EP1774046A2 - Neue nukleotid- und aminosäuresequenzen sowie assays und verfahren zu deren verwendung bei der diagnose von lungenkrebs - Google Patents

Neue nukleotid- und aminosäuresequenzen sowie assays und verfahren zu deren verwendung bei der diagnose von lungenkrebs

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Publication number
EP1774046A2
EP1774046A2 EP05857765A EP05857765A EP1774046A2 EP 1774046 A2 EP1774046 A2 EP 1774046A2 EP 05857765 A EP05857765 A EP 05857765A EP 05857765 A EP05857765 A EP 05857765A EP 1774046 A2 EP1774046 A2 EP 1774046A2
Authority
EP
European Patent Office
Prior art keywords
amino acid
pea
amino acids
acid sequence
homologous
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.)
Withdrawn
Application number
EP05857765A
Other languages
English (en)
French (fr)
Other versions
EP1774046A4 (de
Inventor
Sarah Pollock
Zurit Levine
Amit Novik
Dvir Dahary
Rotem Sorek
Amir Toporik
Shirley Sameah-Greenwald
Osnat Sella-Tavor
Alexander Diber
Gad S. Cojocaru
Michal Ayalon-Soffer
Shira Walach
Pinchas Akiva
Naomi Keren
Ronen Shemesh
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 USA Inc
Original Assignee
Compugen USA Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Compugen USA Inc filed Critical Compugen USA Inc
Priority claimed from US11/051,720 external-priority patent/US7569662B2/en
Publication of EP1774046A2 publication Critical patent/EP1774046A2/de
Publication of EP1774046A4 publication Critical patent/EP1774046A4/de
Withdrawn legal-status Critical Current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 lung cancer, and assays and methods of use thereof.
  • Lung cancer is the primary cause of cancer death among both men and women in the U. S., with an estimated 172,000 new cases being reported in 1994.
  • the five-year survival rate among all lung cancer patients, regardless of the stage of disease at diagnosis, is only 13%. This contrasts with a five-year survival rate of 46% among cases detected while the disease is still localized. However, only 16% of lung cancers are discovered before the disease has spread.
  • Lung cancers are broadly classified into small cell or non-small cell lung cancers. Non-small cell lung cancers are further divided into adenocarcinomas, bronchoalveolar- alveolar, squamous cell and large cell carcinomas. Approximately, 75-85 percent of lung cancers are non-small cell cancers and 15-25 percent are small cell cancers of the lung.
  • Treatment regimens are determined by the type and stage of the cancer, and include surgery, radiation therapy and/or chemotherapy.
  • Non- small cell lung cancer diagnosed at an early stage has a significantly better outcome than that diagnosed at more advanced stages.
  • the background art does not teach or suggest markers for lung cancer that are sufficiently sensitive and/or accurate, alone or in combination.
  • the present invention overcomes these deficiencies of the background art by providing novel markers for lung cancer that are both sensitive and accurate. Furthermore, these markers are able to distinguish between different types of lung cancer, such as small cell or non- small cell lung cancer, and further between non- small cell lung cancer types, such as adenocarcinomas, squamous cell and large cell carcinomas. These markers are overexpressed in lung cancer specifically, as opposed to normal lung tissue. The measurement of these markers, alone or in combination, in patient (biological) samples provides information that the diagnostician can correlate with a probable diagnosis of lung cancer. The markers of the present invention, alone or in combination, show a high degree of differential detection between lung cancer and non-cancerous states.
  • suitable biological samples which may optionally be used with preferred embodiments of the present invention include but are not limited to blood, serum, plasma, blood cells, urine, sputum, saliva, stool, spinal fluid or CSF, lymph fluid, the external secretions of the skin, respiratory, intestinal, and genitourinary tracts, tears, milk, neuronal tissue, lung tissue, any human organ or tissue, including any tumor or normal tissue, any sample obtained by lavage (for example of the bronchial system or of the breast ductal system), and also samples of in vivo cell culture constituents.
  • the biological sample comprises lung tissue and/or sputum and/or a serum sample and/or a urine sample and/or any other tissue or liquid sample.
  • the sample can optionally be diluted with a suitable eluant before contacting the sample to an antibody and/or performing any other diagnostic assay.
  • signalp Jimrn and “signalpjnn” 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.
  • An FTId is a unique and stable feature identifier, which allows construction of links directly from position- specific annotation in the feature table to specialized protein-related databases.
  • the 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.
  • Library-based statistics refer to statistics over an entire library, while EST clone statistics refer to expression only for ESTs from a particular tissue or cancer.
  • microarrays As a microarray reference, in the specific segment paragraphs, the unabbreviated tissue name was used as the reference to the type of chip for which expression was measured. There are two types of microarray results: those from microarrays prepared according to a design by the present inventors, for which the microarray fabrication procedure is described in detail in Materials and Experimental Procedures section herein; and those results from microarrays using Affymetrix technology. As a microarray reference, in the specific segment paragraphs, the unabbreviated tissue name was used as the reference to the type of chip for which expression was measured.
  • the probe name begins with the name of the cluster (gene), followed by an identifying number.
  • Oligonucleotide microarray results taken from Affymetrix data were from chips available from Affymetrix Inc, Santa Clara, CA, USA (see for example data regarding the Human Genome Ul 33 (HG-Ul 33) Set at www.affymetrix.com/products/arrays/specific/hgul33.affx; GeneChip Human Genome U133A 2.0 Array at www.affymetrix.com/products/arrays/specific/hgul33av2.affx; and Human Genome Ul 33 Plus 2.0 Array at www.affymetrix.com/products/arrays/specific/hgul33plus.affx).
  • the probe names follow the
  • TAA histograms represent the cancerous tissue expression pattern as predicted by the biomarkers selection engine, as described in detail in examples 1-5 below:
  • BRAIN for "brain”
  • UTERUS for "uterus”
  • 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.
  • lung cancer refers to cancers of the lung including small cell lung cancer and non- small cell lung cancer, including but not limited to lung adenocarcinoma, squamous cell carcinoma, and adenocarcinoma.
  • marker in the context of the present invention refers to a nucleic acid fragment, a peptide, or a polypeptide, which is differentially present in a sample taken from subjects (patients) having lung cancer (or one of the above indicative conditions) as compared to a comparable sample taken from subjects who do not have lung cancer (or one of the above indicative conditions).
  • 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, fcr 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.
  • diagnostic means identifying the presence or nature of a pathologic condition. Diagnostic methods differ in their sensitivity and specificity.
  • the "sensitivity” of a diagnostic assay is the percentage of diseased individuals who test positive (percent of "true positives”). Diseased individuals not detected by the assay are “false negatives.” Subjects who are not diseased and who test negative in the assay are termed “true negatives.”
  • the "specificity” of a diagnostic assay is 1 minus the false positive rate, where the "false positive” rate is defined as the proportion of those without the disease who test positive. While a particular diagnostic method may not provide a definitive diagnosis of a condition, it suffices if the method provides a positive indication that aids in diagnosis.
  • diagnosis 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.
  • 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.
  • 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).
  • tissue or fluid collection methods can be utilized to collect the biological sample from the subject in order to determine the level of DNA, RNA and/or polypeptide of the variant of interest in the subject. Examples include, but are not limited to, fine needle biopsy, needle biopsy, core needle biopsy and surgical biopsy (e.g., brain biopsy), and lavage. Regardless of the procedure employed, once a biopsy/sample is obtained the level of the variant can be determined and a diagnosis can thus be made.
  • Determining the level of the same variant in normal tissues of the same origin is preferably effected along-side to detect an elevated expression and/or amplification and/or a decreased expression, of the variant as opposed to the normal tissues.
  • test amount of a marker refers to an amount of a marker in a subject's sample that is consistent with a diagnosis of lung cancer (or one of the above indicative conditions).
  • a test amount can be either in absolute amount (e.g., microgram/ml) or a relative amount (e.g., relative intensity of signals).
  • 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 lung cancer (or one of the above indicative conditions) or a person without lung cancer (or one of the above indicative conditions).
  • a control amount can be either in absolute amount (e.g., microgram/ml) or a relative amount (e.g., relative intensity of signals).
  • Detect refers to identifying the presence, absence or amount of the object to be detected.
  • a “label” includes any moiety or item detectable by spectroscopic, photo chemical, biochemical, immunochemical, or chemical means.
  • useful labels include 32 P, 35 S, fluorescent dyes, electron- dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin-streptavadin, dioxigenin, haptens and proteins for which antisera or monoclonal antibodies are available, or nucleic acid molecules with a sequence complementary to a target.
  • the label often generates a measurable signal, such as a radioactive, chromogenic, or fluorescent signal, that can be used to quantify the amount of bound label in a sample.
  • the label can be incorporated in or attached to a primer or probe either covalently, or through ionic, van der Waals or hydrogen bonds, e.g., incorporation of radioactive nucleotides, or biotinylated nucleotides that are recognized by streptavadin.
  • the label may be directly or indirectly detectable. Indirect detection can involve the binding of a second label to the first label, directly or indirectly.
  • 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 polymorphic variants and alleles of seminal basic protein.
  • This selection may be achieved by subtracting out antibodies that cross-react with seminal basic protein molecules from other species.
  • a variety of immunoassay formats 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.
  • 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.
  • 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.
  • an isolated polynucleotide comprising SEQ ID NOs: 1 and 2.
  • an isolated polynucleotide comprising SEQ ID NOs: 1022, 1023, 1024, 1025, 1026 and 1027.
  • an isolated polypeptide comprising SEQ ID NOs: 1281 and 1282.
  • an isolated polynucleotide comprising SEQ ID NOs: 3 and 4.
  • an isolated polynucleotide comprising SEQ ID NOs: 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037 and 1038.
  • an isolated polypeptide comprising SEQ ID NOs: 1283 and 1284.
  • an isolated polynucleotide comprising SEQ ID NOs: 5, 6, 7 and 8.
  • an isolated polynucleotide comprising SEQ ID NOs: 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065 and 1066.
  • an isolated polypeptide comprising SEQ ID Nos: 1285, 1286, 1287 and 1288.
  • an isolated polynucleotide comprising SEQ ID Nos: 9, 10, 11, 12, 13, 14 and 15.
  • an isolated polynucleotide comprising SEQ ID NOs: 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097, 1098, 1099 and 1100.
  • an isolated polypeptide comprising SEQ ID NOs 1289, 1290, 1291, 1292, 1293 and 1294.
  • an isolated polynucleotide comprising SEQ ID NOs: 20 and 21.
  • an isolated polynucleotide comprising SEQ ID NOs: 1130, 1131, 1132, 1133 and 1134.
  • an isolated polypeptide comprising SEQ ID NOs: 1299 and 1300.
  • an isolated polynucleotide comprising SEQ ID NOs: 22, 23 and 24.
  • an isolated polynucleotide comprising SEQ ID NOs: 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143 and 1144. According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NOs 1301, 1302 and 1303. According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising SEQ ID NOs: 25, 26 and 27.
  • an isolated polynucleotide comprising SEQ ID NOs: 1145, 1146, 1147, 1148, 1149, 1 150, 1151, 1152, 1153, 1154, 1 155 and 1156.
  • an isolated polypeptide comprising SEQ ID NOs 1304 and 1305.
  • an isolated polynucleotide comprising SEQ ID NOs: 28. According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising SEQ ID NOs: 1157, 1158, 1159, 1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170 and 1171.
  • an isolated polypeptide comprising SEQ ID NO: 1306.
  • an isolated polynucleotide comprising SEQ ID NOs: 29 and 30.
  • an isolated polynucleotide comprising SEQ ID NOs: 1172, 1173, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190 and 1191.
  • an isolated polypeptide comprising SEQ ID NOs 1307 and 1308.
  • an isolated polynucleotide comprising SEQ ID NOs: 31.
  • an isolated polynucleotide comprising SEQ ID NOs: 1192, 1193, 1194, 1195, 1196, 1197 and 1198.
  • an isolated polypeptide comprising SEQ ID NO: 1309.
  • an isolated polynucleotide comprising SEQ ID NOs: 32. According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising SEQ ID NOs: 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214 and 1215.
  • an isolated polypeptide comprising SEQ ID NO. 1310.
  • an isolated polynucleotide comprising SEQ ID NOs: 33.
  • an isolated polynucleotide comprising SEQ ID NOs: 1216 and 1217, 1218, 1219, 1220, 1221, 1222, 1223, 1224, 1225, 1226 and 1227.
  • an isolated polypeptide comprising SEQ ID NO: 1311.
  • an isolated polynucleotide comprising SEQ ID NOs: 34. According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising SEQ ID NOs: 1228, 1229, 1230, 1231, 1232 and 1223.
  • an isolated polypeptide comprising SEQ ID NO: 1312.
  • an isolated polynucleotide comprising SEQ ID NOs: 35.
  • an isolated polynucleotide comprising SEQ ID NOs: 1234, 1235, 1236, 1237, 1238, 1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253 and 1254.
  • an isolated polypeptide comprising SEQ ID NO: 1313.
  • an isolated polynucleotide comprising SEQ ID NOs: 36, 37, 38, 39 and 40.
  • an isolated polynucleotide comprising SEQ ID NOs: 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274 and 1275.
  • an isolated polypeptide comprising SEQ ID NOs 1314, 1315, 1316 and 1317.
  • an isolated polynucleotide comprising SEQ ID NOs: 125, 126, 127, 128, 129 and 130. According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising SEQ ID NOs: 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901 and 902.
  • an isolated polypeptide comprising SEQ ID NOs: 1394, 1395, 1396, 1397 and 1398.
  • an isolated polynucleotide comprising a transcript SEQ ID NOs: 131 and 132.
  • an isolated polynucleotide comprising SEQ ID NOs: 903, 904, 905, 906, 907, 907, 908 and 909.
  • an isolated polypeptide comprising SEQ ID NOs 1399 and 1400.
  • an isolated polynucleotide comprising SEQ ID NOs: 99, 100, 101 and 102.
  • an isolated polynucleotide comprising SEQ ID NOs: 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787 and 788.
  • an isolated polypeptide comprising SEQ ID NOs 1372, 1373, 1374 and 1375.
  • an isolated polynucleotide comprising SEQ ID NOs: 134.
  • an isolated polynucleotide comprising SEQ ID NOs: 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935 and 936.
  • an isolated polypeptide comprising SEQ ID NO: 1402.
  • an isolated polynucleotide comprising SEQ ID NO: 133.
  • an isolated polynucleotide comprising SEQ ID NOs: 910, 911 and 912. According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising SEQ ID NOs: 141, 142 and 142.
  • an isolated polynucleotide comprising SEQ ID NOs: 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989 and 990.
  • an isolated polypeptide comprising :
  • an isolated polynucleotide comprising SEQ ID NOs: 51, 52, 53,, 54, 55, 56 and 57.
  • an isolated polynucleotide comprising SEQ ID NOs: 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547,548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563,,, 564, 565, 566, 567, 568, 569 and 570.
  • an isolated polypeptide comprising SEQ ID NOs 1327, 1328, 1329, 1330, 1331, 1332 and 1333.
  • an isolated polynucleotide comprising SEQ ID NOs: 135, 136, 137, 138, 139 and 140.
  • an isolated polynucleotide comprising SEQ ID NOs: 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959 and 960.
  • an isolated polypeptide comprising SEQ ID NOs 1403, 1404, 1405, 1406, 1407 and 1408.
  • an isolated polynucleotide comprising SEQ ID NOs: 41, 42, 43, 44, 45, 46 and 47.
  • an isolated polynucleotide comprising SEQ ID NOs: 482, 483, 484, 495, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500 and 501.
  • an isolated polypeptide comprising SEQ ID NOs: 1318, 1319, 1320, 1321, 1322 and 1323.
  • an isolated polynucleotide comprising SEQ ID NOs: 121, 122, 123 and 124.
  • an isolated polynucleotide comprising SEQ ID NOs: 876, 877, 878, 879, 880, 881, 882, 883, 884, 885 and 886.
  • an isolated polypeptide comprising SEQ ID NOs: 1390, 1391, 1392 and 1393.
  • an isolated polynucleotide comprising SEQ ID NOs: 48, 49 and 50.
  • an isolated polynucleotide comprising SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516 and 517.
  • an isolated polypeptide comprising SEQ ID NOs: 1324, 1325 and 1326.
  • an isolated polynucleotide comprising SEQ ID NOs: 1464 and 1465.
  • an isolated polynucleotide comprising a SEQ ID NOs: 1276, 1277, 1278, 1279 and 1280.
  • an isolated polypeptide comprising SEQ ID NO: 1415.
  • Protein Name Corresponding Transcript(s) is provided.
  • HSU33147_PEA_1_P5 HSU33147_PEA_1_T1 ; HSU33147_PEA_1_T2 According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising SEQ ID NO: 58.
  • an isolated polynucleotide comprising SEQ ID NOs: 571, 572, 573, 574, 575, 576, 577 and 578. According to preferred embodiments of the present invention, there is provided an isolated polypeptide comprising SEQ ID NO: 1334.
  • an isolated polynucleotide comprising SEQ ID NOs: 74, 75, 76, 77, 78, 79, 80, 81 and 82.
  • an isolated polynucleotide comprising SEQ ID NOs: 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692 and 693.
  • an isolated polypeptide comprising SEQ ID NOs 1350, 1351, 1352, 1353, 1354, 1355, 1356 and 1357.
  • an isolated polynucleotide comprising SEQ ID NOs:
  • T23580_T10 According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising SEQ ID NOs: 579, 580, 581, 582 and 583.
  • an isolated polypeptide comprising SEQ ID NOs 1335.
  • an isolated polynucleotide comprising SEQ ID NOs: 59, 60, 61, 62, 63 and 64.
  • an isolated polynucleotide comprising SEQ ID NOs: 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614 and 615.
  • an isolated polypeptide comprising SEQ ID NOs: 1336, 1337, 1338, 1339 and 1340.
  • an isolated polynucleotide comprising SEQ ID NOs: 65, 66, 67, 68, 69, 70, 71, 72 and 73.
  • an isolated polynucleotide comprising SEQ ID NOs: 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658 and 659.
  • an isolated polypeptide comprising SEQ ID NOs: 1341, 1342, 1343, 1344, 1345, 1346, 1347, 1348 and 1349.
  • an isolated polynucleotide comprising SEQ ID NOs: 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 and 96.
  • an isolated polynucleotide comprising SEQ ID NOs: 695, 696, 697, 698, 699, 700, 701, 702, 703, 704 and 705.
  • an isolated polypeptide comprising SEQ ID NOs 1358, 1359, 1360, 1361, 1362, 1363, 1364, 1365, 1366, 1367, 1368 and 1369.
  • an isolated polynucleotide comprising SEQ ID NOs: 97 and 98.
  • an isolated polynucleotide comprising SEQ ID NOs: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740 and 741.
  • an isolated polypeptide comprising SEQ ID NOs: 1370 and 1371.
  • an isolated polynucleotide comprising SEQ ID NOs: 103, 104, 105, 106, 107 and 108.
  • an isolated polynucleotide comprising SEQ ID NOs: 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 8 09, 810, 811, 812 and 813.
  • an isolated polypeptide comprising SEQ ID NOs: 1376, 1377, 1378 and 1379.
  • an isolated polynucleotide comprising SEQ ID NOs: 114, 115, 116, 117, 118 and 119.
  • an isolated polynucleotide comprising SEQ ID NOs: 856, 857, 858, 859, 860, 861 , 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874 and 875.
  • an isolated polypeptide comprising SEQ ID NOs: 1385, 1386, 1387, 1388 and 1389.
  • an isolated polynucleotide comprising SEQ ID NOs: 144, 145, 146, 147, 148 and 149.
  • an isolated polynucleotide comprising SEQ ID NOs: 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015 and 1016.
  • an isolated polypeptide comprising SEQ ID NOs: 1409, 1410, 1411, 1412 and 1413.
  • an isolated polynucleotide comprising SEQ ID NO: 150. According to preferred embodiments of the present invention, there is provided an isolated polynucleotide comprising SEQ ID NOs: 1017, 1018, 1019, 1020 and 1021.
  • an isolated polypeptide comprising SEQ ID NO: 1414.
  • an isolated polynucleotide comprising SEQ ID NOs: 109, 110, 111 , 112 and 113.
  • an isolated polynucleotide comprising SEQ ID NOs: 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854 and 855.
  • an isolated polypeptide comprising SEQ ID NOs 1380, 1381, 1382, 1383 and 1384.
  • an isolated chimeric polypeptide encoding for.HSSTROL3_P4 comprising a first amino acid sequence being at least 90 % homologous to
  • MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS PAP APATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVLSGGRWEKTDLTYRILRFP WQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW corresponding to amino acids 1 - 163 of MMl IJHUMAN, which also corresponds to amino acids 1 - 163 of HSSTROL3_P4, a bridging amino acid H corresponding to amino acid 164 of HSSTROL3_P4, a second amino acid sequence being at least 90 % homologous to GDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWTIGDDQGTDLLQVAAHEFGHVLG LQHTTAAKALMSAFYTFRYPLSLSPDDCRGVQHLYGQPWPTVTSRTPALGPQAGIDTN EIAPLEPDAPPDACEASFDAVSTIRGELFFF
  • an isolated polypeptide encoding for a tail of HSSTROL3 P4 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence
  • an isolated chimeric polypeptide encoding for HSSTROL3_P5 comprising a first amino acid sequence being at least 90 % homologous to MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS PAP APATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVLSGGRWEKTDLTYRILRFP WQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW coiresponding to amino acids 1 - 163 of MMI l HUMAN, which also corresponds to amino acids 1 - 163 of HSSTROL3_P5, a bridging amino acid H corresponding to amino acid 164 of HSSTROL3_P5, a second amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of HSSTROL3_P5 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence ELGFPSSTGRDESLEHCRCQGLHK in HSSTROL3_P5.
  • an isolated chimeric polypeptide encoding for HSSTROL3_P7 comprising a first amino acid sequence being at least 90 % homologous to MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS PAPAPATQEAPRPASSLRPPRCGWDPSDGLSARNRQKRFVLSGGRWEKTDLTYRILRFP WQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW corresponding to amino acids 1 - 163 of MMI l JHUMAN, which also corresponds to amino acids 1 - 163 of HSSTROL3_P7, a bridging amino acid H corresponding to amino acid 164 of HSSTROL3_P7, a second amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of HSSTROL3_P7 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TTGVSTPAPGV in HSSTROL3_P7.
  • an isolated chimeric polypeptide encoding for HSSTROL3_P8 comprising a first amino acid sequence being at least 90 % homologous to
  • MAPAAWLRSAAARALLPPMLLLLLQPPPLLARALPPDVHHLHAERRGPQPWHAALPSS PAP APATQEAPRPASSLRPPRCGVPDPSDGLSARNRQKRFVLSGGRWEKTDLTYRILRFP WQLVQEQVRQTMAEALKVWSDVTPLTFTEVHEGRADIMIDFARYW corresponding to amino acids 1 - 163 of MMl IJHUMAN, which also corresponds to amino acids 1 - 163 of HSSTROL3JP8, a bridging amino acid H corresponding to amino acid 164 of HSSTROL3JP8, a second amino acid sequence being at least 90 % homologous to GDDLPFDGPGGILAHAFFPKTHREGDVHFDYDETWTIGDDQGTDLLQVAAHEFGHVLG LQHTTAAKALMSAFYTFRYPLSLSPDDCRGVQHLYGQPWPTVTSRTPALGPQAGIDTN EIAPLE corresponding to amino acids 165 - 286 of
  • an isolated polypeptide encoding for a tail of HSSTROL3_P8 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VRPCLPVPLLLCWPL in HSSTROL3 P8.
  • an isolated chimeric polypeptide encoding for HSSTROL3_P9 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for an edge portion of HSSTROL3 P9 comprising a polypeptide having a length "n", wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise KR, having a structure as follows: a sequence starting from any of amino acid numbers 96-x to 96; and ending at any of amino acid numbers 97+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated polypeptide encoding for a tail of HSSTROL3 P9 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TTGVSTPAPGV in HSSTROL3_P9.
  • HUMCA1XIA_P14 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 HUMCA1XIA_P14 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence
  • PIGPPGEK corresponding to amino acids 1 - 714 of CA IBJHUMAN, which also corresponds to amino acids 1 - 714 of HUMCA1XIA_P15, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MCCNLSFGILIPLQK corresponding to amino acids 715 - 729 of HUMC AlXI A JM 5, 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 HUMCA1XIA_P15 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence MCCNLSFGILIPLQK in HUMCA IXIAJPl 5.
  • an isolated chimeric polypeptide encoding for HUMCA IXIA P 16 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for an edge portion of HUMCA1XIA_P16 comprising a polypeptide having a length "n", wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise AG, having a structure as follows: a sequence starting from any of amino acid numbers 648-x to 648; and ending at any of amino acid numbers 649+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated polypeptide encoding for a tail of HUMCA IXI A_P 16 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VSFSFSLFYKKV ⁇ CFACDKRFVGRHDERKVVKLSLPLYLIYE in HUMCA1XIA_P16.
  • an isolated chimeric polypeptide encoding for HUMCA1XIA_P17 comprising a first amino acid sequence being at least 90 % homologous to MEPWSSRWKTKRWLWDFTVTTLALTFLFQAREVRGAAPVDVLKALDFHNSPEGISKTT GFCTNRKNSKGSDTAYRVSKQAQLSAPTKQLFPGGTFPEDFSILFTVKPKKGIQSFLLSIY NEHGIQQIGVEVGRSPVFLFEDHTGKPAPEDYPLFRTVNIADGKWHRVAISVEKKTVTM IVDCKKKTTKPLDRSERAIVDTNGITVFGTRILDEEVFEGDIQQFLITGDPKAAYDYCEH YSPDCDSSAPKAAQAQEPQIDE corresponding to amino acids 1 - 260 of CA1B_HUMAN, which also corresponds to amino acids 1 - 260 of HUMCA1XIA_P17, and a second amino acid sequence being at least 70%, optional
  • an isolated polypeptide encoding for a tail of HUMCA1XIA_P17 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VRSTRPEKVFVFQ in HUMCA 1XIA_P 17.
  • an isolated chimeric polypeptide encoding for R20779_P2 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of R20779_P2 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence CYKIEITMPKRRKVKLRD in R20779_P2.
  • an isolated chimeric polypeptide encoding for HUMOSTRO_PEA_1_PEA_1_P21 comprising a first amino acid sequence being at least 90 % homologous to MRIAVICFCLLGITCAIPVKQADSGSSEEKQLYNKYPDAVATWLNPDPSQKQNLLAPQ corresponding to amino acids 1 - 58 of OSTP_HUMAN, which also corresponds to amino acids 1 - 58 of HUMOSTRO_PEA_1_PEA_1_P21, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VFLNFS corresponding to amino acids 59 - 64 of HUMOSTRO_PEA_1_PEA_1_P21, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of HUMOSTRO_PEA_1_PEA_1_P21 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VFLNFS in HUMOSTROJPEA 1 JPEA_1_P21.
  • an isolated chimeric polypeptide encoding for HUMOSTRO_PEA_1_PEA_1_P25 comprising a first amino acid sequence being at least 90 % homologous to MPJAVICFCLLGITCAIPVKQADSGSSEEKQ corresponding to amino acids 1 - 31 of OSTP_HUMAN, which also corresponds to amino acids 1 - 31 of
  • HUMOSTRO_PEA_1_PEA_1_P25 and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence H corresponding to amino acids 32 - 32 of HUMOSTRO_PEA_1_PEA_1_P25, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated chimeric polypeptide encoding for HUMOSTRO_PEA_1_PEA_1_P30 comprising a first amino acid sequence being at least 90 % homologous to MRIAVICFCLLGITCAIPVKQADSGSSEEKQ corresponding to amino acids 1 - 31 of OSTP_HUMAN, which also corresponds to amino acids 1 - 31 of
  • HUMOSTRO_PEA_1_PEA_1_P30 and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VSIFYVFI corresponding to amino acids 32 - 39 of HUMOSTRO_PEA_1_PEA_1_P30, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of HUMOSTRO_PEA_1_PEA_1_P30 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VSIFYVFI in HUMOSTRO_PEA_1_PEA_1_P30.
  • an isolated chimeric polypeptide encoding for HUMPHOSLIP_PEA_2_P10 comprising a first 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_PEA_2_P12.
  • an isolated chimeric polypeptide encoding for HUMPHOSLIP_PEA_2_P31 comprising a first amino acid sequence being at least 90 % homologous to MALFGALFLALLAGAHAEFPGCKIRVTSKALELVKQEGLRFLEQELETITIPDLRGKEGH FYYNISE corresponding to amino acids 1 - 67 of PLTP HUMAN, which also corresponds to amino acids 1 - 67 of HUMPHOSLIP_PEA_2_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 PGLERGADKFPWGGSSLFLALDLTLRPPVG corresponding 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
  • 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 PGLERGADKFPWGGSSLFLALDLTLRPPVG in HUMPHOSLIP_PEA_2_P31.
  • an isolated chimeric polypeptide encoding for HUMPHOSLIPJPEA 2JP33 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of HUMPHOSLIPJPEA 2JP33 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VWAATGRRVARVGMLSL in HUMPHOSLIP PEA 2JP33.
  • 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 corresponding to amino acids 206 - 217 of HUMPHOSLIP_PEA_2_P34, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of HUMPHOSLIPJPEA 2 P34 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence LWTSLLALTIPS in HUMPHOSLIP_PEA_2_P34.
  • an isolated chimeric polypeptide encoding for HUMPHOSLIP_PEA_2_P35 comprising a first amino acid sequence being at least 90 % homologous to MALFGALFLALLAGAHAEFPGCKIRVTSKALELVKQEGLRFLEQELETITIPDLRGKEGH FYYNISEVKVTELQLTSSELDFQPQQELMLQITNASLGLRFRRQLLYWF corresponding to amino acids 1 - 109 of PLTP_HUMAN, which also corresponds to amino acids 1 - 109 of HUMPHOSLIP_PEA_2_P35, a second amino acid sequence bridging amino acid sequence comprising of L, a third amino acid sequence being at least 90 % homologous to KVYDFLSTFITSGMRFLLNQQ corresponding to amino acids 163 - 183 of PLTP_HUMAN, which also corresponds to amino acids 111 - 131 of HUMPHOSLIP J > EA_2_
  • 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 HUMPHOSLIPJPEA_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 2 P35 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VWAATGRRVARVGMLSL in HUMPHOSLIP_PEA_2_P35.
  • an isolated chimeric polypeptide encoding for R38144_PEA_2_P6 comprising a first amino acid sequence being at least 90 % homologous to MPFRLLIPLGLLCALLPQHHGAPGPDGSAPDPAHYRERVKAMFYHAYDSYLENAFPFD ELRPLTCDGHDTWGSFSLTLIDALDTLLILGNVSEFQRVVEVLQDSVDFDIDVNASVFET NIRVVGGLLSAHLLSKKAGVEVEAGWPCSGPLLRMAEEAARKLLPAFQTPTGMPYGTV NLLHGVNPGETPVTCTAGIGTFIVEFATLSSLTGDPVFEDVARVALMRLWESRSDIGLV GNmDVLTGKWVAQDAGIGAGVDSYFEYLVKGAILLQDKKLMAMFLEYNKAIRNYTR FDDWYLWVQMYKGTVSMPVFQSLEAYWPGLQSLIGDIDNAMRTFLNYYTVWKQF
  • an isolated polypeptide encoding for a tail of R38144_PEA_2_P6 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence LASFSHMSDQRSARPQAGQPHGWLPGRDCEIPLPPV in R38144_PEA_2_P6.
  • an isolated chimeric polypeptide encoding for R38144_PEA_2_P13 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of R38144_PEA_2_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 NLLKAQCTSTVPRGIPPS in R38144_PEA_2_P13.
  • an isolated chimeric polypeptide encoding for R38144_PEA_2_P15 comprising a first amino acid sequence being at least 90 % homologous to MPFRLLIPLGLLCALLPQHHGAPGPDGSAPDPAHYRERVKAMFYHAYDSYLENAFPFD ELRPLTCDGHDTWGSFSLTLIDALDTLLILGNVSEFQRWEVLQDSVDFDIDVNASVFET NIRVVGGLLSAHLLSKKAGVEVEAGWPCSGPLLRMAEEAARKLLPAFQTPTGMPYGTV NLLHGVNPGETPVTCTAGIGTFIVEFATLSSLTGDPVFEDVARVALMRLWESRSDIGLV GNHIDVLTGKWVAQDAGIGAGVDSYFEYLVKGAILLQDKKLMAMFLE corresponding to amino acids 1 - 282 of CT3 IJHUMAN, which also corresponds to amino acids 1 - 282 of R38144_PEA_2_P15,
  • an isolated polypeptide encoding for a tail of R38144_PEA_2_P15 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence PHWRH in R38144_PEA_2_P 15.
  • an isolated chimeric polypeptide encoding for R38144_PEA_2_P19 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of R38144_PEA_2_P19 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence KRSRSVAQAGVQWCDHDSPQP in R38144_PEA_2_P19.
  • an isolated chimeric polypeptide encoding for R38144_PEA_2_P24 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for an edge portion of R38144_PEA_2_P24 comprising a polypeptide having a length "n", wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise RE, having a structure as follows: a sequence starting from any of amino acid numbers 121-x to 121; and ending at any of amino acid numbers 122+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for R38144_PEA_2_P36 comprising a first amino acid sequence being at least 90 % homologous to MPFRLLIPLGLLCALLPQHHGAPGPDGSAPDPAHYR corresponding to amino acids 1 - 36 of AAH16184, which also corresponds to amino acids 1 - 36 of R38144_PEA_2_P36, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence FWGMSQNSKEWLKCSRTAWTLILM corresponding to amino acids 37 - 60 of R38144_PEA_2_P36, 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 R38144JPEA_2_P36 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence FWGMSQNSKEWLKCSRTAWTLILM in R38144JPEA_2_P36.
  • an isolated chimeric polypeptide encoding for R38144_PEA_2_P36 comprising a first amino acid sequence being at least 90 % homologous to MPFRLLIPLGLLCALLPQHHGAPGPDGSAPDPAHY corresponding to amino acids 1 - 35 of AAQ88943, which also corresponds to amino acids 1 - 35 of R38144_PEA_2_P36, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence RFWGMSQNSKEWLKCSRTAWTLILM corresponding to amino acids 36 - 60 of R38144_PEA_2_P36, 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 R38144_PEA_2_P36 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence RFWGMSQNSKEWLKCSRTAWTLILM in R38144_PEA_2_P36.
  • an isolated chimeric polypeptide encoding for R38144_PEA_2_P36 comprising a first amino acid sequence being at least 90 % homologous to MPFRLLIPLGLLCALLPQHHGAPGPDGSAPDPAHYR corresponding to amino acids 1 - 36 of CT31_HUMAN, which also corresponds to amino acids 1 - 36 of R38144_PEA_2_P36, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence FWGMSQNSKEWLKCSRTAWTLILM corresponding to amino acids 37 - 60 of R38144_PEA_2_P36, 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 R38144_PEA_2_P36 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence FWGMSQNSKEWLKCSRTAWTLILM in R38144_PEA_2_P36.
  • an isolated chimeric polypeptide encoding for AAl 61187_P6, comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence HTREGTLGGQKRAFPDGVEGEKGRGRAWGAASRGSAVPLTIR corresponding to amino acids 1 - 42 of AA161187_P6, and a second amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a head of AAl 61187_P6 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence HTREGTLGGQKRAFPDGVEGEKGRGRAWGAASRGSAVPLTIR of AA161187_P6.
  • an isolated chimeric polypeptide encoding for AA161187JP13 comprising a first amino acid sequence being at least 90 % homologous to MGARGALLLALLLARAGLRKPESQEAAPLSGPCGRRVITSRIVGGEDAELGRWPWQGS LRLWDSHVCGVSLLSHRWALTAAHCFETYSDLSDPSGWMVQFGQLTSMPSFWSLQAY YTRYFVSNIYLSPRYLGNSPYDIALVKLSAPVTYTKHIQPICLQASTFEFENRTDCWVTG WGYIKEDE corresponding to amino acids 1 - 183 of TEST_HUMAN, which also corresponds to amino acids 1 - 183 of AA161187_P13, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence GSSGRHHKQ
  • an isolated polypeptide encoding for a tail of AAl 61187_P13 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence GSSGRHHKQLYVQPPLPQVQFPQGHLWRHG in AA161187_P13.
  • an isolated chimeric polypeptide encoding for AA161187_P14 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of AAl 61187_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
  • an isolated chimeric polypeptide encoding for AA161187_P18 comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence HTREGTLGGQKRAFPDGVEGEKGRGRAWGAASRGSAVPLTIR corresponding to amino acids 1 - 42 of AA161187_P18, a second amino acid sequence being at least 90 % homologous to GPCGRRVITSRIVGGEDAELGRWPWQGSLRLWDSHVCGVSLLSHRWALTAAHCFET corresponding to amino acids 31 - 86 of TEST_HUMAN, which also corresponds to amino acids 43 - 98 of AAl 61187JP18, a third amino acid sequence being at least 90 % homologous to DLSDPSGWMVQFGQLTSMPSFWSLQAYYTRYFVSNI
  • an isolated polypeptide encoding for a head of AAl 61187_P18 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence HTREGTLGGQKRAFPDGVEGEKGRGRAWGAASRGSAVPLTIR of AA161187_P18.
  • an isolated chimeric polypeptide encoding for an edge portion of AA161187_P18 comprising a polypeptide having a length "n", wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise TD, having a structure as follows: a sequence starting from any of amino acid numbers 98-x to 99; and ending at any of amino acid numbers 99+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated polypeptide encoding for a tail of AA161187JP18 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VSVPATTPSPGKHPVSLCLI in AAl 61187_P 18.
  • an isolated chimeric polypeptide encoding for AA161187 P19 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of AA161187_P19 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DKRTQ in AA161187_P19.
  • an isolated chimeric polypeptide encoding for Z25299_PEA_2_P2 comprising a first amino acid sequence being at least 90 % homologous to
  • 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
  • an isolated chimeric polypeptide encoding for Z25299_PEA_2_P7 comprising a first amino acid sequence being at least 90 % homologous to MKSSGLFPFLVLLALGTLAPWAVEGSGKSFKAGVCPPKKSAQCLRYKKPECQSDWQCP GKKRCCPDTCGIKCLDPVDTPNP corresponding to amino acids 1 - 81 of ALK1JHUMAN, which also corresponds to amino acids 1 - 81 of Z25299_PEA_2_P7, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence RGSLGSAQ corresponding to amino acids 82 - 89 of Z25299JPEA_2J?7, wherein said first and second amino acid sequences are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of Z25299JPEA 2JP7 comprising a polypeptide being at least 70%, optionally at least 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 Z25299JPEA_2_P7.
  • an isolated chimeric polypeptide encoding for Z25299_PEA_2_P10 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for R66178_P3, comprising a first amino acid sequence being at least 90 % homologous to MARMGLAGAAGRWWGLALGLTAFFLPGVHSQWQVNDSMYGFIGTDVVLHCSFANP LPSVKITQVTWQKSTNGSKQNVA ⁇ YNPSMGVSVLAPYRERVEFLRPSFTDGTIRLSRLEL EDEGVYICEFATFPTGNRESQLNLTVMAKPTNWIEGTQA VLRAKKGQDDKVLVATCTS ANGKPPSWSWETRLKGEAEYQEIRNPNGTVTVISRYRLVPSREAHQQSLACIVNYHM DRFKESLTLNVQYEPEVTIEGFDGNWYLQRMDVKLTCKADANPPATEYHWTTLNGSLP KGVEAQNRTLFFKGPINYSLAGTYICEATNPIGTRSGQVEVNIT corresponding to amino acids 1 - 334 of
  • an isolated polypeptide encoding for a tail of R66178_P3, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence GEGHSLPISPGVLQTQNCGP in R66178_P3.
  • an isolated chimeric polypeptide encoding for R66178_P4 comprising a first amino acid sequence being at least 90 % homologous to MARMGLAGAAGRWWGLALGLTAFFLPGVHSQWQVNDSMYGFIGTDVVLHCSFANP LPSVKITQVTWQKSTNGSKQNVAIYNPSMGVSVLAPYRERVEFLRPSFTDGTIRLSRLEL EDEGVYICEFATFPTGNRESQLNLTVMAKPTNWIEGTQAVLRAKKGQDDKVLVATCTS ANGKPPSVVSWETRLKGEAEYQEIRNPNGTVTVISRYRLVPSREAHQQSLACIVNYHM DRFKESLTLNVQYEPEVTIEGFDGNWYLQRMDVKLTCKADANPPATEYHWTTLNGSLP KGVEAQNRTLFFKGPINYSLAGTYICEATNPIGTRSGQVEVNIT corresponding to amino acids 1 - 334 of P
  • an isolated polypeptide encoding for a tail of R66178_P4 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence AFCQLIYPGKGRTRARMF in R66178_P4.
  • an isolated chimeric polypeptide encoding for R66178_P8 comprising a first amino acid sequence being at least 90 % homologous to MARMGLAGAAGRWWGLALGLTAFFLPGVHSQWQVNDSMYGFIGTDVVLHCSFANP LPSVKITQVTWQKSTNGSKQNVAIYNPSMGVS VLAPYRERVEFLRPSFTDGTIRLSRLEL EDEGVYICEFATFPTGNRESQLNLTVMAKPTNWIEGTQAVLRAKKGQDDKVLVATCTS ANGKPPSVVSWETRLKGEAEYQEIRNPNGTVTVISRYRLVPSREAHQQSLACIVNYHM DRFKESLTLNVQYEPEVTIEGFDGNWYLQRMDVKLTCKADANPPATEYHWTTLNGSLP KGVEAQNRTLFFKGPINYSLAGTYICEATNPIGTRSGQVE corresponding to amino acids 1
  • PVR1_HUMAN which also corresponds to amino acids 1 - 330 of R66178_P8, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence NSPTPRLLPNMGGAPGRCPRPSLGAWRGASCWC corresponding to amino acids 331 - 363 of R66178 P8, 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 R66178_P8 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence NSPTPRLLPNMGGAPGRCPRPSLGAWRGASCWC in R66178_P8.
  • an isolated chimeric polypeptide encoding for HSU33147_PEA_1_P5 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for HSU33147_PEA_1_P5 comprising a first amino acid sequence being at least 90 % homologous to
  • HSU33147_PEA_1_P5 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 M78076_PEA_l_P4 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence ECLTVNPSLQIPLNP in M78076_PEA_l_P4.
  • an isolated chimeric polypeptide encoding for M78076_PEA_l_P12 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of M78076_PEA_l_P12 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence ECVCSKGFPFPLIGDSEG in M78076_PEA_l_P12.
  • an isolated chimeric polypeptide encoding for M78076_PEA_l_P14 comprising a first amino acid sequence being at least 90 % homologous to
  • EQDAASPEKEKMNPLEQYERKVNASVPRGFPFHSSEIQRDEL corresponding to amino acids 1 - 570 of APP1JHUMAN, which also corresponds to amino acids 1 - 570 of M78076_PEA_l_P14, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence
  • VRGGTAGYLGEETRGQRPGCDSQSHTGPSKKPSAPSPLPAGTSWDRGVP corresponding to amino acids 571 - 619 of M78076_PEA_l_P14, 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 M78076_PEA_l_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 VRGGTAGYLGEETRGQRPGCDSQSHTGPSKKPSAPSPLPAGTSWDRGVP in M78076_PEA_l_P14.
  • an isolated chimeric polypeptide encoding for M78076_PEA_l_P21 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for an edge portion of M78076_PEA_l_P21 comprising a polypeptide having a length "n", wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise EA, having a structure as follows: a sequence starting from any of amino acid numbers 352-x to 352; and ending at any of amino acid numbers 353+ ((n-2) - x), in which x varies fromO to n-2.
  • an isolated chimeric polypeptide encoding for M78076_PEA_l_P24 comprising a first amino acid sequence being at least 90 % homologous to MGPASPAARGLSRRPGQPPLPLLLPLLLLLLRAQPAIGSLAGGSPGAAEAPGSAQVAGL CGRLTLHRDLRTGRWEPDPQRSRRCLRDPQRVLEYCRQMYPELQIARVEQATQAIPME RWCGGSRSGSCAHPHHQVVPFRCLPGEFVSEALLVPEGCRFLHQERMDQCESSTRPVHQ
  • QNPHLAQELRPQI corresponding to amino acids 1 - 481 of APP1_HUMAN, which also corresponds to amino acids 1 - 481 of M78076_PEA_l_P24, 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 M78076_PEA_l_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
  • an isolated chimeric polypeptide encoding for M78076_PEA_l_P2 comprising a first amino acid sequence being at least 90 % homologous to
  • 1 - 449 of APPl HUMAN which also corresponds to amino acids 1 - 449 of M78076JPEA_l_P2, and a second amino acid sequence being at least 70%, optionally at least
  • an isolated polypeptide encoding for a tail of M78076JPEA_l_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 LTSFQLPNAPLFLRRPRJLRLFSCPLDPLSVSWTPSYPLNTASLPLPSLSAQLPDPETWTLT CCVFDPCFLALGFLLPPPSILCSVPWIFTAFPRIVFFFFFFLRQVLALSPRQESSVRSWLIAT STSWVQAILLPQPLE in M78076_PEA_l_P2.
  • ALRRYLRAEQKEQRHTLRHYQHVAAVDPEKAQQMRFQ corresponding to amino acids 1 - 448 of APP IJHUMAN, which also corresponds to amino acids 1 - 448 of
  • M78076_PEA_l_P25 and a second amino acid sequence being at least 70%, optionally at least
  • PQNPNSQPRAAGSLEVIISHPFVRRLEILISPFQFQNSIPKNSQIVPAASPRGTSSP corresponding to amino acids 449 - 505 of M78076_PEA_l_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 M78076_PEA_l_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
  • an isolated chimeric polypeptide encoding for M79217_PEA_1_P1 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for M79217_PEA_1_P2 comprising a first amino acid sequence being at least 90 % homologous to MTGYTMLRNGGAGNGGQTCMLRWSNMRLTWLSFTLFVILVFFPLIAHYYLTTLDEAD EAGKRIFGPRVGNELCEVKHVLDLCRIRESVSEELLQLEAKRQELNSEIAKLNLKIEACK KSIENAKQDLLQLKNVISQTEHSYKELMAQNQPKLSLPIRLLPEKDDAGLPPPKATRGC RLHNCFDYSRCPLTSGFPVYVYDSDQFVFGSYLDPLVKQAFQATARANVYVTENADIA CLYVILVGEMQEP WLRPAELEKQLYSLPHWRTDGHNHVIINLSRKSDTQNLLYNVSTG RAMVAQSTFYTVQYRPGFDLWSPLVHAMSEPNFMEIPPQVPVKR
  • an isolated chimeric polypeptide encoding for an edge portion of M79217_PEA_1_P2, comprising a polypeptide having a length "n", wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise KA, having a structure as follows: a sequence starting from any of amino acid numbers 807-x to 807; and ending at any of amino acid numbers 808+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for M79217_PEA_1JP4 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
  • an isolated polypeptide encoding for a head of M79217_PEA_1_P4 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence PELRQPARLGLPECWDYRHEPRCP AQMGSHFIVQAGLKLLASSKPPKCWDY of M79217_PEA_1_P4.
  • an isolated chimeric polypeptide encoding for M79217_PEA_1_P8 comprising a first amino acid sequence being at least 90 % homologous to MTGYTMLRNGGAGNGGQTCMLRWSNRIRLTWLSFTLFVILVFFPLIAHYYLTTLDEAD EAGKRIFGPRVGNELCEVKHVLDLCRIRESVSEELLQLEAKRQELNSEIAKLNLKIEACK KSIENAKQDLLQLKNVISQTEHSYKELMAQNQPKLSLPIRLLPEKDDAGLPPPKATRGC RLHNCFDYSRCPLTSGFPVYVYDSDQFVFGSYLDPLVKQAFQATARANVYVTENADIA CLYVILVGEMQEPVVLRPAELEKQLYSLPHWRTDGHNHVIINLSRKSDTQNLLYNVSTG RAMVAQSTFYTVQYRPGFDLVVSPLVHAMSEPNFMEIPPQVPV
  • an isolated polypeptide encoding for a tail of M79217_PEA_1_P8 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VRKSW in M79217_PEA_1_P8.
  • an isolated chimeric polypeptide encoding for M62096_PEA_l_P4 comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MATYIH corresponding to amino acids 1 - 6 of M62096JPEA_l_P4, and a second amino acid sequence being at least 90 % homologous to VSKTGAEGAVLDEAKNINKSLSALGNVISALAEGTKTHVPYRDSKMTRILQDSLGGNC RTTIVICCSPSVFNEAETKSTLMFGQRAKTIKNTVSVNLELTAEEWKKKYEKEKEKNKT
  • VHAIRGGGGSSSNSTHYQK corresponding to amino acids 239 - 957 of KF5C_HUMAN, which also corresponds to amino acids 7 - 725 of M62096_PEA_l_P4, 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 M62096_PEA_l_P4 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence MATYIH of M62096_PEA_l_P4.
  • an isolated chimeric polypeptide encoding for M62096_PEA_l_P5 comprising a first amino acid sequence being at least 90 % homologous to
  • RPGHYPASSPTAVHAIRGGGGSSSNSTHYQK corresponding to amino acids 284 - 957 of KF5C_HUMAN, which also corresponds to amino acids 1 - 674 of M62096_PEA_l_P5.
  • an isolated chimeric polypeptide encoding for M62096_PEA_l_P3 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for M62096JPEA_l_P7 comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MTQNFRLMWNILLFPLNFS corresponding to amino acids 1 - 19 of M62096JPEA_l_P7, and a second amino acid sequence being at least 90 % homologous to LNQKLQLEQEKLSSDYNKLKJEDQEREMKLEKLLLLNDKREQAREDLKGLEETVSREL QTLHNLRKLFVQDLTTRVKKSVELDNDDGGGSAAQKQKISF
  • an isolated polypeptide encoding for a head of M62096_PEA_l_P7 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence MTQNFRLMWNILLFPLNFS of M62096_PEA_l_P7.
  • an isolated chimeric polypeptide encoding for M62096_PEA_l_P9 comprising a first amino acid sequence being at least 90 % homologous to
  • M62096_PEA_l_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 VKNAIYFFFHKVLLLLFVVDVCSRNLIGIEAFHNYRIMWKFLGRCPFTASYKLIITEFRK corresponding to amino acids 455 - 514 of M62096_PEA_l_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 M62096_PEA_l_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 VKNAIYFFFHKVLLLLFVVDVCSRNLIGIEAFHNYRIMWKFLGRCPFTASYKLIITEFRK in M62096_PEA_l_P9.
  • an isolated chimeric polypeptide encoding forM62096_PEA_l_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
  • MTQNFRLMWNILLFPLNFS corresponding to amino acids 1 - 19 of M62096_PEA_l_P10, a second amino acid sequence being at least 90 % homologous to
  • VSSLCLNGTEKKIKDGREESFSVEISLA corresponding to amino acids 98 - 125 of M62096_PEA_l_P10, 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 a head of M62096_PEA_l_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
  • an isolated polypeptide encoding for a tail of M62096_PEA_l_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
  • an isolated chimeric polypeptide encoding for M62O96JPEA_1_P11 comprising a first amino acid sequence being at least 90 % homologous to MADPAECSIKVMCRFRPLNEAEILRGDKFIPKFKGDETWIGQGKPYVFDRVLPPNTTQ
  • an isolated polypeptide encoding for a tail of M62O96_PEA_1_P11 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DFLAAHVFGKLLE in M62O96_PEA_1_P11.
  • an isolated chimeric polypeptide encoding for M62096_PEA_l_P12 comprising a first amino acid sequence being at least 90 % homologous to MADPAECSIKVMCRFRPLNEAEILRGDKFIPKFKGDETVVIGQGKPYVFDRVLPPNTTQ EQVYNACAKQIVKDVLEGYNGTIFAYGQTSSGKTHTMEGKLHDPQLMGIIPRIAHDIFD HIYSMDENLEFHIKVSYFEIYLDKIRDLLDVSKTNLAVHEDKNRVPYVKGCTERFVSSPE EVMDVIDEGKANRHVAVTNMNEHSSRSHSIFLINIKQENVETEKKLSGKLYLVDLAGSE KVSKTGAEGAVLDEAKNINKSLSALGNVISALAEGTKTHVPYRDSKMTRILQDSLGGN CRTTIVICCSPSVFNEAETKSTLMFGQR corresponding to amino acids 1 - 323
  • KF5C_HUMAN which also corresponds to amino acids 1 - 323 of M62096JPEA_l_P12, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence V corresponding to amino acids 324 - 324 of M62O96_PEA_1JP12, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated chimeric polypeptide encoding for T99080_PEA_4_P5 comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MPASARLAGAGLLLAFLRALGCAGRAPGLS co ⁇ -esponding to amino acids 1 - 30 of T99080_PEA_4_P5, and a second amino acid sequence being at least 90 % homologous to MAEGNTLISVDYEIFGKVQGVFFRKHTQAEGKKLGLVGWVQNTDRGTVQGQLQGPIS KVRHMQEWLETRGSPKSHIDKANFNNEKVILKLDYSDFQIVK corresponding to amino acids 1 - 99 of ACYO_HUMAN_V1, which also corresponds to amino acids 31 - 129 of T99080_PEA _4_P5, wherein said
  • an isolated polypeptide encoding for a head of T99080_PEA_4_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 MPASARLAGAGLLLAFLRALGCAGRAPGLS of T99080_PEA_4_P5.
  • an isolated chimeric polypeptide encoding for T99080_PEA_4_P8 comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence M corresponding to amino acids 1 - 1 of T99080_PEA_4_P8, and a second amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for T08446_PEA_l_P18 comprising a first amino acid sequence being at least 90 % homologous to MLSLSLCSHLWGPLILSALQARSTDSLDGPGEGSVQPLPTAGGPSVKGKPGKRLSAPRG PFPRLADCAHFHYENVDFGHIQLLLSPDREGPSLSGENELVFGVQVTCQGRSWPVLRSY DDFRSLD AHLHRCIFDRRFSCLPELPPPPEGARAAQMLVPLLLQYLETLSGLVDSNLNC GPVLTWME corresponding to amino acids 1 - 185 of SNXQ_HUMAN, which also corresponds to amino acids 1 - 185 of T08446_PEA_l_P18, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide
  • an isolated polypeptide encoding for a tail of T08446_PEA_l_P18 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence
  • T08446_PEA__l_P18 there is provided an isolated chimeric polypeptide encoding for T08446JPEA_l_P18, comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MLSLSLCSHLWGPLILSALQARSTDSLDGPGEGSVQPLPTAGGPSVKGKPGKRLSAPRG PFPRLADCAHFHYENVDFGHIQLLLSPDREGPSLSGENELVFGVQVTCQGRSWPVLRSY DDFRSLDAHLHRCIFDRRFSCLPELPPPPEGARAAQMLVPLLLQYLETLSGLVDSNLNC GPVLTWMELDNHGRRLLLSEEASLNIPAVAAAHVIKRYTAQAPDELSFEVGDIVSVIDM PPTEDRSWWRGKRGFQVGFFPSECVELFTER
  • an isolated polypeptide encoding for a head of TO8446_PEA_1_P18 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence
  • an isolated chimeric polypeptide encoding for T08446_PEA_l_P18 comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MLSLSLCSHLWGPLILSALQARSTDSLDGPGEGSVQPLPTAGGPSVKGKPGKRLSAPRG PFPRLADCAHFHYENVDFGHIQLLLSPDREGPSLSGENELVFGVQ VTCQGRSWPVLRSY DDFRSLDAHLHRCIFDRRFSCLPELPPPPEGARAAQMLVPLLLQYLETLSGLVDSNLNC GPVLTWMELDNHGRRLLLSEEASLNIPAVAAAHVIKRYTAQAPDELSFEVGDIVSVIDM PPTEDRSWWRGKRGFQVGFFPSECVELFTERPGPGLKAD ADGPPCGIPAPQGISSLT
  • an isolated polypeptide encoding for a head of T08446_PEA_l_P18 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence
  • an isolated chimeric polypeptide encoding for T08446_PEA_l_P18 comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MLSLSLCSHLWGPLILSALQARSTDSLDGPGEGSVQPLPTAGGPSVKGKPGKRLSAPRG PFPRLADCAHFHYENVDFGHIQLLLSPDREGPSLSGENEL VFGVQVTCQGRSWPVLRSY DDFRSLDAHLHRCIFDRRFSCLPELPPPPEGARAAQ corresponding to amino acids 1 - 154 of T08446_PEA_l_P18, a second amino acid sequence being at least 90 % homologous to MLVPLLLQYLETLSGLVDSNLNCGPVLTWMELDNHGRRLLLSEEASLNIPAVAAAHVI KRYTAQAPD
  • QQSDGSLLRSQRPMGTSRRGLRGPA corresponding to amino acids 1 - 861 ofBAC86902, which also corresponds to amino acids 155 - 1015 of T08446_PEA_l_P18
  • a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence QVSAQLRAGGGGRDAPEAAAQSPCSVPS corresponding to amino acids 1016 - 1043 of T08446_PEA_l_P18
  • a fourth amino acid sequence being at least 90 % homologous to QVPTPGFFSPAPRECLPPFLGVPKPGLYPLGPPSFQPSSPAPVWRSSLGPPAPLDRGENLY YEIGASEGSPYSGPTRSWSPFRSMPPDRLNASYGMLGQSPPLHRSPDFLLSYPPAPSCFPP DHLGYS corresponding to amino acids 862 - 989 of BAC86902,
  • an isolated polypeptide encoding for a head of T08446_PEA_l_P18 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence MLSLSLCSHLWGPLILSALQARSTDSLDGPGEGSVQPLPTAGGPSVKGKPGKRLSAPRG PFPRLADCAHFHYENVDFGHIQLLLSPDREGPSLSGENELVFGVQVTCQGRSWPVLRSY DDFRSLDAHLHRCIFDRRFSCLPELPPPPEGARAAQ of T08446 PEA 1 P 18.
  • an isolated polypeptide encoding for an edge portion of T08446_PEA_l_P18 comprising an amino acid sequence being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence encoding for QVSAQLRAGGGGRDAPEAAAQSPCSVPS, corresponding to T08446_PEA_l_P18.
  • an isolated polypeptide encoding for a tail of TO8446_PEA_1JP18 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence APQHPARRPTPPEPLYVNLALGPRGPSPASSSSSSPPAHPRSRSDPGPPVPRLPQKQRAP WGPRTPHRVPGPWGPPEPLLLYRAAPPAYGRGGELHRGSLYRNGGQRGEGAGPPPPYP TPSWSLHSEGQTRSYC in T08446_PEA_l_P18.
  • an isolated chimeric polypeptide encoding for Tl 1628JPEA_1_P2 comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MGLSDGEWQLVLNVWGKVEADIPGHGQEVLIRLFKGHPETLEKFDKFKHLKSEDE corresponding to amino acids 1 - 55 of Tl 1628_PEA_1_P2, and a second amino acid sequence being at least 90 % homologous to MKASEDLKKHGATVLTALGGILKKKGHHEAEIKPLAQSHATKHKIP VKYLEFISECIIQV LQSK ⁇ PGDFGADAQGAMNKALELFRKDMASNYKELGFQG corresponding to amino acids 1 - 99 of Q8WVH6, which also corresponds to amino acids 56 - 154 of Tl 1628_PE
  • an isolated polypeptide encoding for a head of Tl 1628_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 MGLSDGEWQLVLNVWGKVEADIPGHGQEVLIRLFKGHPETLEKFDKFKHLKSEDE of Tl 1628_PEA_1_P2.
  • an isolated chimeric polypeptide encoding for Tl 1628_PEA_ 1_P5 comprising a first amino acid sequence being at least 90 % homologous to MKASEDLKKHGATVLTALGGILKKKGHHEAEIKPLAQSHATKHKIPVKYLEFISECIIQV LQSKHPGDFGADAQGAMNKALELFRKDMASNYKELGFQG corresponding to amino acids 56 - 154 of MYG_HUMAN_V1, which also corresponds to amino acids 1 - 99 of T11628_PEA_1_P5.
  • an isolated chimeric polypeptide encoding for Tl 1628_PEA_1_P7 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for Tl 1628_PEA_l_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 MGLSDGEWQLVLNVWGKVEADIPGHGQEVLIRLFKGHPETLEKFDKFKHLKSEDE corresponding to amino acids 1 - 55 of Tl 1628_PEA_l_P10, and a second amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a head of Tl 1628_PEA_1JP1O comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence MGLSDGEWQLVLNVWGKVEADIPGHGQEVLIRLFKGHPETLEKFDKFKHLKSEDE of T11628_PEA_l_P10.
  • an isolated chimeric polypeptide encoding for R35137_PEA_1_PEA_1JPEA_1_P9 comprising a first amino acid sequence being at least 90 % homologous to MASSTGDRSQAVRHGLRAKVLTLDGMNPRVRRVEYAVRGPIVQRALELEQELRQGVK KPFTEVIRANIGDAQAMGQRPITFLRQVLALCVNPDLLSSPNFPDDAKKRAERILQACG GHSLGAYSVSSGIQLIREDVARYIERRDGGIPADPNNVFLSTGASDAIVTVLKLLVAGEG HTRTGVLIPIPQYPLYSATLAELGAVQVDYYLDEERAWALDVAELHRALGQARDHCRP RALCVINPGNPTGQVQTRECIEAVIRFAFEERLFLLADEV corresponding to amino acids 1 - 274 of ALAT_HUMAN_V1, which also corresponds to amino acids 1 - 274 of
  • R35137_PEA_1_PEA_1_PEA_1_P9 and a second amino acid sequerce being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence RGAGEREAGQQSAPVTPCALPGVPGQRVRRGFAVPLIQEGAHGDGAALRRAAGACLLP LHLQGLHGRVRAYEAGGGSRAMARPSSPDGPPPPPHLTWPCAGAGSAAAMWRW corresponding to amino acids 275 - 385 of R35137_PEA_1_PEA_1_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 R35137_PEA_1JPEA_1J?EA_1_P9 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence
  • MEMGPPYAGQQELASFHSTSKGYMGEC corresponding to amino acids 1 - 320 of ALAT_HUMAN_V1, which also corresponds to amino acids 1 - 320 of
  • R35137_PEA_1_PEA_1_PEA_1_P8 and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence VRTRRVGARGPWPGPPRPMGHPLLRT corresponding to amino acids 321 - 346 of R35137_PEA_1_PEA_1_PEA_1_P8, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated chimeric polypeptide encoding for R35137_PEA_1_PEA__1_PEA_1_P11 comprising a first amino acid sequence being at least 90 % homologous to MASSTGDRSQAVRHGLRAKVLTLDGMNPRVRRVEYAVRGPIVQRALELEQELRQGVK KPFTEVIRANIGDAQAMGQRPITFLRQVLALCVNPDLLSSPNFPDDAKKRAERILQACG GHSLGAYSVSSGIQLIREDVARYIERRDGGIPADPNNVFLSTGASDAIVTVLKLLVAGEG HTRTGVLIPIPQYPLYSATLAELGAVQVDYYLDEERAWALDVAELHRALGQAR corresponding to amino acids 1 - 229 of ALAT_HUMAN_V1, which also corresponds to amino acids 1 - 229 of R35137_PEA_1_PEA_1_P11, and a second amino acid sequence being at
  • R35137_PEA_1_PEA_1_PEA_1_P11 comprising a polypeptide having a length "n", wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise RS, having a structure as follows: a sequence starting from any of amino acid numbers 229-x to 229; and ending at any of amino acid numbers 230+ ((n-2) - x), in which x varies from 0 to n-2.
  • R35137_PEA_1_PEA_1_PEA_1_P2 wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of R35137_PEA_1_PEA_1JPEA_1_P2 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence RGAGEREAGQQSAPVTPCALPGVPGQRVRRGFAVPLIQEGAHGDGAALRRAAGACLLP LHLQGLHGRVRVPRRLCGGGEHGRCSAAADAEADECAAVPAGARTGPAGPGGQPAR AHRPLLCAVPG in R35137_PEA_1_PEA_1J ⁇ A_1_P2.
  • R35137_PEA_1_PEA_1_PEA_1_P4 and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence SPGRLWSPLYLLLMPGGVGWGGCWAP ASLQVPNKAVWQSDSKKEALAAAWPAPTCL PFLQA corresponding to amino acids 495 - 555 of R35137_PEA_1_PEA_1_PEA_1_P4, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • Rl 1723JPEA_1_P6 wherein said first and second amino acid sequences are contiguous and in a sequential order.
  • an isolated chimeric polypeptide encoding for Rl 1723_PEA_1_P7 comprising
  • 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 Rl 1723_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 corresponding to amino acids 1 - 64 of Q8N2G4, which also corresponds to amino acids 1 - 64 of Rl 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 corresponding to amino acids 65 - 93 of
  • 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 70%, optionally at 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 R11723_PEA_1_P7, second amino acid sequence being at least 90 % homologous to
  • R11723_PEA_1_P7 64 of R11723_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
  • SHCVTRLECSGTISAHCNLCLPGSNDHPT corresponding to amino acids 65 - 93 of R11723_PEA_1_P7, wherein said first, second and third amino acid sequences are contiguous and in a sequential order.
  • 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
  • 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_l_P10 comprising a first amino acid sequence being at least 90 % homologous to MWVLGIAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEV MEQSA corresponding to amino acids 1 - 63 of Q96AC2, which also corresponds to amino acids 1 - 63 of Rl 1723_PEA_l_P10, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence
  • DRVSLCHEAGVQWNNFSTLQPLPPRLK corresponding to amino acids 64 - 90 of R11723_PEA_l_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_PEA_1_P 10 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DRVSLCHEAGVQWNNFSTLQPLPPRLK in Rl 1723 JPEAJ JPlO.
  • an isolated chimeric polypeptide encoding for Rl 1723_PEA_l_P10 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of Rl 1723JPEA_l_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 Rl 1723_PEA_l_P10.
  • an isolated chimeric polypeptide encoding for Rl 1723JPEA_l_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 1723_PEA_l_P10, second amino acid sequence being at least 90 % homologous to
  • IAATFCGLFLLPGFALQIQCYQCEEFQLNNDCSSPEFIVNCTVNVQDMCQKEVMEQSA corresponding to amino acids 22 - 79 of BAC85273, which also corresponds to amino acids 6 - 63 of Rl 1723_PEA_l_P10, and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence
  • an isolated polypeptide encoding for a head of Rl 1723_PEA_l_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 R11723_PEA_l_P10.
  • an isolated polypeptide encoding for a tail of Rl 1723_PEA_l_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_l_P10.
  • an isolated chimeric polypeptide encoding for R11723_PEA_l_P10 comprising a first amino acid sequence being at least 90 % homologous to
  • MQSVQSTSFCLRKQCLCLTFLLLHLLGQVAATQRCPPQCPG corresponding to amino acids 1 - 41 of NOV HUMAN, which also corresponds to amino acids 1 - 41 of R16276_PEA_1_P7, a bridging amino acid Q corresponding to amino acid 42 of
  • R16276 PEA 1 P7 a second amino acid sequence being at least 90 % homologous to CPATPPTCAPGVRAVLDGCSCCLVCARQRGESCSDLEPCDESSGLYCDRSADPSNQTGI CT corresponding to amino acids 43 - 103 of NOV HUMAN, which also corresponds to amino acids 43 - 103 of R16276_PEA_1_P7, and a third amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence GNPAPSAV corresponding to amino acids 104 - 111 of R16276JPEA_1_P7, wherein said first amino acid sequence, bridging amino acid, second amino acid sequence and third amino acid sequence are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of R16276_PEA_1_P7 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence GNPAPSAV in R16276_PEA_1_P7.
  • an isolated chimeric polypeptide encoding for R16276_PEA_1_P7 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of R16276_PEA_1_P7 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence GNPAPSAV in R16276_PEA_1_P7.
  • an isolated chimeric polypeptide encoding for HUMCEA_PEA_1_P4 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of HUMCEA_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 CEYICSSLAQAASPNPQGQRQDFSVPLRFKYTDPQPWTSRLSVTFCPRKTWADQVLTKN RRGGAASVLGGSGSTPYDGRNR in HUMCEA_PEA_1_P4.
  • an isolated chimeric polypeptide encoding for HUMCEA_PEA_1_P5 comprising a first amino acid sequence being at least 90 % homologous to
  • SNLATGRNNSIVKSITVS corresponding to amino acids 1 - 675 of CEA5 JHUMAN, which also corresponds to amino acids 1 - 675 of HUMCEA_PEA_1_P5, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence GKWLPGASASYSGVESIWFSPKSQEDIFFPSLCSMGTRKSQILS corresponding to amino acids 676 - 719 of HUMCEA_PEA_1_P5, wherein said first amino acid sequence and second amino acid sequence are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of HUMCEA_PEA_1_P5 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence GKWLPGASASYSGVESIWFSPKSQEDIFFPSLCSMGTRKSQILS in HUMCEA_PEA_1JP5.
  • an isolated chimeric polypeptide encoding for HUMCEA_PEA_1_P19 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for an edge portion of HUMCEA PEA 1 P19 comprising a polypeptide having a length "n", wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise NV, having a structure as follows: a sequence starting from any of amino acid numbers 232-x to 232; and ending at any of amino acid numbers 233+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for HUMCEA_PEA_l_P20 comprising a first amino acid sequence being at least 90 % homologous to MESPSAPPHRWCIPWQRLLLTASLLTFWNPPTTAKLTIESTPFNVAEGKEVLLLVHNLPQ HLFGYSWYKGERVDGNRQIIGYVIGTQQATPGPAYSGREIIYPNASLLIQNIIQNDTGFYT LHVIKSDL 1 VTS[EEATGQFRVYP corresponding to amino acids 1 - 142 of CEA5JHUMAN, which also corresponds to amino acids 1 - 142 of HUMCEA_PEA_l_P20, and a second amino acid sequence being at least 90 % homologous to ELPKPSISSNNSKP VEDKDAVAFTCEPEAQNTTYLWWVNGQSLPVSPRLQLSNGNRTLT LFNVTRNDARA YVCGIQNSVSAN
  • an isolated chimeric polypeptide encoding for an edge portion of HUMCEA_PEA_l_P20 comprising a polypeptide having a length "n", wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise PE, having a structure as follows: a sequence starting from any of amino acid numbers 142-x to 142; and ending at any of amino acid numbers 143+ ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for Z44808_PEA_l_P5 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of Z44808_PEA_l_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_l_P5.
  • an isolated chimeric polypeptide encoding for Z44808_PEA_l_P6 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of Z44808JPEA_l_P6 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence RSKRNL in Z44808 PEA 1 P6.
  • an isolated chimeric polypeptide encoding for Z44808_PEA_l_P7 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of Z44808_PEA_l_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_l_P7.
  • an isolated chimeric polypeptide encoding for Z448O8_PEA_1_P11 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for an edge portion of Z448O8_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 chimeric polypeptide encoding for H61775_P16 comprising a first amino acid sequence being at least 90 % homologous to MVWCLGLAVLSLVISQGADGRGKPEWSVVGRAGESWLGCDLLPPAGRPPLHVIEWL RFGFLLPIFIQFGLYSPRIDPDYVG corresponding to amino acids 11 - 93 of Q9P2J2, which also corresponds to amino acids 1 - 83 of H61775_P16, and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence DCGFPAFRELKRAETVSPVFFTRRCIWEDLKSTGFSPAGGGRPPGGGPRTQEDSGLPCW RSSCSVTLQV corresponding to amino acids 84 - 152 of H61775_P16, wherein said first and second amino acid sequences are contig
  • 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 DCGFP AFRELKRAETVSPVFFTRRCIWEDLKSTGFSPAGGGRPPGGGPRTQEDSGLPCW
  • an isolated chimeric polypeptide encoding for H61775 P16 comprising a first amino acid sequence being at least 90 % homologous to
  • RFGFLLPIFIQFGLYSPRIDPDYVG corresponding to amino acids 1 - 83 of AAQ88495, which also corresponds to amino acids 1 - 83 of H61775JP16, 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
  • RSSCSVTLQV corresponding to amino acids 84 - 152 of H61775_P16, wherein said first and second amino acid sequences are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of H61775_P16 comprising a polypeptide being at least
  • 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 H61775JP17 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of M85491JPEA_1_P13 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VPIGWVLSPSPTSLRAPLPG in M85491JPEA_1JP13.
  • an isolated chimeric polypeptide encoding for M85491_PEA_1_P14 comprising a first amino acid sequence being at least 90 % homologous to
  • M85491_PEA_1_P14 and a second amino acid sequence being at least 70%, optionally at least
  • an isolated polypeptide encoding for a tail of M85491_PEA_1_P14 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence
  • 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 JP9 comprising a first amino acid sequence being at least 90 % homologous to
  • PAPGHL corresponding to amino acids 357 - 478 of VTNC_HUMAN, which also corresponds to amino acids 326 - 447 of T39971_P9, wherein said first and second amino acid sequences are contiguous and in a sequential order.
  • 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_P11 comprising a first amino acid sequence being at least 90 % homologous to
  • VTNCJHUMAN which also corresponds to amino acids 327 - 363 of T39971 JPl 1, 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 T39971JP11 comprising a first amino acid sequence being at least 90 % homologous to MAPLRPLLILALLAWVALADQESCKGRCTEGFNVDKKCQCDELCSYYQSCCTDYTAEC KPQVTRGDVFTMPEDEYTVYDDGEEKNNATVHEQVGGPSLTSDLQAQSKGNPEQTPV LKPEEEAPAPEVGASKPEGIDSRPETLHPGRPQPPAEEELCSGKPFDAFTDLKNGSLFAFR GQYCYELDEKA VRPGYPKLIRDVWGIEGPIDAAFTRINCQGKTYLFKGSQYWRFEDGV LDPDYPRNISDGFDGIPDNVDAALALPAHSYSGRERVYFFKGKQYWEYQFQHQPSQEE CEGSSLSAVFEHFAMMQRDSWEDIFELLFWGRTS corresponding to amino acids 1 - 326 of Q9BSH7, which
  • an isolated chimeric polypeptide encoding for an edge portion of T39971JP11 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 MAPLRPLLILALLAWVALADQESCKGRCTEGFNVDKKCQCDELCSYYQSCCTDYTAEC KPQVTRGDVFTMPEDEYTVYDDGEEKNNATVHEQVGGPSLTSDLQAQSKGNPEQTPV LKPEEEAPAPEVGASKPEGIDSRPETLHPGRPQPPAEEELCSGKPFDAFTDLKNGSLFAFR
  • 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 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 Z21368_PEA_1_P2 comprising a first amino acid sequence being at least 90 % homologous to MKYSCCALVLA VLGTELLGSLCSTVRSPRFRGRIQQERKNIRPNIILVLTDDQD VELGSL QVMNKTPJ ⁇ MEHGGATFINAPVTTPMCCPSRSSMLTGKYVHNHNVYTNNENCSSPSW QAMHEPRTFA VYLNNTGYRTAFFGKYLNEYNGSYIPPGWREWLGLIKNSRFYNYTVCR NGIKEKHGFDYAKDYFTDLITNESINYFKMSKRMYPHRPVMMVISHAAPHGPEDSAPQ FSKLYPNASQHITPSYNYAPNMDKHWIMQYTGPMLPIHMEFTNILQRKRLQTLMSVDD SVERLYNMLVETGELENTYIIYTADHGYHIGQFGLVKGKSMP
  • an isolated polypeptide encoding for a tail of Z21368_PEA_1_P2 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence PHKYSAHGRTRHFESATRTTNGAQKLSRI in Z21368_PEA_1_P2.
  • an isolated chimeric polypeptide encoding for Z21368_PEA_1_P5 comprising a first amino acid sequence being at least 90 % homologous to
  • MKYSCCALVLA VLGTELLGSLCSTVRSPRFRGRIQQERKNIRPNIILVLTDDQDVEL corresponding to amino acids 1 - 57 of Q7Z2W2, which also corresponds to amino acids 1 - 57 of Z21368_PEA_1JP5, second bridging amino acid sequence comprising A, and a third amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for an edge portion of Z21368_PEA_1_P5 comprising a polypeptide having a length "n", wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise LAF having a structure as follows (numbering according to Z21368_PEA_1_P5): a sequence starting from any of amino acid numbers 57-x to 57; and ending at any of amino acid numbers 59 + ((n-2) - x), in which x varies from 0 to n-2.
  • an isolated chimeric polypeptide encoding for Z21368_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
  • an isolated polypeptide encoding for a head of Z21368_PEA_1_P5 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence MKYSCCAL VLA VLGTELLGSLCSTVRSPRFRGRIQQERKNIRPNIILVLTDDQDVELAFF GKYLNEYNGSYIPPGWREWLGLIKNSRFYNYTVCRNGIKEKHGFDYAKDYFTDLITNES INYFKMSKRMYPHRP VMMVISHAAPHGPEDSAPQFSKLYPNASQHITPSYNYAPNMDK HWIMQYTGPMLPIHMEFTNILQRKRLQTLMSVDDSVERLYNMLVETGELENTYIIYTAD HGYHIGQFGLVKGKSMPYDFDIRVPFFIRGPSVEPGSIVPQ
  • an isolated chimeric polypeptide encoding for Z21368_PEA_1_P5 comprising a first amino acid sequence being at least 90 % homologous to
  • MKYSCCALVLAVLGTELLGSLCSTVRSPRFRGRIQQERKNIRPNIILVLTDDQDVEL corresponding to amino acids 1 - 57 of SUL1_HUMAN, which also corresponds to amino acids 1 - 57 of Z21368_PEA_1_P5, and a second amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for Z21368_PEA_1_P15 comprising a first amino acid sequence being at least 90 % homologous to
  • VERG corresponding to amino acids 1 - 416 of SUL1_HUMAN, which also corresponds to amino acids 1 - 416 of Z21368_PEA_1_P15.
  • an isolated chimeric polypeptide encoding for Z21368_PEA_1_P16 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of Z21368JPEA_1_P16 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence CVIVPPLSQPQIH in Z21368_PEA_1_P16.
  • an isolated chimeric polypeptide encoding for Z21368_PEA_1_P22 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of Z21368JPEA_1_P22 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence ARYDGDQPRCAPRPRGLSPTVF in Z21368_PEA_1_P22.
  • an isolated chimeric polypeptide encoding for Z21368JPEA_1_P23 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of Z21368_PEA_1_P23 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence GLLHRLNH in Z21368_PEA_1_P23.
  • an isolated chimeric polypeptide encoding for Z21368_PEA_1_P23 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of Z21368JPEA_1_P23 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence GLLHRLNH in Z21368JPEA_1_P23.
  • an isolated chimeric polypeptide encoding for HUMGRP5E_P4 comprising a first amino acid sequence being at least 90 % homologous to
  • SSNFKDVGSKGK corresponding to amino acids 1 - 127 of GRPJHUMAN, which also corresponds to amino acids 1 - 127 of HUMGRP5E P4, and a second amino acid sequence being at least 90 % homologous to GSQREGRNPQLNQQ corresponding to amino acids 135 - 148 of GRPJHUMAN, which also corresponds to amino acids 128 - 141 of HUMGRP5EJP4, wherein said first and second amino acid sequences are contiguous and in a sequential order.
  • an isolated chimeric polypeptide encoding for HUMGRP5EJP5 comprising a first amino acid sequence being at least 90 % homologous to MRGSELPLVLLALVLCLAPRGRAVPLPAGGGTVLTKMYPRGNHWAVGHLMGKKSTG ESSSVSERGSLKQQLREYIRWEEAARNLLGLIEAKENRNHQPPQPKALGNQQPSWDSED SSNFKDVGSKGK corresponding to amino acids 1 - 127 of GRPJHUMAN, which also corresponds 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% homologous to a polypeptide having the sequence DSLLQVLNVKEGTPS corresponding to amino acids 128 - 142 of HUMGRP5E_P5, wherein said first and second amino acid sequence
  • an isolated polypeptide encoding for a tail of HUMGRP5EJP5 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence DSLLQVLNVKEGTPS in HUMGRP5E_P5.
  • an isolated chimeric polypeptide encoding for D56406_PEA_l_P2 comprising a first amino acid sequence being at least 90 % homologous to MMAGMKIQLVCMLLLAFSSWSLCSDSEEEMKALEADFLTNMHTSKJSKAHVPSWKMT LLNVCSLVNNLNSPAEETGEVHEEELVARRKLPTALDGFSLEAMLTIYQLHKICHSRAF QHWE corresponding to amino acids 1 - 120 of NEUT JHUMAN, which also corresponds to amino acids 1 - 120 of D56406_PEA_l_P2, second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence
  • ARWLTPVIPALWEAETGGSRGQEMETIPANT corresponding to amino acids 121 - 151 of D564O6_PEA_1JP2, and a third amino acid sequence being at least 90 % homologous to LIQEDILDTGNDKNGKEEVIKRKIPYILKRQLYENKPRRPYILKRDSYYY corresponding to amino acids 121 - 170 of NEUT_HUMAN, which also corresponds to amino acids 152 - 201 of D56406_PEA_l_P2, wherein said first, second and third amino acid sequences are contiguous and in a sequential order.
  • an isolated polypeptide encoding for an edge portion of D56406_PEA_l_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 ARWLTPVIP ALWEAETGGSRGQEMETIP ANT, corresponding to D56406_PEA_l_P2.
  • an isolated chimeric polypeptide encoding for D56406_PEA_l_P5 comprising a first amino acid sequence being at least 90 % homologous to MMAGMKIQLVCMLLLAFSSWSLC corresponding to amino acids 1 - 23 of NEUT_HUMAN, which also corresponds to amino acids 1 - 23 of D56406_PEA_l_P5, and a second amino acid sequence being at least 90 % homologous to SEEEMKALEADFLTNMHTSKISKAHVPSWKMTLLNVCSLVNNLNSPAEETGEVHEEEL VARRKLPTALDGFSLEAMLTIYQLHKICHSRAFQHWELIQEDILDTGNDKNGKEEVIKR KIPYILKRQLYENKPRRPYILKRDSYYYY corresponding to amino acids 26 - 170 of NEUTJHUMAN, which also corresponds to amino acids 24 - 168 of D56406_PEA_l_P5,
  • an isolated chimeric polypeptide encoding for F05068_PEA_l_P7 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for F05068_PEA_l_P8 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for H14624_P15 comprising a first amino acid sequence being at least 90 % homologous to
  • H14624_P15 and a second amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence GKPSLLLPHSLLG corresponding to amino acids 168 - 180 of H14624_P15, wherein said first and second amino acid sequences are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of H14624_P15 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence GKPSLLLPHSLLG in H14624_P15.
  • an isolated chimeric polypeptide encoding for H38804_PEA_l_P5 comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MGRVRTLAGECSAQAQAQSLLAVVLSAPPSGGTPSARLSVRSPSPRDPWGLWAPVLQ corresponding to amino acids 1 - 57 of H38804_PEA_l_P5, and a second amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a head of H38804_PEA_l_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 MGRVRTLAGECSAQAQAQSLLAWLSAPPSGGTPSARLSVRSPSPRDPWGLWAPVLQ of H38804 PEA 1 P5.
  • an isolated chimeric polypeptide encoding for H38804_PEA_l_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 MGRVRTLAGECSAQAQAQSLLAVVLSAPPSGGTPSARLSVRSPSPRDPWGLWAPVLQ corresponding to amino acids 1 - 57 of H38804_PEA_l_P17, and a second amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a head of H38804_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 chimeric polypeptide encoding for HSENA78_P2 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated chimeric polypeptide encoding for HUMODCA_P9 comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MKSLTATSSMKVLLPRTFWTR ⁇ GLMKFLLL corresponding to amino acids 1 - 29 of HUMODCA_P9, and a second amino acid sequence being at least 90 % homologous to LVLRIATDDSKAVCRLSVKFGATLRTSRLLLERAKELNIDVVGVSFHVGSGCTDPETFV QAISDARCVFDMGAEVGFSMYLLDIGGGFPGSEDVKLKFEEITGVINPALDKYFPSDSG
  • an isolated polypeptide encoding for a head of HUMODCA_P9 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence MKSLTATSSMKVLLPRTFWTRKLMKFLLL of HUMODCAJP9.
  • an isolated chimeric polypeptide encoding for HUMODCA_P9 comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MKSLTATSSMKVLLPRTFWTRKLMKFLLL corresponding to amino acids 1 - 29 of HUMODCA_P9, and a second amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a head of HUMODCA_P9 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence MKSLTATSSMKVLLPRTFWTRKLMKFLLL of HUMODCA_P9.
  • an isolated chimeric polypeptide encoding for HUMODCA_P9 comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MKSLTATSSMKVLLPRTFWTRKLMKFLLL corresponding to amino acids 1 - 29 of HUMODCA_P9, and a second amino acid sequence being at least 90 % homologous to LVLRIATDDSKAVCRLSVKFGATLRTSRLLLERAKELNIDWGVSFHVGSGCTDPETFV QAISDARCVFDMGAEVGFSMYLLDIGGGFPGSED VKLKFEEITGVINP ALDKYFPSDSG VRIIAEPGRYYVASAFTLAVNIIAKKIVLKEQTGSDDEDESSEQTFMYYVNDGVYGSFN CILYDHAHVKPLLQKRPKPDEKY
  • an isolated polypeptide encoding for a head of HUMODCA_P9 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence MKSLTATSSMKVLLPRTFWTRKLMKFLLL of HUMODCA_P9.
  • an isolated chimeric polypeptide encoding for R00299JP3, comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MAEKALLCPSSAGLGTWPWVLNSAWPVLPLAVDQGVDWRPRGPV corresponding to amino acids 1 - 44 of R00299_P3, second amino acid sequence being at least 90 % homologous to SSDQIEQLHRRFKQLSGDQPTIRKENFNNVPDLELNPIRSKIVRAFFDNRNLRKGPSGLA DEINFEDFLTIMSYFRPIDTTMDEEQVELSRKEKLRFLFHMYDSDSDGRITLEEYRNV corresponding to amino acids 74 - 191 of Q9NWT9, which also corresponds to amino acids 45 - 162 of R00299 P3, and a third amino acid sequence being
  • an isolated polypeptide encoding for a head of R00299_P3, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence MAEKALLCPSSAGLGTWPWVLNSAWPVLPLAVDQGVDWRPRGPV of R00299_P3.
  • an isolated polypeptide encoding for a tail of R00299 P3, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence VEELLSGNPHIEKESARSIADGAMMEAASVCMGQMEPDQVYEGITFEDFLKIWQGIDIE TKMHVRFLNMETMALCH in R00299_P3.
  • an isolated chimeric polypeptide encoding for R00299_P3, comprising a first amino acid sequence being at least 70%, optionally at least 80%, preferably at least 85%, more preferably at least 90% and most preferably at least 95% homologous to a polypeptide having the sequence MAEKALLCPSSAGLGTWPWVLNSAWPVLPLAVDQGVDWRPRGPV corresponding to amino acids 1 - 44 of R00299_P3, and a second amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a head of R00299 P3, comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence MAEKALLCPSSAGLGTWPWVLNSAWPVLPLAVDQGVDWRPRGPV of R00299JP3.
  • an isolated chimeric polypeptide encoding for W60282_PEA_l_P14 comprising a first amino acid sequence being at least 90 % homologous to
  • TPASHLAMRQHHHH corresponding to amino acids 67 - 80 of W60282_PEA_l_P14, wherein said first and second amino acid sequences are contiguous and in a sequential order.
  • an isolated polypeptide encoding for a tail of W60282JPEA_l_P14 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence TPASHLAMRQHHHH in W60282_PEA_l_P14.
  • an isolated chimeric polypeptide encoding for Z41644_PEA_l_P10 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of Z41644JPEA_l_P10 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence YAPPLLTFLPTRPSCGSQDGKGPPHQVI in Z41644_PEA_l_P10.
  • an isolated chimeric polypeptide encoding for Z41644_PEA_l_P10 comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of Z41644_PEA_l_P10 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence YAPPLLTFLPTRPSCGSQDGKGPPHQVI in Z41644_PEA_l_P10.
  • an isolated chimeric polypeptide encoding for Z41644_PEA_1JP1O comprising a first amino acid sequence being at least 90 % homologous to
  • an isolated polypeptide encoding for a tail of Z41644_PEA_l_P10 comprising a polypeptide being at least 70%, optionally at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95% homologous to the sequence YAPPLLTFLPTRPSCGSQDGKGPPHQVI in Z41644JPEA_l_P10.
  • an antibody capable of specifically binding to an epitope of an amino acid sequences.
  • amino acid sequence corresponds to a bridge, edge portion, tail, head or insertion.
  • the antibody is capable of differentiating between a splice variant having said epitope and a corresponding known protein.
  • a kit for detecting lung cancer comprising a kit detecting overexpression of a splice variant according to any of the above claims.
  • 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 according to any of the above claims.
  • the kit further comprises at least one oligonucleotide capable of selectively hybridizing to a nucleic acid sequence according to any of the above claims.
  • kit comprises an antibody according to any of the above claims.
  • the kit further comprises at least one reagent for performing an ELISA or a Western blot.
  • a method for detecting lung cancer comprising detecting overexpression of a splice variant according to any of the above claims.
  • the detecting overexpression is performed with a NAT-based technology.
  • detecting overexpression is performed with an immunoassay.
  • the immunoassay comprises an antibody according to any of the above claims.
  • a biomarker capable of detecting lung cancer comprising any of the above nucleic acid sequences or a fragment thereof, or any of the above amino acid sequences or a fragment thereof.
  • a method for screening for lung cancer comprising detecting lung cancer cells with a biomarker or an antibody or a method or assay according to any of the above claims.
  • a method for diagnosing lung cancer comprising detecting lung cancer cells with a biomarker or an antibody or a method or assay according to any of the above claims.
  • a method for monitoring disease progression and/or treatment efficacy and/or relapse of lung cancer comprising detecting lung cancer cells with a biomarker or an antibody or a method or assay according to any of the above claims.
  • a method of selecting a therapy for lung cancer comprising detecting lung cancer cells with a biomarker or an antibody or a method or assay according to any of the above claims and selecting a therapy according to said detection.
  • Figure 1 is schematic summary of cancer biomarkers selection engine and the wet validation stages.
  • Figure 2 Schematic illustration, depicting grouping of transcripts of a given contig based on presence or absence of unique sequence regions.
  • Figure 3 is schematic summary of quantitative real-time PCR analysis.
  • Figure 4 is schematic presentation of the oligonucleotide based microarray fabrication.
  • Figure 5 is schematic summary of the oligonucleotide based microarray experimental flow.
  • Figure 6 is a histogram showing Cancer and cell- line vs. normal tissue expression for
  • Cluster H61775 demonstrating overexpression in brain malignant tumors and a mixture of malignant tumors from different tissues.
  • Figure 7 is a histogram showing expression of transcripts of variants of the immunoglobulin superfamily, member 9,H61775 transcripts, which are detectable by amplicon as depicted in sequence name H61775seg8, in normal and cancerous lung tissues.
  • Figure 8 is a histogram showing expression of immunoglobulin superfamily, member 9, H61775 transcripts, which are detectable by amplicon as depicted in sequence name H61775seg8, in different normal tissues.
  • Figure 9 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster M85491, demonstrating overexpression in epithelial malignant tumors and a mixture of malignant tumors from different tissues.
  • Figure 10 is a histogram showing over expression of the above -indicated Ephrin type-B receptor 2 precursor M85491 transcripts, which are detectable by amplicon as depicted in sequence name M85491seg24, in cancerous lung samples relative to the normal samples.
  • Figure 11 is a histogram showing the expression of Ephrin type-B receptor 2 precursor
  • Figure 12 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster T39971, demonstrating overexpression in liver cancer, lung malignant tumors and pancreas carcinoma.
  • Figure 13 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster Z21368, demonstrating overexpression in epithelial malignant tumors, a mixture of malignant tumors from different tissues and pancreas carcinoma.
  • Figure 14 is a histogram showing over expression of the Extracellular sulfatase SuIf-I Z21368 transcripts, which are detectable by amplicon as depicted in sequence name Z21368juncl7-21, in cancerous lung samples relative to the normal samples.
  • Figure 15 is a histogram showing the expression of Extracellular sulfatase SuIf-I
  • Z21368 transcripts which are detectable by amplicon as depicted in sequence name Z21368 juncl7-21, in different normal tissues.
  • Figure 16 is a histogram showing over expression of the SUL1_HUMAN -
  • Extracellular sulfatase SuIf-I, Z21368 transcripts which are detectable by amplicon as depicted in sequence name Z21368seg39, in cancerous lung samples relative to the normal samples.
  • Figure 17 is a histogram showing expression of SULl-HUMAN - Extracellular sulfatase SuIf- 1 , Z21368 transcripts, which are detectable by amplicon as depicted in sequence name Z21368seg39, in different normal tissues.
  • Figure 18 is a histogram showing the expression of SMO2_HUMAN SPARC related modular calcium-binding protein 2 precursor (Secreted modular calcium-binding protein 2) (SMOC-2) (Smooth muscle-associated protein 2) Z44808 transcripts which are detectable by amplicon as depicted in sequence name Z44808 junc8-l 1 in different normal tissues.
  • SMO2_HUMAN SPARC related modular calcium-binding protein 2 precursor Secreted modular calcium-binding protein 2) (SMOC-2) (Smooth muscle-associated protein 2) Z44808 transcripts which are detectable by amplicon as depicted in sequence name Z44808 junc8-l 1 in different normal tissues.
  • Figure 19 is a histogram showing over expression of the gastrin- releasing peptide (HUMGRP5E) transcripts, which are detectable by amplicon as depicted in sequence name HUMGRP5Ejunc3-7, in several cancerous lung samples relative to the normal samples.
  • HUMGRP5E gastrin- releasing peptide
  • Figure 20 is a histogram showing the expression of gastrin-releasing peptide (HUMGRP5E) transcripts, which are detectable by amplicon as depicted in sequence name HUMGRP5Ejunc3-7, in different normal tissues.
  • HUMGRP5E gastrin-releasing peptide
  • Figure 21 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster F05068, demonstrating overexpression in uterine malignancies.
  • Figure 22 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster H 14624, demonstrating overexpression in colorectal cancer, epithelial malignant tumors, a mixture of malignant tumors from different tissues, lung malignant tumors and pancreas carcinoma.
  • Figure 23 is a histogram showing Cancer and cell- line vs. normal tissue expression for
  • Cluster H38804 demonstrating overexpression in transitional cell carcinoma, brain malignant tumors, a mixture of malignant tumors from different tissues and gastric carcinoma.
  • Figure 24 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster HSENA78, demonstrating overexpression in epithelial malignant tumors and lung malignant tumors.
  • Figure 25 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster HUMODCA, demonstrating overexpression in : brain malignant tumors, colorectal cancer, epithelial malignant tumors and a mixture of malignant tumors from different tissues.
  • Figure 26 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster R00299, demonstrating overexpression in lung malignant tumors.
  • Figure 27 is a histogram showing Cancer and cell- line vs. normal tissus expression for Cluster Z41644, demonstrating overexpression in lung malignant tumors, breast malignant tumors and pancreas carcinoma.
  • Figure 28 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster Z44808, demonstrating overexpression in colorectal cancer, lung cancer and pancreas carcinoma.
  • Figure 29 is a histogram showing over expression of the SMO2_HUMAN SPARC related modular calcium-binding protein 2 Z44808 transcripts, which are detectable by amplicon as depicted in sequence name Z44808junc8-ll, in cancerous lung samples relative to the normal samples.
  • Figure 30 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster AAl 61187, demonstrating overexpression in brain malignant tumors, epithelial malignant tumors and a mixture of malignant tumors from different tissues.
  • Figure 31 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster AAl 61187, demonstrating overexpression in brain malignant tumors and a mixture of malignant tumors from different tissues.
  • Figure 32 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster HUMCAlXIA, demonstrating overexpression in bone malignant tumors, epithelial malignant tumors, a mixture of malignant tumors from different tissues and lung malignant tumors.
  • Figure 33 is a histogram showing Cancer and cell- line vs. normal tissue expression for
  • Cluster HUMCEA demonstrating overexpression in epithelial malignant tumors, a mixture of malignant tumors from different tissues and pancreas carcinoma.
  • Figure 34 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster R35137, demonstrating overexpression in hepatocellular carcinoma.
  • Figure 35 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster R35137.
  • Cluster Z25299 demonstrating overexpression in brain malignant tumors, a mixture of malignant tumors from different tissues and ovarian carcinoma.
  • Figure 36 is a histogram showing down regulation of the Secretory leukocyte protease inhibitor Acid-stable proteinase inhibitor Z25299 transcripts, which are detectable by amplicon as depicted in sequence name Z25299 June 13- 14-21, in cancerous lung samples relative to the normal samples.
  • Figure 37 is a histogram showing down regulation of the Secretory leukocyte protease inhibitor Acid-stable proteinase inhibitor Z25299 transcripts, which are detectable by amplicon as depicted in sequence name Z25299 seg20, in cancerous lung samples relative to the normal samples.
  • Figure 38 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster HSSTROL3, demonstrating overexpression in transitional cell carcinoma, epithelial malignant tumors, a mixture of malignant tumors from different tissues and pancreas carcinoma.
  • Figure 39 is a histogram showing over expression of the Stromelysin-3 HSSTROL3 transcripts, which are detectable by amplicon as depicted in sequence name HSSTROL3 seg24, in cancerous lung samples relative to the normal samples.
  • Figure 40 is a histogram showing the expression of Stromelysin-3
  • HSSTROL3 transcripts which are detectable by amplicon as depicted in sequence name HSSTROL3 seg24, in different normal tissues.
  • Figure 41 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster HUMTREFAC, demonstrating overexpression in a mixture of malignant tumors from different tissues, breast malignant tumors, pancreas carcinoma and prostate cancer.
  • Figure 42 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster HSSlOOPCB, demonstrating overexpression in a mixture of malignant tumors from different tissues.
  • Figure 43 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster HSU33147, demonstrating overexpression in a mixture of malignant tumors from different tissues.
  • Figure 44 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster HSU33147.
  • Cluster R20779 demonstrating overexpression in epithelial malignant tumors, a mixture of malignant tumors from different tissues and lung malignant tumors.
  • Figure 45 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster R38144, demonstrating overexpression in epithelial malignant tumors, lung malignant tumors, skin malignancies and gastric carcinoma.
  • Figure 46 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster HUMOSTRO, demonstrating overexpression in epithelial malignant tumors, a mixture of malignant tumors from different tissues, lung malignant tumors, breast malignant tumors, ovarian carcinoma and skin malignancies.
  • Figure 47 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster HUMOSTRO.
  • Cluster HUMOSTRO demonstrating overexpression in epithelial malignant tumors, a mixture of malignant tumors from different tissues and kidney malignant tumors.
  • Figure 48 is a histogram showing over expression of the Rl 1723 transcripts, which are detectable by amplicon as depicted in sequence name Rl 1723 segl3, in cancerous lung samples relative to the normal samples.
  • Figure 49 is a histogram showing the expression of Rl 1723 transcripts which are detectable by amplicon as depicted in sequence name Rl 1723segl3 in different normal tissues.
  • Figure 50 is a histogram showing over expression of the Rl 1723 transcripts, which are detectable by amplicon as depicted in sequence name Rl 1723 juncl 1-18 in cancerous lung samples relative to the normal samples.
  • Figure 51 is a histogram showing Cancer and cell- line vs. normal tissue expression for
  • FIGS. 52-53 are histograms, showing differential expression of the 6 sequences H61775seg8, HUMGRP5E junc3-7, M85491Seg24, Z21368 juncl7-21, HSSTROL3seg24 and Z25299seg20 in cancerous lung samples relative to the normal samples.
  • Figure 54a is a histogram showing the relative expression of trophinin associated protein (tastin) ) [T86235] variants (e.g., variant no. 23-26, 31, 32) in normal and tumor derived lung samples as determined by real time PCR using primers for SEQ ID NO: 1480.
  • Figure 54b is a histogram showing the relative expression of trophinin associated protein
  • Figure 55 is a histogram showing the relative expression of Homeo box ClO (HOXClO)
  • variants e.g., variant no. 3 in normal and tumor derived lung samples as determined by real time PCR using primers for SEQ ID NO: 1517.
  • Figures 56a-b are histograms showing on two different scales the relative expression of Nucleolar protein 4 (NOL4) [T06014] variants (e.g., variant no. 3, 11 and 12) in normal and tumor derived lung samples as determined by real time PCR using primers for SEQ ID NO: 1529.
  • Figure 56a shows the results on scale:0-1200.
  • Figure 56b shows the results on scale:0- 24.
  • Figures 57a-b is a histogram showing on two different scales the relative expression of Nucleolar protein 4 (NOL4) [T06014] variants (e.g., variant no. 3, 11 and 12) in normal and tumor derived lung samples as determined by real time PCR using primers for SEQ ID NO:
  • Figure 57a shows the results on scale:0-2000.
  • Figure 57b shows the results on scale:0-
  • Figure 58 is a histogram showing the relative expression of AA281370 variants (e.g., variant no. 0, 1, 4 and 5) in normal and tumor derived lung samples as determined by real time PCR using primers for SEQ ID NO: 1558.
  • Figure 59 is a histogram showing the relative expression of Sulfatase 1 (SULFl)- [Z21368] variants (e.g., variant no. 13 and 14) in normal and tumor derived lung samples as determined by real time PCR using primers for SEQ ID NO: 1574.
  • SULFl Sulfatase 1
  • Figure 60 is a histogram showing the relative expression of SRY (sex determining region Y)-box 2 (SOX2))- [HUMHMGBOX] variants (e.g., variant no. 0) in normal and tumor derived lung samples as determined by real time PCR using primers for SEQ ID NO: 1594.
  • Figure 61 is a histogram showing the relative expression of Plakophilin 1 (ectodermal dysplasia/skin fragility syndrome) (PKPl) -[HSB6PR] variants (e.g., variant no. 0, 5 and 6) in normal and tumor derived lung samples as determined by real time PCR using primers for SEQ ID NO: 1600.
  • PGPl Plakophilin 1 (ectodermal dysplasia/skin fragility syndrome)
  • Figure 62 is a histogram showing the relative expression of transcripts detectable by SEQ ID NOs: 1480, 1517, 1529, 1532, 1558, 1574, 1594, 1600, 1616, 1619, 1622, 1625 in no ⁇ nal and tumor derived lung samples as determined by real time PCR.
  • Figure 63 is an amino acid sequence alignment, using NCBI BLAST default parameters, demonstrating similarity between the AA281370 lung cancer biomarker if the present invention to WD40 domains of various proteins involved in MAPK signal transduction pathway.
  • Figure 63a amino acids at positions 40-790 of AA281370 polypeptide SEQ ID NO: 99 has 75% homology to mouse Mapkbpl protein (gi
  • Figure 63b amino acids at positions 40- 886 of the AA281370 polypeptide SEQ ID NO: 99 has 70% homology to rat JNK-binding protein JNKBPl (gi
  • Figure 64 is a histogram showing over expression of the Homo sapiens protease, serine, 21 (testisin) (PRSS21) AA161187 transcripts, which are detectable by amplicon as depicted in sequence name AA161187 seg25, in cancerous lung samples relative to the normal samples.
  • Figure 65 is a histogram showing over expression of the protein tyrosine phosphatase, receptor type, S (PTPRS) M62069 transcripts, which are detectable by amplicon as depicted in sequence name M62069 segl9, in cancerous lung samples relative to the normal samples.
  • PPRS protein tyrosine phosphatase, receptor type, S
  • Figure 66 is a histogram showing over expression of the protein tyrosine phosphatase, receptor type, S (PTPRS) M62069 transcripts, which are detectable by amplicon as depicted in sequence name M62069 seg29, in cancerous lung samples relative to the normal samples.
  • Figure 67 is a histogram showing over expression of the above -indicated Homo sapiens collagen, type XI, alpha 1 (COLI lAl) transcripts which are detectable by amp Ikon as depicted in sequence name HUMCAlXlA seg55 in cancerous lung samples relative to the normal samples.
  • Figure 68 is a histogram showing down regulation of the Homo sapiens secretory leukocyte protease inhibitor (antileukoproteinase) (SLPI) Z25299 transcripts which are detectable by amplicon as depicted in sequence name Z25299 seg23 in cancerous lung samples relative to the normal samples.
  • SLPI Homo sapiens secretory leukocyte protease inhibitor
  • Figure 69 is a histogram showing the expression of Secretory leukocyte protease inhibitor Acid-stable proteinase inhibitor Z25299 transcripts which are detectable by amplicon as depicted in sequence name Z25299seg20 in different normal tissues.
  • Figure 70 is a histogram showing the expression of Secretory leukocyte protease inhibitor Acid-stable proteinase inhibitor Z25299 transcripts which are detectable by amplicon as depicted in sequence name Z25299seg23 in different normal tissues.
  • Figure 71 is a histogram showing over expression of the Homo sapiens matrix metalloproteinase 11 (stromelysin 3) (MMPIl) HSSTROL3 transcripts which are detectable by amplicon as depicted in sequence name HSSTROL3 seg20-2 in cancerous lung samples relative to the normal samples.
  • stromelysin 3 stromelysin 3
  • Figure 72 is a histogram showing over expression of the Homo sapiens matrix metalloproteinase 11 (stromelysin 3) (MMPl 1) HSSTROL3 transcripts which are detectable by amplicon as depicted in sequence name HSSTROL3 junc21-27 in cancerous lung samples relative to the normal samples.
  • MMPl 1 Homo sapiens matrix metalloproteinase 11
  • MMPl 1 HSSTROL3 transcripts which are detectable by amplicon as depicted in sequence name HSSTROL3 junc21-27 in cancerous lung samples relative to the normal samples.
  • Figure 73 is a histogram showing the expression of Rl 1723 transcripts, which were detected by amplicon as depicted in the sequence name Rl 1723 juncl 1-18 in different normal tissues.
  • Figure 74 is a histogram showing over expression of the Homo sapiens fibroblast growth factor receptor- like 1 (FGFRLl) H53626 transcripts, which are detectable by amplicon as depicted in sequence name H53626 junc24-27FlR3 in cancerous lung samples relative to the normal samples.
  • Figure 75 is a histogram showing the expression of the Homo sapiens fibroblast growth factor receptor- like 1 (FGFRLl) H53626 transcripts, which are detectable by amplicon as depicted in sequence name H53626 seg25 in cancerous lung samples relative to the normal samples.
  • FGFRLl Homo sapiens fibroblast growth factor receptor- like 1
  • Figure 76 is a histogram showing Cancer and cell- line vs. normal tissue expression for Cluster H53626, demonstrating overexpression in epithelial malignant tumors, a mixture of malignant tumors from different tissues and myosarcoma.
  • Figure 77 is a histogram showing the expression of of Homo sapiens fibroblast growth factor receptor-like 1 (FGFRLl) H53626 transcripts, which are detectable by amplicon as depicted in sequence name H53626 seg25 in different normal tissues.
  • FGFRLl fibroblast growth factor receptor-like 1
  • Figure 78 is a histogram showing the expression of of Homo sapiens fibroblast growth factor receptor-like 1 (FGFRLl) H53626 transcripts, which are detectable by amplicon as depicted in sequence name H53626 junc24-27FlR3 in different normal tissues.
  • FGFRLl fibroblast growth factor receptor- like 1
  • Figure 79 shows PSEC Rl 1723 PEA 1 T5 PCR product; Lane 1: PCR product; and Lane 2: Low DNA Mass Ladder MW marker (Invitrogen Cat# 10068-013).
  • Figure 80 PSEC Rl 1723_PEA_1 T5 PCR product sequence; In Red- PSEC Forward primer; In Blue- PSEC Reverse complementary sequence; and Highlighted sequence- PSEC variant Rl 1723_PEA_1 T5 ORF.
  • Figure 82 shows a plasmid map of His PSEC T5 pRSETA.
  • Figure 83 Protein sequence of PSEC variant Rl 1723_PEA_1 T5; In red- 6His tag; In blue- PSEC.
  • Figure 84 shows the DNA sequence of HisPSEC T5 pRSETA; bold- HisPSEC T5 open reading frame ; Italic- flanking DNA sequence which was verified by sequence analysis.
  • Figure 85 shows Western blot analysis of recombinant HisPSEC variant R11723_PEA_1 T5; lane l: molecular weight marker (ProSieve color, Cambrex, Cat #50550); lane 2: HisPSEC T5 pRSETA TO; lane 3: His HisPSEC T5 pRSETA T3; lane 4 :His HisPSEC T5 pRSETA To.n; lane 5: pRSET empty vector TO (negative control); lane 6: pRSET empty vector T3 (negative control); lane 7: pRSET empty vector To.n (negative control); and lane 8: His positive control protein (HisTroponinT7 pRSETA T3).
  • the present invention is of novel markers for lung cancer that are both sensitive and accurate. Furthermore, at least certain of these markers are able to distinguish between various types of lung cancer, such as small cell carcinoma; large cell carcinoma; squamous cell carcinoma; and adenocarcinoma, alone or in combination. These markers are differentially expressed, and preferably overexpressed, in lung cancer specifically, as opposed to normal lung tissue. The measurement of these markers, alone or in combination, in patient samples provides information that the diagnostician can correlate with a probable diagnosis of lung cancer. The markers of the present invention, alone or in combination, show a high degree of differential detection between lung cancer and non-cancerous states.
  • the markers of the present invention can be used for prognosis, prediction, screening, early diagnosis, therapy selection and treatment monitoring of lung cancer.
  • these markers may be used for staging lung 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 than lung.
  • one or more of the markers may optionally be used in combination with one or more other lung cancer markers (other than those described herein).
  • a combination may be used to differentiate between various types of lung cancer, such as small cell carcinoma; large cell carcinoma; squamous cell carcinoma; and adenocarcinoma.
  • the markers of the present invention alone or in combination, can be used for detection of other types of tumors by elimination (for example, for such detection of carcinoid tumors, which are 5% of lung cancers).
  • the markers of the present invention can be used for prognosis, prediction, screening, early diagnosis, staging, therapy selection and treatment monitoring of lung cancer. For example, optionally and preferably, these markers may be used for staging lung cancer and/or monitoring the progression of the disease. Furthermore, the markers of the present invention, alone or in combination, can be used for detection of the source of metastasis found in anatomical places other then lung. Also, one or more of the markers may optionally be used in combination with one or more other lung cancer markers (other than those described herein). Biomolecular sequences (amino acid and/or nucleic acid sequences) uncovered using the methodology of the present invention and described herein can be efficiently utilized as tissue or pathological markers and/or as drugs or drug targets for treating or preventing a disease.
  • markers are specifically released to the bloodstream under conditions of lung cancer, and/or are otherwise expressed at a much higher level and/or specifically expressed in lung cancer tissue or cells.
  • the measurement of these markers, alone or in combination, in patient samples provides information that the diagnostician can correlate with a probable diagnosis of lung cancer.
  • the present invention therefore also relates to diagnostic assays for lung cancer and/or an indicative condition, and methods of use of such markers for detection of lung cancer and/or an indicative condition, optionally and preferably in a sample taken from a subject (patient), which is more preferably some type of blood sample.
  • the present invention relates to bridges, tails, heads and/or insertions, and/or analogs, homologs and derivatives of such peptides.
  • bridges, tails, heads and/or insertions are described in greater detail below with regard to the Examples.
  • a "tail” refers to a peptide sequence at the end of an amino acid sequence that is unique to a splice variant according to the present invention. Therefore, a splice variant having such a tail may optionally be considered as a chimera, in that at least a first portion of the splice variant is typically highly homologous (often 100% identical) to a portion of the corresponding known protein, while at least a second portion of the variant comprises the tail.
  • a "head” refers to a peptide sequence at the beginning of an amino acid sequence that is unique to a splice variant according to the present invention. Therefore, a splice variant having such a head may optionally be considered as a chimera, in that at least a first portion of the splice variant comprises the head, while at least a second portion is typically highly homologous (often 100% identical) to a portion of the corresponding known protein.
  • 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_P1 (representing the name of the protein), comprising a polypeptide having a length "n", wherein n is at least about 10 amino acids in length, optionally at least about 20 amino acids in length, preferably at least about 30 amino acids in length, more preferably at least about 40 amino acids in length and most preferably at least about 50 amino acids in length, wherein at least two amino acids comprise XX (2 amino acids in the center of the bridge, one from each end of the edge), having a structure as follows (numbering according to the sequence of CONTIG-NAME_P1): a sequence starting from any of amino acid numbers 49-x to 49 (for example); and ending at any of amino acid numbers 50 + ((n-2) - x) (for example), in which x varies from 0 to n-2.
  • this invention provides antibodies specifically recognizing the splice variants and polypeptide fragments thereof of this invention. Preferably such antibodies differentially recognize splice variants of the present invention but do not recognize a corresponding known protein (such known proteins are discussed with regard to their splice variants in the Examples below).
  • 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 corresponding 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 correlates 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 lung cancer.
  • Each splice variant marker of the present invention can be used alone or in combination, for various uses, including but not limited to, prognosis, prediction, screening, early diagnosis, determination of progression, therapy selection and treatment monitoring of lung cancer.
  • 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 lung cancer, 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 corresponding to a splice variant protein as described herein.
  • Any oligopeptide or peptide relating to such an amino acid sequence or fragment thereof may optionally also (additionally or alternatively) be used as a biomarker, including but not limited to the unique amino acid sequences of these proteins that are depicted as tails, heads, insertions, edges or bridges.
  • the present invention also optionally encompasses antibodies capable of recognizing, and/or being elicited by, such oligopeptides or peptides.
  • the present invention also optionally and preferably encompasses any nucleic acid sequence or fragment thereof, or amino acid sequence or fragment thereof, corresponding to a splice variant of the present invention as described above, optionally for any application.
  • Non-limiting examples of methods or assays are described below.
  • the present invention also relates to kits based upon such diagnostic methods or assays.
  • 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).
  • 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 w 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.
  • Preferred embodiments of the present invention encompass oligonucleotide probes.
  • An example of an oligonucleotide probe which can be utilized by the present invention is a single stranded polynucleotide which includes a sequence complementary to the unique 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.
  • Equipment and reagents for executing solid-phase synthesis are commercially available from, for example, Applied Biosystems. Any other means for such synthesis may also be employed; the actual synthesis of the oligonucleotides is well within the capabilities of one skilled in the art and can be accomplished via established methodologies as detailed in, for example, "Molecular Cloning: A laboratory Manual” Sambrook et al., (1989);
  • 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
  • the oligonucleotides of the present invention may comprise heterocylic nucleosides consisting of purines and the pyrimidines bases, bonded in a 3' to 5' phosphodiester linkage.
  • oligonucleotides are those modified at one or more of the backbone, internucleoside linkages or bases, as is broadly described hereinunder.
  • oligonucleotides useful according to this aspect of the present invention include oligonucleotides containing modified backbones or non-natural internucleoside linkages. Oligonucleotides having modified backbones include those that retain a phosphorus atom in the backbone, as disclosed in U.S. Pat. NOs: 4,469,863; 4,476,301;
  • Preferred modified oligonucleotide backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkyl phosphotriesters, methyl and other alkyl phosphonates including 3'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3'-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3'-5 r 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'
  • modified oligonucleotide backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl interaucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside 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; and others having mixed N, O, S and CH 2 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 internucleoside linkage, i.e., the backbone, of the nucleotide units are replaced with novel groups. The base units are maintained for complementation with the appropriate polynucleotide target.
  • An example for such an oligonucleotide mimetic includes peptide nucleic acid (PNA).
  • PNA peptide nucleic acid
  • United States patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference.
  • Other backbone modifications, which can be used in the present invention are disclosed in U.S. Pat. No: 6,303,374.
  • Oligonucleotides of the present invention may also include base modifications or substitutions.
  • "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-ammoadenine, 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, S 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 0 C and are presently preferred base substitutions, even more particularly when combined with 2'-O-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 palmity
  • 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.
  • the nucleic acid construct 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 construct of the present invention preferably further includes an appropriate selectable marker and/or an origin of replication.
  • the nucleic acid construct utilized is a shuttle vector, which can propagate both in E.
  • the construct according to the present invention can be, for example, a plasmid, a bacmid, a phagemid, a cosmid, a phage, a virus or an artificial chromosome.
  • 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. (www.invitrogen.com).
  • retroviral vector and packaging systems are those sold by Clontech, San Diego, Calif., includingRetro-X vectors pLNCX and pLXSN, which permit cloning into multiple cloning sites and the trasgene is transcribed from CMV promoter.
  • Vectors derived from Mo-MuLV are also included such as pBabe, where the transgene will be transcribed from the 5'LTR promoter.
  • nucleic acid transfer techniques include transfection with viral or non- viral constructs, such as adenovirus, lentivirus, Herpes simplex I virus, or adeno- associated virus (AAV) and lipid-based systems.
  • viral or non- viral constructs such as adenovirus, lentivirus, Herpes simplex I virus, or adeno- associated virus (AAV) and lipid-based systems.
  • Useful lipids for lipid- mediated transfer of the gene are, for example, DOTMA, DOPE, and DC-Choi [Tonkinson et al., Cancer Investigation, 14(1): 54-65 (1996)].
  • the most preferred constructs for use in gene therapy are viruses, most preferably adenoviruses, AAV, Antiviruses, or retroviruses.
  • a viral construct such as a retroviral construct includes at least one transcriptional promoter/enhancer or locus -defining element(s), or other elements that control gene expression by other means such as alternate splicing, nuclear RNA export, or post-translational modification of messenger.
  • Such vector constructs also include a packaging signal, long terminal repeats (LTRs) or portions thereof, and positive and negative strand primer binding sites appropriate to the virus used, unless it is already present in the viral construct.
  • LTRs long terminal repeats
  • such a construct 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.
  • a signal that directs polyadenylation 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).
  • kits containing probes on a dipstick setup and the like.
  • Hybridization based assays which allow the detection of a variant of interest (i.e., DNA or RNA) in a biological sample rely on the use of oligonucleotides which can be 10, 15, 20, or 30 to 100 nucleotides long preferably from 10 to 50, more preferably from 40 to 50 nucleotides long.
  • 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 10 ⁇ cpm 32 P labeled probe, at 65 0 C, with a final wash solution of 0.2 x SSC and 0.1 % SDS and final wash at 65 0 C and whereas moderate hybridization is effected using a hybridization solution containing 10 % dextrane sulfate, 1 M NaCl, 1 % SDS and 5 x 10 6 cpm 32 P labeled probe, at 65 0 C, with a final wash solution of 1 x SSC and 0.1 % SDS and final wash at 50 0 C.
  • a hybridization solution such as containing 10 % dextrane sulfate, 1 M NaCl, 1 % SDS and 5 x 10 ⁇ cpm 32 P labeled probe, at 65 0 C
  • moderate hybridization is effected using
  • 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.
  • Non-limiting examples of detectable markers include ligands, fluorophores, chemiluminescent agents, enzymes, and antibodies.
  • Other detectable markers for use with probes, which can enable an increase in sensitivity of the method of the invention, include biotin and radio- nucleotides. It will become evident to the person of ordinary skill that the choice of a particular label dictates the manner in which it is bound to the probe.
  • oligonucleotides of the present invention can be labeled subsequent to synthesis, by incorporating biotinylated dNTPs or rNTP, or some similar means (e.g., photo- cross- linking a psoralen derivative of biotin to RNAs), followed by addition of labeled streptavidin (e.g., phycoerythrin-conjugated streptavidin) or the equivalent.
  • biotinylated dNTPs or rNTP or some similar means (e.g., photo- cross- linking a psoralen derivative of biotin to RNAs)
  • streptavidin e.g., phycoerythrin-conjugated streptavidin
  • 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.
  • wash steps may be employed to wash away excess target DNA or probe as well as unbound conjugate.
  • standard heterogeneous assay formats are suitable for detecting the hybrids using the labels present on the oligonucleotide primers and probes.
  • samples may be hybridized to an irrelevant probe and treated with RNAse A prior to hybridization, to assess false hybridization.
  • RNAse A RNAse A prior to hybridization
  • the present invention is not specifically dependent on the use of a label for the detection of a particular nucleic acid sequence, such a label might be beneficial, by increasing the sensitivity of the detection. Furthermore, it enables automation. Probes can be labeled according to numerous well known methods.
  • radioactive nucleotides can be incorporated into probes of the invention by several methods.
  • Non- limiting examples of radioactive labels include 3 H, 14 C, 32 P, and 35 S.
  • wash steps may be employed to wash away excess target DNA or probe as well as unbound conjugate.
  • standard heterogeneous assay formats are suitable for detecting the hybrids using the labels present on the oligonucleotide primers and probes. It will be appreciated that a variety of controls may be usefully employed to improve accuracy of hybridization assays.
  • Probes of the invention can be utilized with naturally 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 constructed of either ribonucleic acid (RNA) or deoxyribonucleic acid (DNA), and preferably of DNA.
  • RNA ribonucleic acid
  • DNA deoxyribonucleic acid
  • 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).
  • 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
  • amplification techniques 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, 1173-1177; Lizardi et al., 1988,
  • 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
  • the nucleic acid 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 Current Protocols in Molecular Biology, John Wiley & Sons Inc., N.Y.).
  • antisense oligonucleotides may be employed to quantify expression of a splice isoform of interest. Such detection is effected at the pre-niRNA 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 0 C, preferably less than 5 0 C, more preferably less than 4 0 C, most preferably less than 3 0 C, ideally between 3 0 C and 0 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 MuWis 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. Because the desired segments of the target sequence become the dominant sequences (in terms of concentration) in the mixture, they are said to be "PCR-amplif ⁇ ed.”
  • LCR Ligase Chain Reaction
  • LAR Ligase Amplification Reaction
  • LCR 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.
  • 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.
  • 3SR to detect mutations is kinetically limited to screening small segments of DNA (e.g., 200-300 base pairs).
  • Q-B eta (Q ⁇ ) Replicase In this method, a probe which recognizes the sequence of interest is attached to the replicatable RNA template for Q ⁇ replicase.
  • a previously identified major problem with false positives resulting from the replication of unhybridized probes has been addressed through use of a sequence-specific ligation step.
  • available thermostable DNA ligases are not effective on this RNA substrate, so the ligation must be performed by T4 DNA ligase at low temperatures (37 degrees C). This prevents the use of high temperature as a means of achieving specificity as in the LCR, the ligation event can be used to detect a mutatbn at the junction site, but not elsewhere.
  • a successful diagnostic method must be very specific.
  • a straight-forward method of controlling the specificity of nucleic acid hybridization is by controlling the temperature of the reaction. While the 3SR/NASBA, and Q ⁇ systems are all able to generate a large quantity of signal, one or more of the enzymes involved in each cannot be used at high temperature (i.e., > 55 degrees C). Therefore the reaction temperatures cannot be raised to prevent non-specific hybridization of the probes. If probes are shortened in order to make them melt more easily at low temperatures, the likelihood of having more than one perfect match in a complex genome increases. For these reasons, PCR and LCR currently dominate the research field in detection technologies. The basis of the amplification procedure in the PCR and LCR is the fact that the products of one cycle become usable templates in all subsequent cycles, consequently doubling the population with each cycle. The final ⁇ ield of any such doubling system can be expressed as:
  • 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.
  • the direct detection method may be, for example a cycling probe reaction (CPR) or a branched DNA analysis.
  • CPR cycling probe reaction
  • Cycling probe reaction uses a long chimeric oligonucleotide in which a central portion is made of RNA while the two termini are made of DNA. Hybridization of the probe to a target DNA and exposure to a thermostable RNase H causes the RNA portion to be digested. This destabilizes the remaining DNA portions of the duplex, releasing the remainder of the probe from the target DNA and allowing another probe molecule to repeat the process. The signal, in the fo ⁇ n of cleaved probe molecules, accumulates at a linear rate. While the repeating process increases the signal, the RNA portion of the oligonucleotide is vulnerable to RNases that may carried through sample preparation.
  • Branched DNA involves oligonucleotides with branched structures that allow each individual oligonucleotide to carry 35 to 40 labels (e.g., alkaline phosphatase enzymes). While this enhances the signal from a hybridization event, signal from non-specific binding is similarly increased.
  • 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 Polymorphism (SSCP) analysis or Dideoxy fingerprinting (ddF).
  • RFLP analysis restriction fragment length polymorphism
  • ASO allele specific oligonucleotide
  • DGGE/TGGE Denaturing/Temperature Gradient Gel Electrophoresis
  • SSCP Single -Strand Conformation Polymorphism
  • ddF Dideoxy fingerprinting
  • nucleic acid segments for mutations.
  • One option is to determine the entire gene sequence of each test sample (e.g., a bacterial isolate). For sequences under approximately 600 nucleotides, this may be accomplished using amplified material (e.g., PCR reaction products). This avoids the time and expense associated with cloning the segment of interest.
  • 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 run on the same gel.
  • a more detailed picture of the molecule may be achieved by cleavage with combinations of restriction enzymes prior to electrophoresis, to allow construction of an ordered map.
  • the presence of specific sequences within the fragment can be detected by hybridization of a labeled probe, or the precise nucleotide sequence can be determined by partial chemical degradation or by primer extension in the presence of chain- terminating nucleotide analogs.
  • Restriction fragment length polymorphism For detection of single-base differences between like sequences, the requirements of the analysis are often at the highest level of resolution. For cases in which the position of the nucleotide in question is known in advance, several methods have been developed for examining single base changes without direct sequencing. For example, if a mutation of interest happens to fall within a restriction recognition sequence, a change in the pattern of digestion can be used as a diagnostic tool (e.g., restriction fragment length polymorphism [RFLP] analysis).
  • RFLP restriction fragment length polymorphism
  • MCC Mismatch Chemical Cleavage
  • 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.
  • Allele specific oligonucleotide 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 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.
  • the precise location of the suspected mutation must be known in advance of the test. That is to say, they are inapplicable when one needs to detect the presence of a mutation within a gene or sequence of interest.
  • DGGE/TGGE Denaturing/Temperature Gradient Gel Electrophoresis
  • the fragments to be analyzed 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 fraction of mutations that can be recognized by DGGE. Attaching a GC clamp to one primer is critical to ensure that the amplified sequence has a low dissociation temp erature. Modifications of the technique have been developed, using temperature gradients, and the method can be also applied to RNA:RNA duplexes.
  • TGGE uses a thermal gradient rather than a chemical denaturant gradient.
  • TGGE requires the use of specialized equipment which can generate a temperature gradient perpendicularly oriented relative to the electrical field.
  • TGGE can detect mutations in relatively small fragments of DNA therefore scanning of large gene segments requires the use of multiple PCR products prior to running the gel.
  • 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 run.
  • This technique is extremely sensitive to variations in gel composition and temperature. A serious limitation of this method is the relative difficulty encountered in comparing data generated in different laboratories, under apparently similar conditions.
  • Dideoxy fingerprinting (ddF) The dideoxy fingerprinting (ddF) is another technique developed to scan genes for the presence of mutations. The ddF technique combines components of Sanger dideoxy sequencing with SSCP.
  • a dideoxy sequencing reaction is performed using one dideoxy terminator and then the reaction products are electrophoresed on nondenaturing polyacrylamide gels to detect alterations in mobility of the termination segments as in SSCP analysis. While ddF is an improvement over SSCP in terms of increased sensitivity, ddF requires the use of expensive dideoxynucleotides and this technique is still limited to the analysis of fragments of the size suitable for SSCP (i.e., fragments of 200-300 bases for optimal detection of mutations).
  • 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 polymorphism analysis, mismatch chemical cleavage, heteroduplex analysis, allele- specific oligonucleotides, denaturing gradient gel electrophoresis, constant denaturant gel electrophoresis, temperature gradient gel electrophoresis and dideoxy fingerprinting.
  • 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 polymorphism analysis, mismatch chemical cleavage, heteroduplex analysis, allele- specific oligonucleotides, denaturing gradient gel electrophor
  • 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.
  • the chip is inserted into a scanner and patterns of hybridization are detected.
  • the hybridization data is collected, as a signal emitted from the reporter groups already incorporated into the nucleic acid, which is now bound to the probes attached to the chip. Since the sequence and position of each probe immobilized on the chip is known, the identity of the nucleic acid hybridized to a given probe can be determined.
  • polypeptide peptide
  • protein protein
  • polypeptide polypeptide
  • the terms apply to amino acid polymers in which one or more amino acid residue is an analog or mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers.
  • Polypeptides can be modified, e.g., by the addition of carbohydrate residues to form glycoproteins.
  • polypeptide include glycoproteins, as well as non-glycoproteins.
  • 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 Morrow Stewart and Janis Dillaha Young, Solid Phase Peptide Syntheses (2nd
  • Synthetic polypeptides can optionally be purified by preparative high performance liquid chromatography [Creighton T. (1983) Proteins, structures and molecular principles. WH Freeman and Co. N.Y.], after which their composition can be confirmed via amino acid sequencing.
  • the present invention also encompasses polypeptides encoded by the polynucleotide sequences of the present invention, as well as polypeptides according to the amino acid sequences described herein.
  • the present invention also encompasses homologues of these polypeptides, such homologues can be at least 50 %, at least 55 %, at least 60%, at least 65 %, at least 70 %, at least 75 %, at least 80 %, at least 85 %, at least 95 % or more say 100 % homologous to the amino acid sequences set forth below, as can be determined using BlastP software of the National Center of Biotechnology Information (NCBI) using default parameters, optionally and preferably including the following: filtering on (this option filters repetitive or low-complexity sequences from the query using the Seg (protein) program), scoring matrix is BLOSUM62 for proteins, word size is 3, E value is 10, gap costs are 11, 1 (initialization and extension), and number of alignments shown is 50.
  • NCBI National Center of Biotechnology Information
  • nucleic acid sequence identity/homology may be determined by using 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 11.
  • 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 occurring 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 stable while in a body or more capable of penetrating into cells.
  • Natural aromatic amino acids, Trp, Tyr and Phe may be substituted for synthetic non- natural acid such as Phenylglycine, TIC, naphthylelanine (NoI), ring- methylated derivatives of Phe, halogenated derivatives of Phe or o- methyl- Tyr.
  • synthetic non- natural acid such as Phenylglycine, TIC, naphthylelanine (NoI), 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.
  • the peptides of the present invention are preferably utilized in diagnostics which require the peptides to be in soluble form, the peptides of the present invention preferably include one or more non-natural or natural polar amino acids, including but not limited to serine and threonine which are capable of increasing peptide solubility due to their hydroxyl-containing side chain.
  • the peptides of the present invention are preferably utilized in a linear form, although it will be appreciated that in cases where cyclicization does not severely interfere with peptide characteristics, cyclic forms of the peptide can also be utilized.
  • the peptides of present invention can be biochemically synthesized such as by using standard solid phase techniques. These methods include exclusive solid phase synthesis well known in the art, partial solid phase synthesis methods, fragment condensation, classical solution synthesis. These methods are preferably used when the peptide is relatively short (i.e., 10 kDa) and/or when it cannot be produced by recombinant techniques (i.e., not encoded by a nucleic acid sequence) and therefore involves different chemistry. Synthetic peptides can be purified by preparative high performance liquid chromatography and the composition of which can be confirmed via amino acid sequencing.
  • the peptides of the present invention can be generated using recombinant techniques such as described by Bitter et al., (1987) Methods in Enzymol. 153:516-544, Studier et al. (1990) Methods in Enzymol. 185:60-89, Brisson et al. (1984) Nature 310:511-514, Takamatsu et al. (1987) EMBO J. 6:307-311, Coruzzi et al. (1984) EMBO J. 3:1671-1680 and Brogli et al., (1984) Science 224:838-843, Gurley et al. (1986) MoI. Cell. Biol. 6:559-565 and Weissbach & Weissbach, 1988, Methods for Plant Molecular Biology, Academic Press, NY, Section VIII, pp 421-463 and also as described above.
  • Antibody refers to a polypeptide ligand that is preferably substantially encoded by an immunoglobulin gene or immunoglobulin genes, or fragments thereof, which specifically binds and recognizes an epitope (e.g., an antigen).
  • the recognized immunoglobulin genes include the kappa and lambda light chain constant region genes, the alpha, gamma, delta, epsilon and mu heavy chain constant region genes, and the myriad- immunoglobulin variable region genes.
  • Antibodies exist, e.g., as intact immunoglobulins or as a number of well characterized fragments produced by digestion with various peptidases. This includes, e.g., Fab' and F(ab)' 2 fragments.
  • 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 constant region domains, CHl, CH2 and CH3, but does not include the heavy chain variable region.
  • 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 and the variable region of the heavy chain expressed as two chains
  • SCA Single chain antibody
  • 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.
  • cleaving antibodies such as separation of heavy chains to form monovalent light-heavy chain fragments, further cleavage of fragments, or other enzymatic, chemical, or genetic techniques may also be used, so long as the fragments bind to the antigen that is recognized by the intact antibody.
  • Fv fragments comprise an association of VH and VL chains. This association may be noncovalent, as described in Inbar et al. [Proc. Nat'l Acad. Sci. USA 69:2659-62 (1972O]. Alternatively, the variable chains can be linked by an intermolecular disulfide bond or cross- linked by chemicals such as glutaraldehyde. Preferably, the Fv fragments comprise VH and VL chains connected by a peptide linker. These single- chain antigen binding proteins (sFv) are prepared by constructing a structural gene comprising DNA sequences encoding the VH and VL domains connected by an oligonucleotide.
  • sFv single- chain antigen binding proteins
  • the structural gene is inserted into an expression vector, which is subsequently introduced into a host cell such as E. coli.
  • the recombinant host cells synthesize a single polypeptide chain with a linker peptide bridging the two V domains.
  • Methods for producing sFvs are described, for example, by [Whitlow and Filpula, Methods 2: 97-105 (1991); Bird et al., Science 242:423-426 (1988); Pack et al., Bio/Technology 11:1271-77 (1993); and U.S. Pat. No. 4,946,778, which is hereby incorporated by reference in its entirety.
  • CDR peptides (“minimal recognition units") can be obtained by constructing genes encoding the CDR of an antibody of interest. Such genes are prepared, for example, by using the polymerase chain reaction to synthesize the variable region from RNA of antibody-producing cells. See, for example, Larrick and Fry [Methods, 2: 106-10 (1991)].
  • Humanized forms of non-human (e.g., murine) antibodies are chimeric molecules of immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab') or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin.
  • Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity.
  • CDR complementary determining region
  • donor antibody such as mouse, rat or rabbit having the desired specificity, affinity and capacity.
  • Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences.
  • 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, Curr. Op. Struct. 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 referred to as import residues, which are typically taken from an import variable domain. Humanization can be essentially performed following the method of Winter and co-workers [Jones et al., Nature, 321:522-525 (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 corresponding 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 corresponding 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. MoI. Biol., 227:381 (1991); Marks et al., J. MoI. Biol., 222:581 (1991)].
  • the techniques of Cole et al. and Boerner et al. are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boerner et al., J. Immunol., 147(l):86-95 (1991)].
  • human antibodies can be made by introduction of human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Pat. Nos.
  • 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 structural 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 invention in combination with at least one other portion of the variant which is not contiguous to the unique sequence portion in the linear polypeptide itself, yet which are able to form an epitope in combination.
  • One or more unique sequence portions may optionally combine with one or more other non- contiguous portions of the variant (including a portion which may have high homology to a portion of the known protein) to form an epitope.
  • 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.
  • a marker can be detected and/or quantified using any of a number of well recognized immunological binding assays.
  • Useful assays include, for example, an enzyme immune assay (EIA) such as enzyme- linked immunosorbent assay (ELISA), a radioimmune assay (RIA), a Western blot assay, or a slot blot assay see, e.g., U.S. Pat. Nos. 4,366,241; 4,376,110; 4,517,288; and 4,837,168).
  • EIA enzyme immune assay
  • ELISA enzyme- linked immunosorbent assay
  • RIA radioimmune assay
  • Western blot assay e.g., Western blot assay
  • slot blot assay see, e.g., U.S. Pat. Nos. 4,366,241; 4,376,110; 4,517,288; and 4,837,168.
  • a sample obtained from a subject can be contacted with the antibody that
  • 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.
  • 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.
  • 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 Radioimmunoassay
  • radiolabeled antibody binding protein e.g., protein A labeled with ⁇
  • a precipitable carrier such as agarose beads.
  • 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. 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 radiolabeled 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 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.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • 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.
  • PET positron emission tomography
  • 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.
  • US Patent No. 6,696,686 describes the use of SPECT for detection of breast cancer, and is hereby incorporated by reference as if fully set forth herein.
  • a display library comprising a plurality of display vehicles (such as phages, viruses or bacteria) each displaying at least 6, at least 7, at least 8, at least 9, at least 10, 10-15, 12-17, 15-20, 15-30 or 20- 50 consecutive amino acids derived from the polypeptide sequences of the present invention.
  • display vehicles such as phages, viruses or bacteria
  • GenBank versions 136 June 15, 2003 ftp.ncbi.nih.gov/genbank/release.notes/gbl36.release.notes); NCBI genome assembly of April 2003; RefSeq sequences from June 2003; Genbank version 139 (December 2003); Human Genome from NCBI (Build 34) (from Oct 2003); and RefSeq sequences from December 2003; and from the LifeSeq library of Incyte Corporation (ESTs only; Wilmington, DE, USA).
  • GenBank sequences the human EST sequences from the EST (GBEST) section and the human mRNA sequences from the primate (GBPRI) section were used; also the human nucleotide RefSeq mRNA sequences were used (see for example www.ncbi.nlm.nih.gov/Genbank/GenbankOverview.html and for a reference to the EST section, see www.ncbi.nlm.nih.gov/dbEST/; a general reference to dbEST, the EST database in GenBank, may be found in Boguski et al, Nat Genet. 1993 Aug;4(4):332-3; all of which are hereby incorporated by reference as if fully set forth herein).
  • Novel splice variants were predicted using the LEADS clustering and assembly system as described in Sorek, R., Ast, G. & Graur, D. Alu-containing exons are alternatively spliced. Genome Res 12, 1060-7 (2002); US patent No: 6,625,545; and U.S. Pat. Appl. No. 10/426,002, published as US20040101876 on May 27 2004; all of which are hereby incorporated by reference as if fully set forth herein. Briefly, the software cleans the expressed sequences from repeats, vectors and immunoglobulins. It then aligns the expressed sequences to the genome taking alternatively splicing into account and clusters overlapping expressed sequences into "clusters" that represent genes or partial genes.
  • the GeneCarta platform includes a rich pool of annotations, sequence information (particularly of spliced sequences), chromosomal information, alignments, and additional information such as SNPs, gene ontology terms, expression profiles, functional analyses, detailed domain structures, known and predicted proteins and detailed homology reports.
  • Biological source Examples of frequently used biological sources for construction 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 construction various methods are known in the art for library construction including normalized library construction; non-normalized library construction; subtracted libraries; ORESTES and others. It will be appreciated that at times the protocol of library construction is not indicated.
  • 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.
  • Clones number score The total weighted number of EST clones from cancer libraries was compared to the EST clones from normal libraries. To avoid cases where one library contributes to the majority of the score, the contribution of the library that gives most clones for a given cluster was limited to 2 clones. The score was computed as
  • Clones number score significance - Fisher exact test was used to check if EST clones from cancer libraries are significantly over-represented in the cluster as compared to the total number of EST clones from cancer and normal libraries. Two search approaches were used to find either general cancer-specific candidates or tumor specific candidates.
  • 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”.
  • Each cluster includes at least 2 libraries from the tissue T. At least 3 clones (weighed - as described above) from tissue T in the cluster; and
  • Clones from the tissue T are at least 40 % from all the clones participating in the tested cluster Fisher exact test P-values were computed both for library and weighted clone counts to check that the counts are statistically significant.
  • a Region is defined as a group of adjacent exons that always appear or do not appear together in each splice variant.
  • a “segment” (sometimes referred also as “seg” or “node”) is defined as the shortest contiguous transcribed region without known splicing inside.
  • Each unique sequence region divides the set of transcripts into 2 groups: (i) Transcripts containing this region (group TA).
  • Region 1 common to all transcripts, thus it is not considered for detecting variants

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