Novel anti- alpha5 beta1 antibodies and uses thereof

Abstract

The present invention provides new anti-α5β1 antibodies, compositions and kits comprising the antibodies, and methods of making and using the antibodies.

We claim: 
     
         1 . An anti-β5β1 antibody comprising 
       
         
           
                 
               
                   (SEQ ID NO: 15) 
                 
                   a VL domain comprising a CDR-L1 comprising TL-S/ 
                 
                     
                 
                   T-S/P/T-Q/N-H-F/S-T/I-Y-K/T-I-G/D/S; 
                 
                     
                 
                   (SEQ ID NO: 16) 
                 
                   a CDR-L2 comprising L/I-N/T-S-D/H/S-G/S-S/L/T-H/ 
                 
                     
                 
                   Y-N/K/Q/I-K/T-G/A-D/S/V; 
                 
                     
                 
                   (SEQ ID NO: 17) 
                 
                   a CDR-L3 comprising G/A-S/A/Y-S/Y-Y-S/A/Y-S/Y/T- 
                 
                     
                 
                   GY-V/I; 
                 
                   and 
                 
                     
                 
                   (SEQ ID NO: 18) 
                 
                   a VH domain comprising a CDR-H1 comprising GFTFS- 
                 
                     
                 
                   N/A-RW-I/V-Y; 
                 
                     
                 
                   (SEQ ID NO: 19) 
                 
                   a CDR-H2 comprising GIKTKP-N/A/T-I/R-YAT-E/Q- 
                 
                     
                 
                   YADSVKG; 
                 
                   and 
                 
                     
                 
                   (SEQ ID NO: 20) 
                 
                   a CDR-H3 comprising L/V-TG-M/K-R/K-YFDY. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         2 . The antibody of  claim 1 , wherein
 the VL domain comprises a CDR-L1, CDR-L2, and CDR-L3, each comprising a sequence set forth in  FIG. 3  and   the VH domain comprises a CDR-H1, CDR-H2, and CDR-H3, each comprising a sequence set forth in  FIG. 3 .   
     
     
         3 . The anti-α 5 β 1  antibody of  claim 1 , wherein
 the VL domain comprises any one of SEQ ID NOS:3-8 and 
 the VH domain comprises any one of SEQ ID NOS: 11-14. 
 
     
     
         4 . The antibody of  claim 1 , wherein
 the VL domain comprises SEQ ID NO:8 and   the VH domain comprises SEQ ID NO:14.   
     
     
         5 . The antibody of  claim 1 , which is a human, humanized, chimeric, bispecifc or multispecific antibody. 
     
     
         6 . The antibody of  claim 1 , which is an antibody fragment that binds α5β1. 
     
     
         7 . The antibody of  claim 1 , which is a full length IgG1 antibody. 
     
     
         8 . The antibody according to  claim 7 , wherein the antibody comprises an Fc portion comprising a N297A substitution. 
     
     
         9 . An isolated nucleic acid molecule encoding the antibody of  claim 1 . 
     
     
         10 . A host cell comprising the nucleic acid of  claim 9 . 
     
     
         11 . A method of producing an anti-β5β1 antibody comprising culturing the host cell of  claim 10  so that the antibody is produced. 
     
     
         12 . An immunoconjugate comprising the antibody of any one of  claim 1  and a cytotoxic agent. 
     
     
         13 . A pharmaceutical composition comprising the antibody of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         14 . The pharmaceutical composition of  claim 13 , further comprising a VEGF antagonist. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the VEGF antagonist is an anti-VEGF antibody. 
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein the anti-VEGF antibody is bevacizumab. 
     
     
         17 . The antibody of  claim 1  further comprising a detectable label. 
     
     
         18 . The antibody of  claim 17 , wherein the detectable label is a member selected from the group consisting of: a radioisotope, a fluorescent dye, and an enzyme. 
     
     
         19 . The antibody of  claim 1  for use as a medicament. 
     
     
         20 . The antibody of  claim 1  any one for use in treating a disease or disorder involving abnormal angiogenesis and/or vascular permeability or leakage. 
     
     
         21 . The antibody of  claim 20 , wherein the disease is a member selected from the group consisting of: cancer, ocular disease, autoimmune disease. 
     
     
         22 . The antibody of  claim 1  any one for use in inhibiting angiogenesis. 
     
     
         23 . A method of detecting α5β1 protein in a sample suspected of containing the α5β1 protein, the method comprising
 (a) contacting the antibody of  claim 17  with the sample; and 
 (b) detecting formation of a complex between the anti-β5β1 antibody and the α5β1 protein. 
 
     
     
         24 . The method of  claim 23 , wherein the sample is from a patient diagnosed with a disease involving abnormal angiogenesis, abnormal vascular permeability, and/or vascular leakage. 
     
     
         25 . A method for treating an individual having a disease or disorder involving abnormal angiogenesis and/or vascular permeability or leakage, the method comprising administering to the individual an effective amount of an antibody of  claim 1 . 
     
     
         26 . The method of  claim 25 , wherein the disease or disorder is a member selected from the group consisting of: cancer, an ocular disease, and an autoimmune disease. 
     
     
         27 . The method of  claim 26 , wherein the cancer is a selected from the group consisting of colorectal cancer, lung cancer, breast cancer, renal cell cancer, and glioblastoma. 
     
     
         28 . The method of  claim 25 , wherein the disease or disorder is a member selected from the group consisting of retinopathy, age-related macular degeneration, corneal neovascularization, corneal graft neovascularization, retinal neovascularization, and neovascular glaucoma. 
     
     
         29 . The method of  claim 25 , further comprising administering an effective amount of a VEGF antagonist to the individual. 
     
     
         30 . The method of  claim 29 , wherein the VEGF antagonist is an anti-VEGF antibody. 
     
     
         31 . The method of  claim 30 , wherein the anti-VEGF antibody is bevacizumab. 
     
     
         32 . The method of  claim 29 , wherein the VEGF antagonist is administered prior to the anti-β5β1 antibody. 
     
     
         33 . The method of  claim 29 , wherein the VEGF antagonist and the anti-α5β1 antibody are administered simultaneously. 
     
     
         34 . The method of  claim 29 , where the subject is first treated with the VEGF antagonist until the subject is unresponsive to VEGF antagonist treatment and then the subject is treated with the anti-β5β1 antibody. 
     
     
         35 . The method of  claim 29 , further comprising administering a therapeutic agent selected from the group consisting of an anti-neoplastic agent, a chemotherapeutic agent, a growth inhibitory agent and a cytotoxic agent. 
     
     
         36 . A kit for detecting α5β1 in a subject who has been treated with a VEGF antagonist, said kit comprising
 (a) an anti-β5β1 antibody of  claim 1 ; and 
 (b) instructions for use.