Antagonist antibody for the treatment of cancer

Abstract

Antibodies, humanized antibodies, resurfaced antibodies, antibody fragments, derivatized antibodies, and conjugates of same with cytotoxic agents, which specifically bind to, and inhibit A class of Eph receptors, antagonize the effects of growth factors on the growth and survival of tumor cells, and which have minimal agonistic activity or are preferrentially devoid of agonist activity. Said antibodies and fragments thereof may be used in the treatment of tumors that express elevated levels of A class of Eph receptors, such as breast cancer, colon cancer, lung cancer, ovarian carcinoma, synovial sarcoma and pancreatic cancer, and said derivatized antibodies may be used in the diagnosis and imaging of tumors that express elevated levels of A class of Eph receptors. Also provided are cytotoxic conjugates comprising a cell binding agent and a cytotoxic agent, therapeutic compositions comprising the conjugate, methods for using the conjugates in the inhibition of cell growth and the treatment of disease, and a kit comprising the cytotoxic conjugate are disclosed are all embodiments of the invention. In particular, the cell binding agent is a monoclonal antibody, and epitope-binding fragments thereof, that recognizes and binds the A class of Eph receptors.

1 . An antibody or an epitope-binding fragment thereof that specifically binds to an EphA2 receptor and is an antagonist of said receptor. 
     
     
         2 . The antibody or epitope-binding fragment thereof according to  claim 1 , wherein one or more of the following conditions is met:
 a) said antibody or epitope-binding fragment thereof is a monoclonal antibody   b) said antibody or epitope-binding fragment thereof is a Fab, Fab′, F(ab′) 2  or F v  fragment;   c) said antibody or epitope-binding fragment thereof is capable of inhibiting growth of a cancer cell;   d) said antibody or epitope-binding fragment thereof is capable of inhibiting migration of a cancer cell;   e) said antibody or epitope-binding fragment thereof is capable of inhibiting angiogenesis;   f) said antibody or epitope-binding fragment thereof is devoid of agonist activity;   g) said antibody or epitope-binding fragment thereof is capable of inhibiting the binding of a ligand to said receptor;   h) said antibody or epitope-binding fragment thereof is capable of inhibiting EphA2 tyrosine phosphorylation;   i) said antibody or epitope-binding fragment thereof is capable of inhibiting EphA2-mediated signaling;   j) said antibody or epitope-binding fragment thereof binds EphA2 with a K D  of 3×10 −10  M or smaller; and   k) said EphA2 receptor is human.   
     
     
         3 - 5 . (canceled) 
     
     
         6 . The antibody or an epitope-binding fragment thereof according to  claim 2 , wherein one or more of the following conditions are met:
 a) said cancer cell is a cell of a cancer selected from the group consisting of a breast cancer, colon cancer, endometrial cancer, ovarian carcinoma, osteosarcoma, cervical cancer, prostate cancer, lung cancer, synovial carcinoma pancreatic cancer, a sarcoma, a glioma, head and neck cancer, gastric cancer, liver cancer, and other carcinomas;   b) said antibody or epitope-binding fragment thereof does not stimulate EphA2 tyrosine phosphorylation;   c) said ligand is ephrinA1;   d) said antibody or epitope-binding fragment thereof is capable of inhibiting EphA2 tyrosine phosphorylation in presence of ephrinA1; and   e) wherein the inhibition of EphA2-mediated signaling results in an increase in Akt phosphorylation.   
     
     
         7 - 17 . (canceled) 
     
     
         18 . An antibody or epitope-binding fragment thereof according to  claim 1 , wherein one or more of the following conditions are met:
 a) said antibody or epitope-binding fragment thereof comprises one or more complementarity-determining region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72;   b) said antibody or epitope-binding fragment thereof comprises a light chain variable region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 28, 30, 78, and 80;   c) said antibody or epitope-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 20, 22, 24, 74, and 76;   d) said antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOs: 1, 2, and 3, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOs: 4, 5, and 6;   e) said antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOs: 7, 8, and 9, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOs: 10, 11, and 12;   f) said antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOs: 13, 14, and 15, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOs: 16, 17, and 18;   g) said antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity determining regions having amino acid sequences represented by SEQ ID NOs: 61, 62, and 63, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOs: 64, 65, and 66;   h) said antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity determining regions having amino acid sequences represented by SEQ ID NOs: 67, 68, and 69, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOs: 70, 71, and 72; and   i) said antibody or epitope-binding fragment thereof is a murine antibody or epitope-binding fragment thereof and is produced by a hybridoma designated 37.3D7, wherein said hybridoma is deposited at the American Type Culture Collection under the accession number PTA-7660; a hybridoma designated 37.1F5, wherein said hybridoma is deposited at the American Type Culture Collection under the accession number PTA-7661; a hybridoma designated 53.2H11, wherein said hybridoma is deposited at the American Type Culture Collection under the accession number PTA-7662; a hybridoma EphA2-N1, wherein said hybridoma is deposited at the American Type Culture Collection under the accession number PTM-8407; or a hybridoma designated EphA2-N2, wherein said hybridoma is deposited at the American Type Culture Collection under the accession number PTM-8408.   
     
     
         19 - 36 . (canceled) 
     
     
         37 . A humanized or resurfaced antibody or epitope-binding fragment thereof that binds the same epitope as an antibody or epitope-binding fragment thereof according to  claim 18 . 
     
     
         38 . A humanized or resurfaced antibody or epitope-binding fragment thereof according to  claim 37  wherein one or more of the following conditions are met:
 a) said humanized or resurfaced antibody or epitope-binding fragment thereof comprises one or more complementarity-determining region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72 
 b) said humanized or resurfaced antibody or epitope-binding fragment thereof comprises a light chain variable region having an amino acid sequence selected from the group consisting of SEQ ID NOS: 47, 48, 49, 50, and 52; 
 c) said humanized or resurfaced antibody or epitope-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence selected from the group consisting of SEQ ID NOS: 32, 34, 36, 37, 38, 40, 42, 43, and 45; 
 d) said humanized or resurfaced antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 1, 2, and 3, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 4, 5, and 6; 
 e) said humanized or resurfaced antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences by SEQ ID NOS: 7, 8, and 9, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 10, 11, and 12; 
 f) said humanized or resurfaced antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 13, 14, and 15, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS:16, 17, and 18; 
 g) said humanized or resurfaced antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, and said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences selected from the group consisting of SEQ ID NOs: 61, 62, and 63, and said light chain comprises three sequential complementarity-determining regions having amino acid sequences selected from the group consisting of SEQ ID NOs: 64, 65, and 66; 
 h) said humanized or resurfaced antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, and said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences selected from the group consisting of SEQ ID NOs: 67, 68, and 69, and said light chain comprises three sequential complementarity-determining regions having amino acid sequences selected from the group consisting of SEQ ID NOs: 70, 71, and 72; and 
 i) said humanized or resurfaced antibody or epitope-binding fragment thereof is selected from a group consisting of hu37.3D7, hu37.1F5, hu53.2H11, huEphA2-N1, and huEphA2-N2. 
 
     
     
         39 - 52 . (canceled) 
     
     
         53 . A conjugate comprising the antibody or epitope-binding fragment thereof according to  claim 1  linked to a cytotoxic agent. 
     
     
         54 . The conjugate of  claim 53 , characterized in that said cytotoxic agent is selected from the group consisting of a maytansinoid, a small drug, a tomaymycin derivative, a leptomycin derivative, a prodrug, a taxoid, CC-1065 and a CC-1065 analog. 
     
     
         55 . The conjugate of  claim 53 , characterized in that said cytotoxic agent is:
 a) the maytansine DM1 of formula:   
       
         
           
           
               
               
           
         
         b) the maytansine DM4 of formula: 
       
       
         
           
           
               
               
           
         
         c) a tomaymycin derivative selected group the mu consisting of:
 8,8′-[1,3-benzenediylbis(methyleneoxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[5-methoxy-1,3-benzenediylbis(methyleneoxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[1,5-pentanediylbis(oxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[1,4-butanediylbis(oxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[3-methyl-1,5-pentanediylbis(oxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[2,6-pyridinediylbis(oxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[4-(3-tert-butoxycarbonylaminopropyloxy)-2,6-pyridinediylbis-(methyleneoxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[5-(3-aminopropyloxy)-1,3-benzenediylbis(methyleneoxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[5-(N-methyl-3-tert-butoxycarbonylaminopropyl)-1,3-benzenediylbis-(methyleneoxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-{5-[3-(4-methyl-4-methyldisulfanyl-pentanoylamino)propyloxy]-1,3-benzenediylbis(methleneoxy)}-bis[(S)-2-eth-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[5-acetylthiomethyl-1,3-benzenediylbis(methyleneoxy)]-bis[(S)-2-methylene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 bis-{2-[(S)-2-methylene-7-methoxy-5-oxo-1,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yloxy]-ethyl}-carbamic acid tert-butyl ester 
 8,8′-[3-(2-acetylthioethyl)-1,5-pentanediylbis(oxy)]-bis[(S)-2-methylene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[5-(N-4-mercapto-4,4-dimethylbutanoyl)amino-1,3-benzenediylbis(methyleneoxy)]-bis[7-methoxy-2-methylene-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[5-(N-4-methyldithio-4,4-dimethylbutanoyl)-amino-1,3-benzenediylbis(methyleneoxy)]-bis[7-methoxy-2-methylene-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[5-(N-methyl-N-(2-mercapto-2,2-dimethylethyl)amino-1,3-benzenediyl(methyleneoxy)]-bis[7-methoxy-2-methylene-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[5-(N-methyl-N-(2-methyldithio-2,2-dimethylethyl)amino-1,3-benzenediyl(methyleneoxy)]-bis[7-methoxy-2-methylene-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[(4-(2-(4-mercapto-4-methyl)-pentanamido-ethoxy)-pyridin-2,6-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[(1-(2-(4-methyl-4-methyldisulfanyl)-pentanamido-ethoxy)-benzene-3,5-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[(4-(3-(4-methyl-4-methyldisulfanyl)-pentanamido-propoxy)-pyridin-2,6-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[(4-(4-(4-methyl-4-methyldisulfanyl)-pentanamido-butoxy)-pyridin-2,6-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[(4-(3-[4-(4-methyl-4-methyldisulfanyl-pentanoyl)-piperazin-1-yl]-propyl)-pyridin-2,6-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[(1-(3-[4-(4-methyl-4-methyldisulfanyl-pentanoyl)-piperazin-1-yl]-propyl)-benzene-3,5-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[(4-(2-{2-[2-(4-methyl-4-methyldisulfanyl-pentanoylamino)-ethoxy]-ethoxy}-ethoxy)-pyridin-2,6-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[(1-(2-{2-[2-(2-{2-[2-(4-methyl-4-methyldisulfanyl-pentanoylamino)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-benzene-3,5-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[(1-(2-{2-[2-(4-methyl-4-methyldisulfanyl-pentanoylamino)-ethoxy]-ethoxy}-ethoxy)-benzene-3,5-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[(4-(2-{2-[2-(2-{2-[2-(4-methyl-4-methyldisulfanyl-pentanoylamino)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-pyridin-2,6-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[(1-(2-[methyl-(2-methyl-2-methyldisulfanyl-propyl)-amino]-ethoxy)-benzene-3,5-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[(4-(3-[methyl-(4-methyl-4-methyldisulfanyl-pentanoyl)-amino]-propyl)-pyridin-2,6-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] 
 8,8′-[(4-(3-[methyl-(2-methyl-2-methyldisulfanyl-propyl)-amino]-propyl)-pyridin-2,6-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]; and 
 8,8′-[(1-(4-methyl-4-methyldisulfanyl)-pentanamido)-benzene-3,5-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]; or 
 
         d) a leptomycin derivative selected from the group consisting of:
 (2-Methylsulfanyl-ethyl)-amid of (2E,10E,12E,16Z,18E)-(R)-6-Hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid (2-methylsulfanyl-ethyl)-amid 
 Bis-[(2-mercaptoethyl)-amid of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid] 
 (2-Mercapto-ethyl)-amid of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid 
 (2-Methyldisulfanyl-ethyl)-amid of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid 
 (2-Methyl-2-methyldisulfanyl-propyl)-amid of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid; and 
 (2-Mercapto-2-methyl-propyl)-amid of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid. 
 
       
     
     
         56 - 58 . (canceled) 
     
     
         59 . A pharmaceutical composition containing an antibody or epitope-binding fragment thereof according to  claim 1  and a pharmaceutically acceptable carrier or excipients. 
     
     
         60 . An antibody or epitope-binding fragment thereof according to  claim 1  for use as a medicament. 
     
     
         61 . The use of an antibody or epitope-binding fragment thereof according to  claim 1  to make a medicament to treat cancer. 
     
     
         62 . The use of  claim 61 , wherein one or more of the following conditions are met:
 a) said cancer is a metastatic cancer;   b) said antibody or epitope-binding fragment thereof inhibits tumor neovascularization; and   c) said cancer is selected from the group consisting of breast cancer, colon cancer, endometrial cancer, ovarian carcinoma, osteosarcoma, cervical cancer, kidney cancer, prostate cancer, lung cancer, synovial carcinoma pancreatic cancer, a sarcoma, glioma, head and neck cancer, gastric cancer, liver cancer, and other carcinomas.   
     
     
         63 - 64 . (canceled) 
     
     
         65 . The use according to  claim 61 , further comprising the use of a further therapeutic agent in the manufacture of the same or different composition. 
     
     
         66 . The use according to  claim 65  characterized in that the further therapeutic agent is an antagonist of fibroblast-growth factor (FGF), hepatocyte growth factor (HGF), tissue factor (TF), protein C, protein S, platelet-derived growth factor (PDGF), or HER2 receptor. 
     
     
         67 . A method of diagnosing a cancer in a subject known to or suspected to have a cancer, said method comprising:
 a) Contacting cells of said patient with an antibody or epitope-binding fragment thereof,   b) Measuring the binding of said antibody or epitope-binding fragment thereof to said cells, and   c) Comparing the expression in part (b) with that of a normal reference subject or standard.   
     
     
         68 . The method of  claim 67 , wherein said cancer is a cell of a cancer selected from the group consisting of a breast cancer, colon cancer, endometrial cancer, ovarian carcinoma, osteosarcoma, cervical cancer, kidney cancer, prostate cancer, lung cancer, synovial carcinoma pancreatic cancer, a sarcoma, glioma, head and neck cancer, gastric cancer, liver cancer, and other carcinomas. 
     
     
         69 . The method of  claim 68 , characterized in that the said cells are in frozen or fixed tissue or cells from said patient. 
     
     
         70 . A polynucleotide encoding a polypeptide selected from the group consisting of SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 37, 38, 40, 42, 43, 45, 47, 48, 49, 50, 52, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 74, 76, 78 and 80. 
     
     
         71 . A polynucleotide according to  claim 70  characterized in that said polynucleotide has a sequence sharing at least 80% homology with a polynucleotide selected from the group consisting of SEQ ID NOs: 19, 21, 23, 25, 27, 29, 31, 33, 35, 39, 41, 44, 46, 51, 73, 75, 77, and 79. 
     
     
         72 . A recombinant vector comprising the polynucleotide of  claim 70 . 
     
     
         73 . A host cell comprising the vector of  claim 72 . 
     
     
         74 . The host cell of  claim 78 , characterised in that it is selected from the group consisting of the hybridoma cell line designated 37.3D7 wherein said hybridoma cell line is deposited at the American Type Culture Collection under the accession number PTA-7660; the hybridoma cell line designated 37.1F5, wherein said hybridoma cell line is deposited at the American Type Culture Collection under the accession number PTA-7661; the hybridoma cell line designated 53.2H11, wherein said hybridoma cell line is deposited at the American Type Culture Collection under the accession number PTA-7662; the hybridoma cell line designated EphA2-N1, wherein said hybridoma cell line is deposited at the American Type Culture Collection under the accession number PTM-8407; or the hybridoma cell line designated EphA2-N2, wherein said hybridoma cell line is deposited at the American Type Culture Collection under the accession number PTM-8408. 
     
     
         75 . A pharmaceutical composition containing a conjugate according to  claim 53  and a pharmaceutically acceptable carrier or excipients. 
     
     
         76 . A conjugate according to  claim 53  for use as a medicament. 
     
     
         77 . The use of a conjugate according to  claim 53  to make a medicament to treat cancer. 
     
     
         78 . A host cell expressing the antibody of  claim 1 .