a tail 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
  • an isolated chimeric polypeptide encoding for Rl 1723 PEA 1 P7 comprising a first amino acid sequence being at least 90 % homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV
  • an isolated polypeptide encoding for a tail of Rl 1723J ⁇ AJ JP7 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 R11723 PEAJ P7.
  • an isolated chimeric polypeptide encoding for Rl 1723 PEA 1 P13 comprising a first amino acid sequence being at least 90 %> homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSA conesponding to amino acids 1 - 63 of Q96AC2, which also conesponds to amino acids 1 - 63 of Rl 1723_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 preferably at least 95% homologous to a polypeptide having the sequence DTKRTNTLLFEMRHFAKQLTT conesponding to amino acids 64 - 84 of
  • Rl 1723 PEAJ P13 wherein said first and second amino acid sequences are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of Rl 1723 PEAJ 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 Rl 1723_PEA_1_P13.
  • an isolated chimeric polypeptide encoding for Rl 1723 PEAJ P10 comprising a first amino acid sequence being at least 90 %> homologous to
  • 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 DRVSLCHEAGVQWNNFSTLQPLPPRLK in R11723J ⁇ AJ J > 10.
  • an isolated chimeric polypeptide encoding for Rl 1723 PEAJ P10 comprising a first amino acid sequence being at least 90 % homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSA conesponding to amino acids 1 - 63 of Q8N2G4, which also conesponds to amino acids 1 - 63 of Rl 1723 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 conesponding to amino acids 64 - 90 of Rl 1723 PEAJ P10, wherein said first and second amino acid sequences are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of Rl 1723 PEAJ 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 R11723_PEA_1_P10.
  • an isolated chimeric polypeptide encoding for Rl 1723 PEAJ 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 Rl 1723J ⁇ AJ P10, second amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a head 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 MWVLG of Rl 1723_PEA_1_P10.
  • an isolated polypeptide encoding for a tail of Rl 1723 PEAJ 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 R11723_PEA_1_P10.
  • an isolated chimeric polypeptide encoding for R11723_PEAJ_P10 comprising a first amino acid sequence being at least 90 %> homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSA conesponding to amino acids 24 - 86 of BAC85518, which also conesponds to amino acids 1 - 63 of Rl 1723 PEAJ J 0, 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 conesponding to amino acids 64 - 90 of R l 1723_PEA_I_P 10, wherein said first and second amino acid sequences are contiguous and in a sequential order.
  • 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%o and most preferably at least about 95% homologous to the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK in R1 1723J ⁇ AJ P10.
  • an isolated chimeric polypeptide encoding for D56406_PEA_1_P2 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for an edge portion of D56406 PEA J 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, conesponding to D56406_PEA_1_P2.
  • 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 NEUTJTUMAN, 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
  • an isolated chimeric polypeptide encoding for H53393_PEA_1_P2 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for H53393 PEAJ P3, comprising a first amino acid sequence being at least 90 % homologous to MRTYRYFLLLFWVGQPYPTLSTPLSKRTSGFPAKKRALELSGNSKNELNRSKRSWMWN QFFLLEEYTGSDYQYVGKLHSDQDRGDGSLKYILSGDGAGDLFIINENTGDIQATKRLD REEK VYILRAQAINRRTGRPVEPESEFID HDINDNEPIFTKEVYTATVPEMSDVGTFVV QVTATDADDPTYGNSAKVVYSILQGQPYFSVESETGIIKTALLNMDRENREQYQWIQA KDMGGQMGGLSGTTTVNITLTDVNDNPPRFPQSTYQFKTPESSPPGTPIGRIKASDADV GENAEIEYSITDGEGLDMFDVITDQETQEGIITVKJOXDFEKKKVYTL
  • an isolated polypeptide encoding for a tail of H53393_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 VMPLLKHHTE in H53393 PEA 1 P6.
  • an isolated chimeric polypeptide encoding for HSU40434 PEAJ JM2 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for HSU40434 PEA 1 P12 comprising a first amino acid sequence being at least 90 % homologous to MALPTARPLLGSCGTPALGSLLFLLFSLGWVQPSRTLAGETGQ conesponding to amino acids 1 - 43 of Q9BTR2, which also conesponds to amino acids 1 - 43 of
  • HSU40434_PEA_1_P12 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 conesponding to amino acids 44 - 44 of HSU40434 PEA 1 P12, and a third amino acid sequence being at least 90 % homologous to AAPLDGVLANPPNISSLSPRQLLGFPCAEVSGLSTERVRELAVALAQK ⁇ WKLSTEQLRC LAHRLSEPPEDLDALPLDLLLFLNPDAFSGPQACTRFFSRITKANVDLLPRGAPERQRLL PAALACWGVRGSLLSEADVRALGGLACDLPGRFVAESAEVLLPRLVSCPGPLDQDQQE AARAALQGGGPPYGPPSTWSVSTMDALRGLLPVLGQPIIRSIPQGIVAAWRQRSSRDPS WRQPERTILRPRFRREVEKTACPSGKKAREIDESLIFYKKW
  • an isolated polypeptide encoding for an edge portion of HSU40434J ⁇ AJ JM2 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 E, conesponding to HSU40434_PEA_1_P12.
  • an isolated chimeric polypeptide encoding for M77904_P2 comprising a first amino acid sequence being at least 90 %> homologous to
  • an isolated polypeptide encoding for a tail of M77904 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 NKIYVVDLSNERAMSLTIEPRPVKQSRKFVPGCFVCLESRTCSSNLTLTSGSKHKISFLCD DLTRLWMNVEK ⁇ SCTDHRYCQRKSYSLQVPSDILHLPVELHDFSWKLLVPKDRLSLVL VPAQKLQQHTHEKPCNTSFSYLVASAIPSQDLYFGSFCPGGSIKQIQVKQNISVTLRTFAP SFQQEASRQGLTVSFIPYFKEEGVFTVTPDTKSKVYLRTPNWDRGLPSLTSVSWNISVPR DQVACLTFFKERSGVVCQTGRAFMIIQEQRTRAEEIFSLDEDVLPK
  • an isolated polypeptide encoding for a tail of M77904_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
  • NKIYWDLSNERAMSLTIEPRPVKQSRKFVPGCFVC LESRTCSSNLTLTSGSKHKISFLCD
  • an isolated chimeric polypeptide encoding for M77904 P4 comprising a first amino acid sequence being at least 90 % homologous to MAGLNCGVSIALLGVLLLGAARLPRGAEAFEIALPRESNITVLIKLGTPTLLAKPCYIVIS KRHITMLSIKSGERIVFTFSCQSPENHFVIEIQKJ IDCMSGPCPFGEVQLQPSTSLLPTLNR
  • an isolated polypeptide encoding for a tail of M77904_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
  • an isolated chimeric polypeptide encoding for M77904 JM comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of M77904 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 TPLNQCICPWPWIALLSPPCLSGVPWVGCKSYQKGPSGRARWLTPVIPALWEAKAGGS LEVRSSRPAWPTW in M77904JM.
  • an isolated chimeric polypeptide encoding for M77904_P5 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for M77904_P5 comprising a first amino acid sequence being at least 90 %> homologous to
  • an isolated chimeric polypeptide encoding for M77904_P7 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of M77904_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 EKAPPCYLIRLKHTRSSLF in M77904 P7.
  • an isolated chimeric polypeptide encoding for M77904_P7 comprising a first amino acid sequence being at least 90 %> homologous to
  • an isolated polypeptide encoding for a tail of M77904_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 EKAPPCYLIRLKHTRSSLF in M77904_P7.
  • an isolated chimeric polypeptide encoding for M77904_P7 comprising a first amino acid sequence being at least 90 %> homologous to
  • an isolated polypeptide encoding for a tail of M77904_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 EKAPPCYLIRLKHTRSSLF in M77904JP7.
  • an isolated chimeric polypeptide encoding for Z25299 PEA 2 P2 comprising a first amino acid sequence being at least 90 % homologous to MKSSGLFPFLVLLALGTLAPWAVEGSGKSFKAGVCPPKKSAQCLRYKKPECQSDWQCP GKKRCCPDTCGIKCLDPVDTPNPTRRKPGKCPVTYGQCLMLNPPNFCEMDGQCKRDLK CCMGMCGKSCVSPVK conesponding to amino acids 1 - 131 of ALK 1 HUMAN, which also conesponds to amino acids 1 - 1 1 of Z25299_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 conesponding to amino acids 132 - 139 of Z25299 J
  • an isolated polypeptide encoding for a tail of Z25299_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 Z25299_PEA_2_P2.
  • an isolated chimeric polypeptide encoding for Z25299 PEA 2 P3, comprising a first amino acid sequence being at least 90 %> homologous to MKSSGLFPFLVLLALGTLAPWAVEGSGKSFKAGVCPPKKSAQCLRYKKPECQSDWQCP GKKRCCPDTCGIKCLDPVDTPNPTRRKPGKCPVTYGQCLMLNPPNFCEMDGQCKRDLK CCMGMCGKSCVSPVK conesponding to amino acids 1 - 131 of ALK1_HUMAN, which also conesponds to amino acids 1 - 131 of Z25299_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 conesponding to amino acids
  • an isolated chimeric polypeptide encoding for Z25299_PEA_2_P7 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of Z25299_PEA_2_P7 comprising a polypeptide being at least 70%o, 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 Z25299J»EA_2JP7.
  • an isolated chimeric polypeptide encoding for Z25299 PEA 2 P10 comprising a first amino acid sequence being at least 90 % homologous to
  • an antibody capable of specifically binding to an epitope of an amino acid sequence as described herein.
  • the amino acid sequence conesponds to a bridge, edge portion, tail, head or insertion as described herein.
  • the antibody is capable of differentiating between a splice variant having said epitope and a conesponding known protein.
  • kits for detecting ovarian cancer comprising a kit detecting overexpression of a splice variant as described herein.
  • the kit comprises a NAT-based technology.
  • the kit further comprises at least one primer pair capable of selectively hybridizing to a nucleic acid sequence as described herein.
  • the kit further comprises at least one oligonucleotide capable of selectively hybridizing to a nucleic acid sequence as described herein.
  • the kit comprises an antibody as described herein.
  • the kit further comprises at least one reagent for performing an ELISA or a Western blot.
  • a method for detecting ovarian cancer comprising detecting overexpression of a splice variant as described herein.
  • detecting overexpression is performed with a NAT-based technology.
  • detecting overexpression is performed with an immunoassay.
  • the immunoassay comprises an antibody as described herein.
  • a biomarker capable of detecting ovarian 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.
  • a method for screening for ovarian cancer comprising detecting ovarian cane er cells with a biomarker or an antibody or a method or assay as described herein.
  • a method for diagnosing ovarian cancer comprising detecting ovarian cancer cells with a biomarker or an antibody or a method or assay as described herein.
  • a method for monitoring disease progression and/or treatment efficacy and/or relapse of ovarian cancer comprising detecting ovarian cancer cells with a biomarker or an antibody or a method or assay as described herein.
  • 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.
  • 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).
  • 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.
  • 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 cluster 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 microanay fabrication.
  • Figure 5 is schematic summary of the oligonucleotide based microanay experimental flow.
  • Figure 6 shows cancer and cell- line vs. normal tissue expression for .
  • Figure 7 shows expression of segment ⁇ in H61775 in cancerous vs. non-cancerous tissues.
  • Figure 8 shows expression of segment ⁇ in H61775 in normal tissues.
  • Figure 9 shows cancer and cell- line vs. normal tissue expression.
  • Figure 10 is a histogram showing over expression of T juncl 1-17 transcripts in cancerous ovary samples relative to the normal samples.
  • Figure 11 is a histogram showing expression of T juncl 1- 17 transcripts in normal tissues.
  • Figure 12 shows cancer and cell- line vs. normal tissue expression.
  • Figure 13 is a histogram showing over expression of HUMGRP5Ejunc3-7 transcripts in cancerous ovary samples relative to the normal samples.
  • Figure 14 is a histogram showing expression of HUMGRP5Ejunc3-7 transcripts in normal tissues.
  • Figure 15 shows cancer and cell- line vs. normal tissue expression.
  • Figure 16 is a histogram showing over expression of Rl 1723 segl3 transcripts in cancerous ovary samples relative to the normal PM samples.
  • Figure 17 is a histogram showing expression of Rl 1723 segl transcripts in normal tissue samples.
  • Figure 18 is a histogram showing over expression of RI 1723 juncl 1- 18 transcripts in cancerous ovary samples relative to the normal samples.
  • Figure 19 is a histogram showing expression of Rl 1723 juncl 1-18 transcripts in normal tissue samples.
  • Figure 20 shows cancer and cell- line vs. normal tissue expression.
  • Figure 21 is a histogram showing over expression of H53393 segl3 transcripts in cancerous ovary samples relative to the normal samples.
  • Figure 22 is a histogram showing over expression of H53393 junc21-22 transcripts in cancerous ovary samples relative to the normal samples.
  • Figure 23 shows cancer and cell- line vs. normal tissue expression.
  • Figure 24 shows cancer and cell- line vs. normal tissue expression.
  • Figure 25 shows cancer and cell- line vs. normal tissue expression.
  • Figure 26 is a histogram showing over expression of Z25299 juncl 3- 14-21 transcripts in cancerous ovary samples relative to the normal samples.
  • Figures 27A and 27B are histograms showing over expression of Z25299 seg20 transcripts in cancerous ovary samples relative to the normal samples (27A) or in normal tissues (27B).
  • Figures 28A and 28B are histograms showing over expression of Z25299 seg23 transcripts in cancerous ovary samples relative to the normal samples (28A) or in normal tissues (28B).
  • Figure 29 shows cancer and cell- line vs. normal tissue expression.
  • Figure 30 is a histogram showing down regulation of T39971 junc23-33R transcripts in cancerous ovary samples relative to the normal samples.
  • Figure 31 is a histogram showing expression of T39971 junc23-33R transcripts in normal tissues.
  • Figure 32 shows cancer and cell- line vs. normal tissue expression.
  • Figures 33A and 33B are histograms showing down regulation of Z44808 junc8- l 1 transcripts in cancerous ovary samples relative to the normal samples (33A) or expression in normal tissues (33 B).
  • Figure 34 shows cancer and cell- line vs. normal tissue expression.
  • Figure 35 shows cancer and cell- line vs. normal tissue expression.
  • Figure 36 shows cancer and cell- line vs. normal tissue expression.
  • Figure 37 shows cancer and cell- line vs. normal tissue expression.
  • Figure 38 shows cancer and cell- line vs. normal tissue expression.
  • Figure 39 shows cancer and cell- line vs. normal tissue expression.
  • Figure 40 shows cancer and cell- line vs. normal tissue expression.
  • Figure 41 shows cancer and cell- line vs. normal tissue expression.
  • Figure 42 shows cancer and cell- line vs. normal tissue expression.
  • Figure 43 is a histogram showing differential expression of a variety of transcripts in cancerous ovary samples relative to the normal samples.
  • Figure 44
  • the present invention is of novel markers for ovarian cancer that are both sensitive and accurate.
  • 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.
  • markers are able to distinguish between various types of ovarian cancer, such as Ovarian epithelial tumors (serous, mucinous, endometroid, clear cell, and Brenner tumor), ovarian germ-cell tumors, (teratoma, dysgerminoma, endodermal sinus tumor, and embryonal carcinoma) and ovarian stromal tumors (originating from granulosa, theca, Sertoli, Leydig, and collagen-producing stromal cells), alone or in combination. These markers are differentially expressed, and preferably overexpressed in ovarian cancer specifically, as opposed to nonnal ovarian tissue.
  • markers of the present invention show a high degree of differential detection between ovarian cancer and non- cancerous states.
  • 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 ovarian cancer.
  • these markers may be used for staging ovarian cancer and/or monitoring the progression of the disease.
  • 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 thenovary.
  • one or more of the markers may optionally be used in combination with one or more other ovarian cancer markers (other than those described herein).
  • a combination may be used to differentiate between various types of ovarian cancer, such as Ovarian epithelial tumors (serous, mucinous, endometroid, clear cell, and Brenner tumor), ovarian germ-cell tumors, (teratoma, dysgerminoma, endodermal sinus tumor, and embryonal carcinoma) and ovarian stromal tumors (originating from either granulosa, theca, Sertoli, Leydig, and collagen-producing stromal cells).
  • markers are specifically released to the bloodstream under conditions of ovarian cancer (or one of the above indicative conditions), and/or are otherwise expressed at a much higher level and/or specifically expressed in ovarian cancer tissue or cells, and/or tissue or cells under one of the above indicative conditions.
  • the measurement of these markers, alone or in combination, in patient samples provides information that the diagnostician can conelate with a probable diagnosis of ovarian cancer and/or a condition that it is indicative of a higher risk for ovarian cancer.
  • the present invention therefore also relates to diagnostic assays for ovarian cancer, and methods of use of such markers for detection of ovarian cancer, optionally and preferably in a sample taken from a subject (patient), which is more preferably some type of blood sample.
  • the present invention relates to bridges, tails, heads and/or insertions, and/or analogs, homologs and derivatives of such peptides.
  • 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 conesponding known protein, while at least a second portion of the variant comprises the tail.
  • 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 conesponding known protein.
  • 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.
  • 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.
  • 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).
  • bridges 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.
  • a bridge between two edges may optionally be described as follows: a bridge portion of CONTIG-NAME_Pl (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.
  • 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 conesponding known protein (such known proteins are discussed with regard to their splice variants in the Examples below).
  • 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.
  • 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.
  • this invention provides an oligonucleotide of at least about 12 nucleotides, specifically hybridizable with the nucleic acid molecules of this invention.
  • this invention provides vectors, cells, liposomes and compositions comprising the isolated nucleic acids of this invention.
  • 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 conesponding proteins (wherein the known protein is discussed with regard to its splice variant(s) in the Examples below), and detecting said interaction; wherein the presence of an interaction conelates with the presence of a splice variant in the biological sample.
  • 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.
  • the splice variants described herein are non- limiting examples of markers for diagnosing ovarian 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 ovarian cancer.
  • 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.
  • 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.
  • the known marker comprises the "known protein" as described in greater detail below with regard to each cluster or gene.
  • 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 ovarian cancer and/or an indicative condition, such that a biomarker may optionally comprise any of the above.
  • the present invention optionally and preferably encompasses any amino acid sequence or fragment thereof encoded by a nucleic acid sequence conesponding 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, conesponding 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.
  • 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).
  • cDNA complementary polynucleotide sequence
  • genomic polynucleotide sequence e.g., a combination of the above.
  • composite polynucleotide sequences e.g., a combination of the above.
  • 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.
  • genomic polynucleotide sequence refers to a sequence derived (isolated) from a chromosome and thus it represents a contiguous portion of a chromosome.
  • 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.
  • Prefened 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 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).
  • 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.
  • 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.
  • 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 consisting of purines and the pyrimidines bases, bonded in a 3' to 5' phosphodi ester linkage.
  • oligonucleotides are those modified at one or more of the backbone, intemucleoside 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 intemucleoside linkages.
  • Oligonucleotides having modified backbones include those that retain a phosphorus atom in the backbone, as disclosed in U.S. Pat.
  • Prefened 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'-5' 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'.
  • modified oligonucleotide backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl intemucleoside linkages, mixed heteroatom and alkyl or cycloalkyl intemucleoside linkages, or one or more short chain heteroatomic or heterocyclic intemucleoside linkages.
  • 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
  • sulfonate and sulfonamide backbones amide backbones
  • others having mixed N, O, S and CFfc component parts, as disclosed in U.S. Pat. Nos.
  • oligonucleotides which can be used according to the present invention, are those modified in both sugar and the intemucleoside 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).
  • PNA peptide nucleic acid
  • United States patents that teach the preparation of PNA compounds include, but are riot 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.
  • Oligonucleotides of the present invention may also include base modifications or substitutions.
  • "unmodified” or “natural” bases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U).
  • 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, 5-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
  • 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 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine.
  • 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6- 1.2 °C and are presently prefened base substitutions, even more particularly when combined with 2'-0-methoxyethyl sugar modifications.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • the promoter utilized by the nucleic acid construct of the present invention is active in the specific cell population transformed.
  • cell type-specific and/or tissue-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.
  • the nucleic acid constmct of the present invention can further 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 constmct of the present invention preferably further includes an appropriate selectable marker and/or an origin of replication.
  • the nucleic acid constmct utilized is a shuttle vector, which can propagate both in E.
  • constmct comprises an appropriate selectable marker and origin of replication
  • the constmct according to the present invention can be, for example, a plasmid, a bacmid, a phagemid, a cosmid, a phage, a vims or an artificial chromosome.
  • suitable constructs include, but are not limited to, pcDNA3, pcDNA3.1 (+/-), pGL3, PzeoSV2 (+/-), pDisplay, pEF/myc/cyto, pCMV/myc/cyto each of which is commercially available from Invitrogen Co.
  • retroviral vector and packaging systems examples include 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.
  • Cunently prefened in vivo nucleic acid transfer techniques include transfection with viral or non-viral constmcts, such as adenovims, lentivims, He ⁇ es simplex I vims, or adeno- associated vims (AAV) and lipid-based systems.
  • viral or non-viral constmcts such as adenovims, lentivims, He ⁇ es simplex I vims, or adeno- associated vims (AAV) and lipid-based systems.
  • Useful lipids for lipid -mediated transfer of the gene are, for example, DOTMA, DOPE, and DC-Choi [Tonkinson et al., Cancer Investigation, 14(1): 54-65 (1996)].
  • the most prefened constructs for use in gene therapy are vimses, most preferably adenovimses, AAV, lentiviruses, or retrovimses.
  • a viral constmct such as a retroviral constmct includes at least one transc ⁇ tional 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 constmcts also include a packaging signal, long terminal repeats (LTRs) or portions thereof, and positive and negative strand primer binding sites appropriate to the vims used, unless it is aheady present in the viral construct.
  • LTRs long terminal repeats
  • such a constmct typically includes a signal sequence for secretion of the peptide from a host cell in which it is placed.
  • the signal sequence for this purpose is a mammalian signal sequence or the signal sequence of the polypeptide variants of the present invention.
  • the construct may also include a signal that directs polyadenylation, as well as one or more restriction sites and a translation termination sequence.
  • constmcts 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, Cunent Opin. Biotechnol. 10:71-75).
  • kits containing probes on a dipstick setup and the like 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 biobgical 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.
  • 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 NaCl, 1 % SDS and 5 x l ⁇ 6 cpm 32 P 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 NaCl, 1 % SDS and 5 x IO 6 cpm 32 P labeled probe, at 65 °C, with a final wash solution of 1 x SSC and 0.1 % SDS and final wash at 50 °C.
  • a hybridization solution such as containing 10 % dextrane sulfate, 1 M NaCl, 1 % SDS and 5 x l ⁇ 6 cpm 32 P labeled probe, at 65 °C
  • moderate hybridization is
  • hybridization of short nucleic acids can be effected using the following exemplary hybridization protocols which can be modified according to the desired stringency;
  • hybridization duplexes are separated from unhybridized nucleic acids and the labels bound to the duplexes are then detected.
  • 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 35S.
  • detectable markers include ligands, fluorophores, chemiluminescent agents, enzymes, and antibodies.
  • oligonucleotides of the present invention can be labeled subsequent to synthesis, by inco ⁇ orating 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.
  • streptavidin e.g., phycoerythrin- conjugated streptavidin
  • oligonucleotide probes when fluorescently- labeled oligonucleotide probes are used, fluorescein, lissamine, phycoerythrin, rhodamine (Perkin Elmer Cetus), Cy2, Cy3, Cy3.5, Cy5, Cy5.5, Cy7, FluorX (Amersham) and others [e.g., Kricka et al. (1992), Academic Press San Diego, Calif] 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.
  • probes can be labeled according to numerous well known methods.
  • radioactive nucleotides can be inco ⁇ orated into probes of the invention by several methods.
  • Non- limiting examples of radioactive labels include 3 H, 14 C, 3 P, and 35 S.
  • Probes of the invention can be utilized with naturally occurring 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 constmcted of either ribonucleic acid (RNA) or deoxyribonucleic acid (DNA), and preferably of DNA.
  • RNA ribonucleic acid
  • DNA deoxyribonucleic acid
  • 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).
  • a "primer” defines an oligonucleotide which is capable of annealing to
  • 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 polymerase 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. Natl. Acad. Sci. USA 86, 1173-1 177; Lizardi et al., 1988, BioTechnology 6:1 197- 1202; Malek et al., 1994, Methods Mol. Biol., 28:253-260; and Sambrook et al., 1989, supra).
  • PCR polymerase chain reaction
  • LCR ligase chain reaction
  • SDA strand displacement amplification
  • amplification 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 polymerase chain reaction.
  • amplification processes include ligase chain reaction, strand displacement amplification, or nucleic acid sequence-based amplification, as explained in greater detail below.
  • the oligos are designed to bind to a complementary sequence under selected conditions.
  • 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.
  • RT-PCR is carried out on an mRNA sample from a patient under conditions which favor the amplification of the most abundant mRNA.
  • 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.
  • the oligonucleotide primers are at least 12 nucleotides in length, preferably between 15 and 24 molecules, and they may be adapted to be especially suited to a chosen nucleic acid amplification system.
  • 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 Cunent 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.
  • PCR Polymerase Chain Reaction
  • PCR The polymerase chain reaction (PCR), as described in U.S. Pat. Nos. 4,683,195 and 4,683,202 to Mullis and Multis 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.
  • the primers are extended with polymerase so as to form complementary strands.
  • the steps of denaturation, hybridization (annealing), and polymerase 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.
  • Ligase Chain Reaction (LCR or LAR): The ligase chain reaction [LCR; sometimes refened to as “Ligase Amplification Reaction” (LAR)] has developed into a well-recognized alternative method of amplifying nucleic acids.
  • 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.
  • ligase will covalently link each set of hybridized molecules.
  • 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 Al (1990).
  • 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 (3SR/NASBA) 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.
  • 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 ⁇ ) Replicase In this method, a probe which recognizes the sequence of interest is attached to the replicatable RNA template for Q ⁇ replicase.
  • thermostable DNA ligases are not effective on this RNA substrate, so the ligation must be perfonned 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.
  • 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.
  • 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.
  • 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.
  • any background products that amplify with a better mean efficiency than the intended target will become the dominant products.
  • PCR has yet to penetrate the clinical market in a significant way.
  • LCR LCR must also be optimized to use different oligonucleotide sequences for each target sequence.
  • both methods require expensive equipment, capable of precise temperature cycling.
  • 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.
  • thermostable ligase 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.
  • the direct detection method may be, for example a cycling probe reaction (CPR) or a branched DNA analysis.
  • CPR cycling probe reaction
  • branched DNA analysis e.g., a method that does not amplify the signal exponentially is more amenable to quantitative analysis.
  • CPR Cycling probe reaction
  • Branched DNA involves oligonucleotides with branched structures that allow each individual oligonucleotide to carry 35 to 40 labels (e.g., alkaline phosphatase enzymes).
  • the detection of at least one sequence change 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 Polymo ⁇ hism (SSCP) analysis or Dideoxy finge ⁇ rinting (ddF).
  • RFLP analysis restriction fragment length polymorphism
  • ASO allele specific oligonucleotide
  • DGGE/TGGE Denaturing/Temperature Gradient Gel Electrophoresis
  • SSCP Single-Strand Conformation Polymo ⁇ hism
  • ddF Dideoxy finge ⁇ rinting
  • nucleic acid sequence data for 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 detennine 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.
  • amplified material e.g., PCR reaction products
  • a given segment of nucleic acid may be characterized on several other levels.
  • the size of the molecule can be determined by electrophoresis by comparison to a known standard n 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 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 polymo ⁇ hism [RFLP] analysis). Single point mutations have been also detected by the creation or destruction of RFLPs.
  • RFLP Restriction fragment length polymorphism
  • MCC Mismatch Chemical Cleavage
  • RFLP analysis 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.
  • 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.
  • DGGE/TGGE Denaturing/Temperature Gradient Gel Electrophoresis
  • 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 conesponding changes in their electrophoretic mobilities.
  • the fragments to be analyzed usually PCR products, are "clamped” at one end by a long stretch of GC 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 action 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.
  • 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)
  • TGGE uses a thermal gradient rather than a chemical denaturant gradient.
  • TGGE requires the use of specialized equipment which can generate a temperature gradient pe ⁇ endicularly 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 mnning the gel.
  • SSCP Single-Strand Conformation Polymorphism
  • 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 intra- molecular interactions can form and not be disturbed during the mn.
  • 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 finge ⁇ rinting (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.
  • 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).
  • all of these methods are limited as to the size of the nucleic acid fragment that can be analyzed.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ -Replicase, cycling probe reaction, branched DNA, restriction fragment length polymo ⁇ hism analysis, mismatch chemical cleavage, heteroduplex analysis, allele- specific oligonucleotides, denaturing gradient gel electrophoresis, constant denaturant gel electrophoresis, temperature gradient gel electrophoresis and dideoxy finge ⁇ rinting.
  • any suitable technique including, but not limited to, nucleic acid sequencing, polymerase chain reaction, ligase chain reaction, self- sustained synthetic reaction, Q ⁇ -Replicase, cycling probe reaction, branched DNA, restriction fragment length polymo ⁇ hism analysis, mismatch chemical cleavage, heteroduplex analysis, allele- specific oligonucleotides
  • 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 inco ⁇ orated into the nucleic acid, which is now bound to the probes attached to the chip.
  • 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.
  • polypeptide amino acid sequences and peptides
  • polypeptide amino acid sequences and peptides
  • polypeptide polypeptide
  • peptide amino acid residues
  • protein 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 conesponding naturally occurring amino acid, as well as to naturally occuning amino acid polymers.
  • Polypeptides can be modified, e.g., by the addition of carbohydrate residues to form glycoproteins.
  • polypeptide polypeptide
  • peptide and protein
  • Polypeptide products can be biochemically synthesized such as by employing standard 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 Monow 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.
  • 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 1 1 , 1 (initialization and extension), and number of alignments shown is 50.
  • NCBI National Center of Biotechnology Information
  • Nucleotide (nucleic acid) sequence homology/identity is preferably determined by using the BlastN software of the National Center of 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 1 1.
  • NCBI National Center of Biotechnology Information
  • 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 occuning or artificially induced, either randomly or in a targeted fashion.
  • 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 Sable while in a body or more capable of penetrating into cells.
  • Natural aromatic amino acids, T ⁇ , 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • Antibodies 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 immunoglobuhns or as a number of well characterized fragments produced by digestion with various peptidases. This includes, e.g., Fab' and F(ab)' 2 fragments.
  • antibody 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 005/116850
  • Fab the fragment which contains a monovalent antigen-binding fragment of an antibody molecule
  • 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
  • (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
  • Fv defined as a genetically engineered fragment containing the variable region of the light chain
  • 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.
  • antibody fragments can be produced by enzymatic cleavage of antibodies with pepsin to provide a 5S 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.
  • a thiol reducing agent optionally a blocking group for the sulfhydryl groups resulting from cleavage of disulfide linkages
  • an enzymatic cleavage using pepsin produces two monovalent Fab' fragments and an Fc fragment directly.
  • Fv fragments comprise an association of VH and VL chains. This association may be noncovalent, as described in hbar et al. [Proc. Nat'l Acad. Sci. USA 69:2659-62 (19720].
  • the variable chains can be linked by an intermolecular disulfide bond or cross- linked by chemicals such as glutaraldehyde.
  • the Fv fragments comprise VH and VL chains connected by a peptide linker.
  • These single-chain antigen binding proteins are prepared by constmcting a stmctural gene comprising DNA sequences encoding the VH and VL domains connected by an oligonucleotide.
  • the stmctural 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.
  • 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., murine) antibodies are chimeric molecules of immunoglobuhns, 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 immunoglobuhns (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 mouse, rat or rabbit having the desired specificity, affinity and capacity.
  • CDR complementary determining region
  • donor antibody non- human species
  • Fv framework residues of the human immunoglobulin are replaced by conesponding 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.
  • 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 :522-525 (1986); Riechmann et al., Nature, 332:323- 329 (1988); and Presta, Cun. Op. Stmct. Biol., 2:593-596 (1992)].
  • Fc immunoglobulin constant region
  • 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 refened 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 :522-525 (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 conesponding sequences of a human antibody.
  • humanized antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the conesponding sequence from a non-human species.
  • 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 Boemer et al.
  • 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 reanangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Pat. Nos.
  • the antibody of this aspect of the present invention specifically binds at least one epitope of the polypeptide variants of the present invention.
  • 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 stmctural characteristics, as well as specific charge characteristics.
  • 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 inventbn 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.
  • 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.
  • 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 ; 4,376,1 10; 4,517,288; and 4,837,168).
  • EIA enzyme immune assay
  • ELISA enzyme- linked immunosorbent assay
  • RIA radioimmune assay
  • Western blot assay e.g., U.S. Pat. Nos. 4,366,241 ; 4,376,1 10; 4,517,288; and 4,837,168.
  • a sample obtained from a subject can be contacted with the antibody that specifically binds the marker.
  • 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.
  • 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.
  • 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.
  • 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.
  • the immunoassay can be used to determine a test amount of a marker in a sample from a subject.
  • 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.
  • 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.
  • RIA Radio-immunoassay
  • the number of counts in the precipitated pellet is proportional to the amount of substrate.
  • a labeled substrate and an unlabelled antibody binding protein are employed in an alternate version of the RIA.
  • 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 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 include but are not limited to, positron emission tomography (PET) single photon emission computed bmography (SPECT). 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, SPECT can optionally be used with two labels simultaneously. SPECT 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 SPECT for detection of breast cancer, and is hereby inco ⁇ orated 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, vimses 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 constmcting such display libraries are well known in the art.
  • display vehicles such as phages, vimses or bacteria
  • 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.
  • 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 inco ⁇ orated by reference as if fully set forth herein. Briefly, the software cleans the expressed sequences from repeats, vectors and immunoglobuhns.
  • 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 stmctures, known and predicted proteins and detailed homology reports.
  • SNPs sequence information
  • chromosomal information chromosomal information
  • alignments and additional information such as SNPs, gene ontology terms, expression profiles, functional analyses, detailed domain stmctures, known and predicted proteins and detailed homology reports.
  • 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.
  • 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.
  • EXAMPLE 1 Identification of differentially expressed gene products - Algorithm
  • 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: (i) Tissue origin (ii) Biological source - Examples of frequently used biological sources for constmction of EST libraries include cancer cell- lines; normal tissues; 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 constmction various methods are known in the art for library construction including normalized library constmction; non- normalized library constmction; subtracted libraries; ORESTES and others. It will be appreciated that at times the protocol of library constmction is not indicated. The following mles were 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.
  • 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.
  • 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
  • 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 arc statistically significant.
  • EXAMPLE 4 Identification of splice variants over expressed in cancer of clusters which are not over expressed in 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 refened 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 if: (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).
  • the set of EST clones of every cluster is divided into 3 groups: (i) Supporting (originating from) transcripts of group TA (SI). (ii) Supporting transcripts of group TB (S2). (iii) Supporting transcripts from both groups (S3). Library and clones number scores described above were given to SI group. Fisher Exact Test P-values were used to check if: SI is significantly enriched by cancer EST clones compared to S2; and SI 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 conesponds to a segment, also termed herein a "node”.
  • Region 1 common to all transcripts, thus it is preferably not considered for determining differential expression between variants; Region 2: specific to Transcript 1 ; Region 3: specific to Transcripts 2+3; Region 4: specific to Transcript 3; Region 5: specific to Transcripts 1 and 2; Region 6: specific to Transcript 1.
  • EXAMPLE 5 Identification of cancer specific splice variants of genes over expressed in cancer
  • 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) 3 libraries.
  • Actual Marker Examples The following examples relate to specific actual marker examples. It should be noted that Table numbering is restarted within each example related to a particular Cluster, as indicated by the titles below.
  • the markers of the present invention were tested with regard to their expression in various cancerous and non-cancerous tissue samples.
  • a description of the samples used in the panel is provided in Table 1 below.
  • a description of the samples used in the normal tissue panel is provided in Table 2 below. Tests were then performed as described in the "Materials and Experimental Procedures" section below.
  • 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
  • RNA samples were obtained from patients or from postmortem. Total RNA samples were treated with DNasel (Ambion) and purified using RNeasy columns (Qiagen). RT PCR - Purified RNA (1 ⁇ g) was mixed with 150 ng Random Hexamer primers (Invitrogen) and 500 ⁇ M dNTP in a total volume of 15.6 ⁇ l. The mixture was incubated for 5 min at 65 °C and then quickly chilled on ice.
  • Real-Time RT-PCR analysis- cDNA (5 ⁇ l), 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).
  • 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 products 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.
  • SDHA (GenBank Accession No. NM 004168) SDHA Forward primer: TGGGAACAAGAGGGCATCTG SDHA Reverse primer: CCACCACTGCATCAAATTCATG SDHA-amplicon : TGGGAACAAGAGGGCATCTGCTAAAGTTTC AG ATTCC ATTTCTGCTCAGTATCC AGT AGTGGATCATGAATTTGATGCAGTGGTGG PBGD (GenBank Accession No. BCO 19323), PBGD Forward primer: TGAGAGTGATTCGCGTGGG PBGD Reverse primer: CCAGGGTACGAGGCTTTCAAT PBGD-amplicon:
  • HPRT1 GenBank Accession No. NMJ3001944
  • HPRT1 Forward primer TGACACTGGCAAAACAATGCA
  • HPRT1 Reverse primer GGTCCTTTTCACCAGCAAGCT
  • GAPDH Forward primer TGCACCACCACCAACTGCTTAGC
  • GAPDH-amplicon TGCACCACCAACTGCTTAGCACCCCTGGCCAAGGTCATCCATGACAACTTTGGTATC
  • RPL19 (GenBank Accession No. NM 000981), RPL19 Forward primer: TGGCAAGAAGAAGGTCTGGTTAG RPL19 Reverse primer: TGATCAGCCCATCTTTGATGAG RPLl 9 -amplicon:
  • TATA box (GenBank Accession No. NM_003194), TATA box Forward primer : CGGTTTGCTGCGGTAATCAT
  • TATA box Reverse primer TTTCTTGCTGCCAGTCTGGAC
  • Ubiquitin C -amplicon ATTTGGGTCGCGGTTCTTGTTTGTGGATCGCTGTGATCGTCACTTGACAATGCAGAT
  • SDHA (GenBank Accession No. NM 004168) SDHA Forward primer:
  • Microarray fabrication Microanays were printed by pin deposition using the MicroGrid II MGII 600 robot from BioRobotics Limited (Cambridge, UK). 50-mer oligonucleotides target sequences were designed by Compugen Ltd (Tel- Aviv, IL) as described by A. Shoshan et al, "Optical technologies and informatics", Proceedings of SPIE. Vol 4266, pp. 86-95 (2001).
  • the designed oligonucleotides were synthesized and purified by desalting with the Sigma-Genosys system (The Woodlands, TX, US) and all of the oligonucleotides were joined to a C6 amino- modified linker at the 5' end, or being attached directly to CodeLink slides (Cat #25-6700-01. Amersham Bioscience, Piscataway, NJ, US).
  • the 50-mer oligonucleotides, fonning the target sequences, were first suspended in Ultra-pure DDW (Cat # 01 -866-1 A Kibbutz Beit-Haemek, Israel) to a concentration of 50 ⁇ M.
  • 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 subanays.
  • 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 Anay Control product (Anay control- sense oligo spots, Ambion Inc. Austin, TX. Cat #1781, Lot #112K06).

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