Combinatorial therapy

Abstract

The present invention relates to the use of VEGF antagonists and alpha5beta1 antagonists for treating cancer and inhibiting angiogenesis and/or vascular permeability, including inhibiting abnormal angiogenesis in diseases. The present invention also relates to use of a VEGFR agonists and alpha5beta1 agonists to promote angiogenesis and vascular permeability. The present invention also relates to new anti-alpha5beta1 antibodies, compositions and kits comprising them and methods of making and using them.

1 - 60 . (canceled) 
     
     
         61 . A method of inhibiting angiogenesis and/or vascular permeability in a subject comprising administering an antibody to the subject, wherein the antibody can bind human alpha5beta1 and competitively inhibit the binding of an anti-alpha5beta1 antibody produced by a hybridoma to human alpha5beta1, wherein the hybridoma is selected from the group consisting of the hybridoma deposited as Alpha5/beta1 7H5.4.2.8 (ATCC No. PTA-7421) and the hybridoma deposited as Alpha5/beta1 7H12.5.1.4 (ATCC No. PTA-7420) in the ATCC on Mar. 7, 2006. 
     
     
         62 . The method of  claim 61 , wherein the antibody comprises at least one hypervariable region substantially corresponding to a hypervariable region of the anti-alpha5beta1 antibody produced by a hybridoma that is selected from the group consisting of the hybridoma deposited as Alpha5/beta1 7H5.4.2.8 (ATCC No. PTA-7421) and the hybridoma deposited as Alpha5/beta1 7H12.5.1.4 (ATCC No. PTA-7420) in the ATCC on Mar. 7, 2006. 
     
     
         63 . The method of  claim 61 , wherein the antibody comprises a variable domain comprising CDRs substantially corresponding to the CDRs of the anti-alpha5beta1 antibody produced by a hybridoma that is selected from the group consisting of the hybridoma deposited as Alpha5/beta1 7H5.4.2.8 (ATCC No. PTA-7421) and the hybridoma deposited as Alpha5/beta1 7H12.5.1.4 (ATCC No. PTA-7420) in the ATCC on Mar. 7, 2006. 
     
     
         64 . The method of  claim 61 , wherein the antibody comprises a heavy chain variable domain comprising the three CDRs and a light chain variable domain comprising the three CDRs, wherein the six CDRs correspond to the CDRs in the anti-alpha5beta1 antibody produced by a hybridoma that is selected from the group consisting of the hybridoma deposited as Alpha5/beta1 7H5.4.2.8 (ATCC No. PTA-7421) and the hybridoma deposited as Alpha5/beta1 7H12.5.1.4 (ATCC No. PTA-7420) in the ATCC on Mar. 7, 2006. 
     
     
         65 . The method of  claim 61 , wherein the antibody comprises a heavy chain variable domain comprising the three hypervariable regions and a light chain variable domain comprising the three hypervariable regions, wherein the six hypervariable regions correspond to the hypervariable regions in the anti-alpha5beta1 antibody produced by a hybridoma that is selected from the group consisting of the hybridoma deposited as Alpha5/beta1 7H5.4.2.8 (ATCC No. PTA-7421) and the hybridoma deposited as Alpha5/beta1 7H12.5.1.4 (ATCC No. PTA-7420) in the ATCC on Mar. 7, 2006. 
     
     
         66 . The method of  claim 61 , wherein the antibody comprises the heavy chain variable domain sequence and the light chain variable domain sequence of the anti-alpha5beta1 antibody produced by the hybridoma deposited as Alpha5/beta1 7H5.4.2.8 (ATCC No. PTA-7421) in the ATCC on Mar. 7, 2006. 
     
     
         67 . The method of  claim 61 , wherein the antibody comprises the heavy chain variable domain sequence and the light chain variable domain sequence of the anti-alpha5beta1 antibody produced by the hybridoma deposited as Alpha5/beta1 7H12.5.1.4 (ATCC No. PTA-7420) in the ATCC on Mar. 7, 2006. 
     
     
         68 . The method of  claim 61 , wherein the antibody is produced by a hybridoma selected from the group consisting of the hybridoma deposited as Alpha5/beta1 7H5.4.2.8 (ATCC No. PTA-7421) and the hyridoma deposited as Alpha5/beta1 7H12.5.1.4 (ATCC No. PTA-7420) in the ATCC on Mar. 7, 2006. 
     
     
         69 . The method of  claim 61 , wherein the antibody is a humanized or chimeric antibody. 
     
     
         70 . The method of  claim 61 , wherein the antibody binds a human alpha5beta1 with a Kd between 500 nM and 1 pM. 
     
     
         71 . The method of  claim 61 , wherein the antibody comprises a Fc sequence of a human IgG. 
     
     
         72 . The method of  claim 71 , wherein the human IgG is IgG1 or IgG4. 
     
     
         73 . The method of  claim 71 , wherein the antibody comprises a Fc sequence that lacks antibody dependent cellular cytotoxicity (ADCC) effector function. 
     
     
         74 . The method of  claim 61 , wherein the antibody is selected from the group consisting of a Fab, Fab′, a F(ab)′ 2 , single-chain Fv (scFv), an Fv fragment, a diabody and a linear antibody. 
     
     
         75 . The method of  claim 61 , wherein the antibody is a multi-specific antibody. 
     
     
         76 . The method of  claim 61 , wherein the antibody is conjugated to a therapeutic agent. 
     
     
         77 . The method of  claim 76 , wherein the therapeutic agent is selected from the group consisting of a cytotoxic agent, a radioisotope and a chemotherapeutic agent. 
     
     
         78 . The method of  claim 61 , wherein the subject has abnormal angiogenesis or vascular permeability. 
     
     
         79 . The method of  claim 61 , wherein the subject has excessive angiogenesis or vascular permeability. 
     
     
         80 . The method of  claim 61 , wherein the subject suffers from a disease that is cancer, ocular disease, or autoimmune disease. 
     
     
         81 . The method of  claim 80 , wherein the subject has elevated alpha5beta1 levels in a diseased tissue compared to a tissue from a subject not suffering from the disease. 
     
     
         82 . The method of  claim 61 , wherein the subject is further administered with a therapeutic agent selected from the group consisting of an anti-neoplastic agent, a chemotherapeutic agent, a growth inhibitory agent, and a cytotoxic agent. 
     
     
         83 . The method of  claim 61 , wherein the subject suffers from a disease, wherein the subject had been responsive to treatment for the disease with a VEGF antagonist but is partially or no longer responsive to the VEGF antagonist.