Stabilized Angiopoietin-2 Antibodies And Uses Thereof

Abstract

Stabilized antibodies directed to Angiopoeitin-2 and uses of such antibodies are described. Nucleic acid and amino acid sequences, hybridomas or other cell lines for expressing such antibodies are also provided.

We claim: 
     
         1 . An isolated antibody that binds to Ang-2, wherein said antibody comprises a variable light chain, said light chain comprising a sequence selected from the group consisting of SEQ ID No:3 (MEDI1); SEQ ID No:4 (MEDI2); SEQ ID No:5 (MEDI3); SEQ ID No:6 (MEDI4); and SEQ ID No:8 (MEDI6). 
     
     
         2 . The antibody of  claim 1 , wherein said antibody is an IgG1 or an IgG2 isotype antibody. 
     
     
         3 . The antibody of  claim 1  or  2 , wherein said antibody further comprises a variable heavy chain region comprising SEQ ID No:7 (MEDI5). 
     
     
         4 . The antibody of any of  claims 1 - 3 , wherein said antibody, when produced, exhibits a production efficiency in a mammalian host cell equal to or greater than 2 times the production efficiency of the Ang-2 antibody 3.19.3. 
     
     
         5 . The antibody of  claim 4 , wherein said production efficiency is equal to or greater than 3 times the production efficiency of the Ang-2 antibody 3.19.3. 
     
     
         6 . The antibody of  claim 4 , wherein said production efficiency is equal to or greater than 5 times the production efficiency of the Ang-2 antibody 3.19.3. 
     
     
         7 . A nucleic acid encoding the antibody of any of  claims 1 - 6 . 
     
     
         8 . A vector comprising the nucleic acid of  claim 7   
     
     
         9 . A host cell comprising the vector of  claim 8 . 
     
     
         10 . A pharmaceutical composition comprising the antibody of any of  claims 1 - 6  and an excipient. 
     
     
         11 . A method of preventing, treating, or managing cancer in an animal in need thereof, said method comprising administering to said animal a dose of an effective amount of the composition of  claim 10 . 
     
     
         12 . A method of preventing metastasis of cancer in an animal in need thereof, said method comprising administering to said animal a dose of an effective amount of the composition of  claim 10 . 
     
     
         13 . A method of preventing recurrences of cancer in an animal in need thereof, said method comprising administering to said animal a dose of an effective amount of the composition of  claim 10 . 
     
     
         14 . A method of preventing advancement of cancer in an animal in need thereof, said method comprising administering to said animal a dose of an effective amount of the composition of  claim 10 . 
     
     
         15 . A method of preventing development of cancer from a pre-cancerous state in an animal in need thereof, said method comprising administering to said animal an effective amount of the composition of  claim 10 . 
     
     
         16 . A method of preventing symptoms of cancer in an animal in need thereof, said method comprising administering to said animal a dose of an effective amount of the composition of  claim 10 . 
     
     
         17 . A method of promoting tumor regression of a cancer in an animal in need thereof, said method comprising administering to said animal a dose of an effective amount of the composition of  claim 10 . 
     
     
         18 . A method of inhibiting tumor cell proliferation in an animal in need thereof, said method comprising administering to said animal a dose of an effective amount of the composition of  claim 10 . 
     
     
         19 . A method of depleting malignant tumor cells in an animal in need thereof, said method comprising administering to said animal a dose of an effective amount of the composition of  claim 10 . 
     
     
         20 . A method of inhibiting angiogenesis of a cancer tumor in an animal in need thereof, said method comprising administering to said animal a dose of an effective amount of the composition of  claim 10 . 
     
     
         21 . The method of any of  claims 11 - 20 , wherein said method comprises an additional dosing to said animal of one or more other cancer therapies. 
     
     
         22 . The method of  claim 21 , wherein said one or more other cancer therapies are chemotherapies, biological therapies/immunotherapies, radiation therapies, hormonal therapies, or surgery. 
     
     
         23 . The method of any of  claims 11 - 22 , wherein said method further comprises the administration of another therapeutic agent that is not a cancer therapeutic agent. 
     
     
         24 . The method of  claim 23 , wherein said therapeutic agent is an anti-emetic agent, anti-fungal agent, anti-parasitic agent, anti-inflammatory agent, immunomodulatory agent, anti-viral agent, or antibiotic. 
     
     
         25 . The method of any of  claims 21 - 24 , wherein said chemotherapy is selected from the group consisting of 5-Fluorouracil, carboplatin, and paclitaxel. 
     
     
         26 . The method of any of  claims 21 - 25 , wherein said immunotherapy is the administration of bevacizumab or an antibody that competes for the same epitope as bevacizumab. 
     
     
         27 . The method of any of  claims 11 - 26 , wherein said cancer or tumor is selected from the group consisting of melanoma, colon, colorectal, lung, small cell lung carcinoma, non-small cell lung carcinoma, breast, rectum, stomach, glioma, prostate, ovary, testes, thyroid, blood, kidney, liver, hepatocellular carcinoma pancreas, brain, neck, glioblastoma, endometrial cancer, and central nervous system cancer. 
     
     
         28 . The method of any of  claims 11 - 27 , wherein said animal has been previously treated by administration of one or more cancer therapies but not by administration of the composition of  claim 10 . 
     
     
         29 . The method of any  claims 11 - 27 , wherein said animal has been previously treated with chemotherapy alone, or in combination with one or more radiation therapies, biological/immunotherapies, hormonal therapies or surgery. 
     
     
         30 . The method of any of  claims 11 - 27 , wherein said animal has been previously treated with radiation therapy alone, or in combination with one or more chemotherapies, biological therapies/immunotherapies, hormonal therapies or surgery. 
     
     
         31 . The method of any of  claims 11 - 27 , wherein said animal has been previously treated with biological therapies/immunotherapies alone, or in combination with one or more chemotherapies, radiation therapy, hormonal therapies or surgery. 
     
     
         32 . The method of any of  claims 11 - 27 , wherein said animal has been previously treated with hormonal therapies alone, or in combination with one or more chemotherapies, radiation therapy, biological therapies/immunotherapies or surgery. 
     
     
         33 . The method of any of  claims 11 - 27 , wherein said animal has been previously treated with surgery alone, or in combination with one or more chemotherapies, radiation therapy, hormonal therapies or biological therapies/immunotherapies. 
     
     
         34 . The method of any of  claims 11 - 33 , wherein said cancer is refractory to chemotherapy or radiation therapy. 
     
     
         35 . The method of any of  claims 11 - 34 , wherein said administration is intravenously, subcutaneously, intratumorally, intramuscularly, parenterally, or orally. 
     
     
         36 . The method of any of  claims 21 - 35 , wherein said composition and cancer therapy are administered by the same mode of administration. 
     
     
         37 . The method of any of  claims 21 - 35 , wherein said composition and cancer therapy are administered by a different mode of administration. 
     
     
         38 . The method of any of  claims 21 - 35 , wherein said composition and cancer therapy are administered in the same dosage form. 
     
     
         39 . The method of any of  claims 21 - 35 , wherein said composition and cancer therapy are administered in different dosage forms. 
     
     
         40 . The method of any of  claims 21 - 39 , wherein said cancer therapy is selected from the group consisting of radiation therapies, biological therapies/immunotherapies, hormonal therapies and surgery. 
     
     
         41 . A method of preventing, treating, or managing disease-related angiogenesis in an animal in need thereof, said method comprising administering to said animal a dose of an effective amount of the composition of  claim 10 . 
     
     
         42 . The method of  claim 41 , wherein the disease-related angiogenesis is associated with seronegative arthritis, seropositive arthritis, arthritis related to other arthropathies, osteoarthritis or SLE. 
     
     
         43 . The method of  claim 42 , wherein the seropositive arthritis is rheumatoid arthritis. 
     
     
         44 . A method of preventing recurrences of disease-related angiogenesis in an animal in need thereof, said method comprising administering to said animal a dose of an effective amount of the composition of  claim 10 . 
     
     
         45 . A method of preventing advancement of disease-related angiogenesis in an animal in need thereof, said method comprising administering to said animal a dose of an effective amount of the composition of  claim 10 . 
     
     
         46 . A method of treating rheumatoid arthritis in an animal in need thereof, said method comprising administering to said animal an effective amount of the composition of  claim 10 . 
     
     
         47 . A method of preventing symptoms of disease-related angiogenesis in an animal in need thereof, said method comprising administering to said animal a dose of an effective amount of the composition of  claim 10 . 
     
     
         48 . The method of any of  claims 41 - 47 , wherein said method comprises an additional dosing to said animal of one or more other anti-inflammatory therapies. 
     
     
         49 . The method of  claim 48 , wherein said one or more other anti-inflammatory therapies are chemotherapies, biological therapies/immunotherapies, radiation therapies, hormonal therapies, or surgery. 
     
     
         50 . The method of  claim 49 , wherein said biological therapy/immunotherapy is a TNF-α antagonist. 
     
     
         51 . The method of  claim 50 , wherein said TNF-α is selected from etanercept (ENBREL®), adalimumab (HUMIRA®), and infliximab (REMICADE®). 
     
     
         52 . The method of any of  claims 41 - 51 , wherein said method further comprises the administration of another therapeutic agent that is not an anti-inflammatory therapeutic agent. 
     
     
         53 . The method of  claim 52 , wherein said therapeutic agent is an anti-emetic agent, anti-fungal agent, anti-parasitic agent, anti-cancer agent, immunomodulatory agent, anti-viral agent, or antibiotic. 
     
     
         54 . The method of any of  claims 41 - 53 , wherein said animal has been previously treated by administration of one or more anti-inflammatory therapies but not by administration of the composition of  claim 10 . 
     
     
         55 . The method of any of  claims 41 - 53 , wherein said animal has been previously treated with chemotherapy alone, or in combination with one or more radiation therapies, biological/immunotherapies, hormonal therapies or surgery. 
     
     
         56 . The method of any of  claims 41 - 53 , wherein said animal has been previously treated with radiation therapy alone, or in combination with one or more chemotherapies, biological therapies/immunotherapies, hormonal therapies or surgery. 
     
     
         57 . The method of any of  claims 41 - 53 , wherein said animal has been previously treated with biological therapies/immunotherapies alone, or in combination with one or more chemotherapies, radiation therapy, hormonal therapies or surgery. 
     
     
         58 . The method of any of  claims 41 - 53 , wherein said animal has been previously treated with hormonal therapies alone, or in combination with one or more chemotherapies, radiation therapy, biological therapies/immunotherapies or surgery. 
     
     
         59 . The method of any of  claims 41 - 53 , wherein said animal has been previously treated with surgery alone, or in combination with one or more chemotherapies, radiation therapy, hormonal therapies or biological therapies/immunotherapies. 
     
     
         60 . A method of reducing endothelial cell proliferation in an animal, said method comprising administration of a dose of an effective amount of the composition of  claim 10 . 
     
     
         61 . A method of inhibiting Ang-2 and/or Ang-1 binding to Tie-2 in an animal, said method comprising administration of a dose of an effective amount of the composition of  claim 10 . 
     
     
         62 . A method of inhibiting Tie-2 phosphorylation in an animal, said method comprising administration of a dose of an effective amount of the composition of  claim 10 . 
     
     
         63 . A method of reducing levels of circulating Ang-2 and/or Ang-1 polypeptide in an animal, said method comprising administration of a dose of an effective amount of the composition of  claim 10 . 
     
     
         64 . A pharmaceutical composition comprising a combination of i) an antagonist of the biological activity of Angiopoietin-2 and/or Tie-2, and ii) an antagonist of the biological activity of CSF1R, and/or CSF1. 
     
     
         65 . The composition according to  claim 64 , wherein the antagonist of Angiopoietin-2 is an antibody. 
     
     
         66 . The composition according to  claim 65 , wherein the antagonist of Angiopoietin-2 is a fully human monoclonal antibody. 
     
     
         67 . The composition according to  claim 65  or  66 , wherein the antibody binds to the same epitope as any one of fully human monoclonal antibodies selected from the group consisting of 3.31.2, 5.16.3, 5.86.1, 5.88.3, 3.3.2, 5.103.1, 5.101.1, 3.19.3, 5.28.1, 5.78.3, MEDI1/5, MEDI2/5, MEDI3/5, MEDI6/5, and MEDI4/5. 
     
     
         68 . The composition according to  claim 65 , wherein the antibody is a fully human monoclonal antibody selected from the group consisting of: 33.31.2, 5.16.3, 5.86.1, 5.88.3, 3.3.2, 5.103.1, 5.101.1, 3.19.3, 5.28.1, 5.78.3, MEDI1/5, MEDI2/5, MEDI3/5, MEDI6/5, and MEDI4/5. 
     
     
         69 . The composition according to any of  claims 64 - 68 , wherein the antagonist of the biological activity of CSF1R is a tyrosine kinase inhibitor. 
     
     
         70 . The composition according to  claim 69 , wherein the antagonist of the biological activity of CSF1R is selected from any one of:
 2-chloro-N-pyridin-3-yl-5-{[3-(trifluoromethyl)benzoyl]amino}benzamide;   2-chloro-N-(5-fluoropyridin-3-yl)-5-{[3-(trifluoromethyl)benzoyl]amino}benzamide;   2-chloro-N-(5-fluoropyridin-3-yl)-5-{[3-fluoro-5-(trifluoromethyl)benzoyl]amino}-benzamide;   2-methyl-N-pyridin-3-yl-5-{[3-(trifluoromethyl)benzoyl]amino}benzamide;   5-{[3-fluoro-5-(trifluoromethyl)benzoyl]amino}-2-methyl-N-pyridin-3-ylbenzamide;   2-chloro-5-[(3-cyclopropylbenzoyl)amino]-N-pyridin-3-ylbenzamide;   2-chloro-5-[(3-chlorobenzoyl)amino]-N-pyridin-3-ylbenzamide;   5-[(3-chloro-5-fluorobenzoyl)amino]-2-methyl-N-pyridin-3-ylbenzamide;   5-[(3-cyclopropyl-5-fluorobenzoyl)amino]-2-methyl-N-pyridin-3-ylbenzamide;   5-[(3-chlorobenzoyl)amino]-2-methyl-N-pyridin-3-ylbenzamide;   5-{[3-(1-cyano-1-methylethyl)benzoyl]amino}-2-methyl-N-(2-methyl-1,3-thiazol-5-yl)benzamide;   2-chloro-N-1,3-thiazol-5-yl-5-{[3-(trifluoromethyl)benzoyl]amino}benzamide;   2-chloro-5-[(3-chlorobenzoyl)amino]-N-1,3-thiazol-5-ylbenzamide;   2-chloro-5-[(3,5-dimethylbenzoyl)amino]-N-1,3-thiazol-5-ylbenzamide;   5-{[3-(1-cyano-1-methylethyl)benzoyl]amino}-2-methyl-N-1,3-thiazol-5-ylbenzamide;   2-methyl-N-(2-methyl-1,3-thiazol-5-yl)-5-{[3-(trifluoromethyl)benzoyl]amino}benzamide;   2-chloro-5-[(3-chlorobenzoyl)amino]-N-(2-methyl-1,3-thiazol-5-yl)benzamide;   2-chloro-5-[(3,5-dimethylbenzoyl)amino]-N-(2-methyl-1,3-thiazol-5-yl)benzamide;   2-chloro-N-(2-methyl-1,3-thiazol-5-yl)-5-{[3-(trifluoromethyl)benzoyl]amino}benzamide;   2-chloro-5-{[3-fluoro-5-(trifluoromethyl)benzoyl]amino}-N-(2-methyl-1,3-thiazol-5-yl)benzamide;   5-[(5-{[3-(1-cyano-1-methylethyl)benzoyl]amino}-2-methylbenzoyl)amino]-N-methyl-1,3-thiazole-2-carboxamide;   5-{[3-fluoro-5-(trifluoromethyl)benzoyl]amino}-2-methyl-N-(2-methyl-1,3-thiazol-5-yl)benzamide;   5-[(3-chloro-5-fluorobenzoyl)amino]-2-methyl-N-(2-methyl-1,3-thiazol-5-yl)benzamide;   5-[(3-cyclopropyl-5-fluorobenzoyl)amino]-2-methyl-N-(2-methyl-1,3-thiazol-5-yl)benzamide;   5-[(3-chlorobenzoyl)amino]-2-methyl-N-(2-methyl-1,3-thiazol-5-yl)benzamide;   5-[3,4-dichlorobenzoyl)amino]-2-methyl-N-(2-methyl-1,3-thiazol-5-yl)benzamide;   5-[(3-cyclopropylbenzoyl)amino]-2-methyl-N-(2-methyl-1,3-thiazol-5-yl)benzamide;   5-[(3,5-dimethylbenzoyl)amino]-2-methyl-N-(2-methyl-1,3-thiazol-5-yl)benzamide;   2-methyl-5-[(3-methylbenzoyl)amino]-N-(2-methyl-1,3-thiazol-5-yl)benzamide;   2,6-dichloro-N-(4-methyl-3-{[(2-methyl-1,3-thiazol-5-yl)amino]carbonyl}phenyl)isonicotinamide;   2-methyl-5-{[(3-methylcyclohexyl)carbonyl]amino}-N-(2-methyl-1,3-thiazol-5-yl)benzamide;   2-methyl-N-(2-methyl-1,3-thiazol-5-yl)-5-(pentanoylamino)benzamide;   2-methyl-5-[(4-methylhexanoyl)amino]-N-(2-methyl-1,3-thiazol-5-yl)benzamide;   4-[(2,4-difluorophenyl)amino]-7-ethoxy-6-(4-methylpiperazin-1-yl)quinoline-3-carboxamide;   4-[(2,3-dichlorophenyl)amino]-7-ethoxy-6-(4-methylpiperazin-1-yl)quinoline-3-carboxamide;   7-ethoxy-4-[(2-fluoro-5-methylphenyl)amino]-6-(4-isopropylpiperazin-1-yl)quinoline-3-carboxamide;   4-[(3-chloro-2-fluorophenyl)amino]-7-ethoxy-6-(4-methylpiperazin-1-yl)quinoline-3-carboxamide;   7-ethoxy-4-[(2-fluoro-5-methylphenyl)amino]-6-(4-methylpiperazin-1-yl)quinoline-3-carboxamide;   7-ethoxy-4-[(2-fluoro-4-methylphenyl)amino]-6-(4-methylpiperazin-1-yl)quinoline-3-carboxamide;   4-[(2,4-difluorophenyl)amino]-7-(2-methoxyethoxy)-6-(4-methylpiperazin-1-yl)quinoline-3-carboxamide;   4-[(2-fluoro-4-methylphenyl)amino]-7-(2-methoxyethoxy)-6-(4-methylpiperazin-1-yl)quinoline-3-carboxamide;   4-[(2-fluoro-5-methylphenyl)amino]-7-(2-methoxyethoxy)-6-(4-methylpiperazin-1-yl)quinoline-3-carboxamide;   4-[(2-fluoro-4-methylphenyl)amino]-6-(4-isopropylpiperazin-1-yl)-7-(2-methoxyethoxy)quinoline-3-carboxamide;   7-ethoxy-4-[(2-fluoro-4-methylphenyl)amino]-6-(1-methylpiperidin-4-yl)quinoline-3-carboxamide;   4-[(2,4-difluorophenyl)amino]-7-ethoxy-6-(1-methylpiperidin-4-yl)quinoline-3-carboxamide;   4-[(2,4-difluorophenyl)amino]-7-ethoxy-6-(1-isopropylpiperidin-4-yl)quinoline-3-carboxamide;   7-ethoxy-4-[(2-fluoro-4-methylphenyl)amino]-6-(1-isopropylpiperidin-4-yl)quinoline-3-carboxamide;   4-[(2-fluoro-4-methylphenyl)amino]-7-methoxy-6-(1-methylpiperidin-4-yl)quinoline-3-carboxamide;   4-[(3-chloro-2-fluorophenyl)amino]-7-methoxy-6-(1-methylpiperidin-4-yl)quinoline-3-carboxamide;   4-[(2,4-difluorophenyl)amino]-7-methoxy-6-(1-methylpiperidin-4-yl)quinoline-3-carboxamide;   4-[(2-fluoro-4-methylphenyl)amino]-6-(1-isopropylpiperidin-4-yl)-7-methoxyquinoline-3-carboxamide;   4-[(2,4-difluorophenyl)amino]-6-(1-isopropylpiperidin-4-yl)-7-methoxyquinoline-3-carboxamide; and   4-[(3-chloro-2-fluorophenyl)amino]-6-(1-isopropylpiperidin-4-yl)-7-methoxyquinoline-3-carboxamide;   7-Ethoxy-4-[(2-fluoro-4-methyl-phenyl)amino]-6-(4-methylpiperazin-1-yl)cinnoline-3-carboxamide;   4-(2-Fluoro-4-methylphenylamino)-7-methoxy-6-(4-methylpiperazin-1-yl)cinnoline-3-carboxamide;   4-[(2,4-Difluorophenyl)amino]-7-methoxy-6-(4-methylpiperazin-1-yl)cinnoline-3-carboxamide;   6-[(3R,5S)-3,5-Dimethylpiperazin-1-yl]-4-[(2-fluoro-4-methylphenyl)amino]-7-methoxycinnoline-3-carboxamide;   4-[(2-Fluoro-4-methylphenyl)amino]-6-[4-(2-hydroxyethyl)piperazin-1-yl]-7-methoxycinnoline-3-carboxamide;   7-Ethoxy-4-[(2-fluoro-4-methylphenyl)amino]-6-[4-(2-hydroxyethyl)piperazin-1-yl]cinnoline-3-carboxamide;   4-[(3-Chloro-2-fluorophenyl)amino]-6-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-7-methoxycinnoline-3-carboxamide;   4-[(2-Fluoro-4-methylphenyl)amino]-6-(1-isopropylpiperidin-4-yl)-7-methoxycinnoline-3-carboxamide hydrochloride;   4-[(2-Fluoro-4-methylphenyl)amino]-6-[1-(2-hydroxyethyl)piperidin-4-yl]-7-methoxycinnoline-3-carboxamide; and   4-[(2-Fluoro-4-methylphenyl)amino]-6-{4-[(2R)-2-hydroxypropanoyl]piperazin-1-yl}-7-methoxycinnoline-3-carboxamide;   or a pharmaceutically acceptable salt thereof.   
     
     
         71 . A pharmaceutical composition comprising a combination according to any one of  claims 62  to  70 , in association with a pharmaceutically-acceptable excipient or carrier. 
     
     
         72 . A pharmaceutical composition according to  claim 71 , for use in the treatment of disease-related angiogenesis or inflammation. 
     
     
         73 . A pharmaceutical composition according to  claim 71 , for use in the treatment of cancer. 
     
     
         74 . A method of treating disease-related angiogenesis or inflammation in an animal in need thereof with a combination according to any one of  claims 62 - 73 . 
     
     
         75 . A method of treating cancer in an animal in need thereof with a combination according to any one of  claims 62 - 73 . 
     
     
         76 . A composition comprising an antagonist of the biological activity of Angiopoietin-2, and/or Tie-2; and a chemotherapeutic agent. 
     
     
         77 . The composition according to  claim 76 , wherein the antagonist of Angiopoietin-2 is an antibody. 
     
     
         78 . The composition according to  claim 77 , wherein the antagonist of Angiopoietin-2 is a fully human monoclonal antibody. 
     
     
         79 . The composition according to any one of  claim 77  or  78 , wherein the antibody binds to the same epitope as an antibody selected from the group consisting of 3.31.2, 5.16.3, 5.86.1, 5.88.3, 3.3.2, 5.103.1, 5.101.1, 3.19.3, 5.28.1, 5.78.3, MEDI1/5, MEDI2/5, MEDI3/5, MEDI6/5, and MEDI4/5. 
     
     
         80 . The composition according to  claim 78 , wherein the antibody is a fully human monoclonal antibody selected from the group consisting of 3.31.2, 5.16.3, 5.86.1, 5.88.3, 3.3.2, 5.103.1, 5.101.1, 3.19.3, 5.28.1, 5.78.3, MEDI1/5, MEDI2/5, MEDI3/5, MEDI6/5, and MEDI4/5. 
     
     
         81 . The composition according to any of  claims 76 - 80 , wherein the chemotherapeutic agent is selected from the group consisting of docetaxel, AZD4877, vincristine, vinblastine, vindesine and vinorelbine, taxol, taxotere, 5-fluorouracil, gemcitabine, fluoropyrimidines tegafur, raltitrexed, capecitabine, methotrexate, pemetrexed, cytosine arabinoside, hydroxyurea; irinotecan, etoposide topotecan, camptothecin teniposide, amsacrine, oxaliplatin, cisplatin oxaliplatin, 5-fluorouracil, irinotecan, gemcitabine and carboplatin. 
     
     
         82 . The composition according to any of  claims 76  to  81  in association with a pharmaceutically acceptable excipient or carrier. 
     
     
         83 . A method of antagonizing the biological activity of Angiopoietin-2, and/or Tie-2 comprising administering the composition according to any of  claims 76  to  82 . 
     
     
         84 . A method of producing an anti-cancer effect in a patient comprising administering a therapeutically effective amount of a composition of any one of  claims 76  to  82 . 
     
     
         85 . A method of reducing tumor growth in an animal comprising administering a therapeutically effective amount of a composition of any one of  claims 76  to  82 .