Anti-Alpha(v)Beta(6) Antibodies and Uses Thereof

Abstract

The present invention is in the fields of cell biology, immunology and oncology. The invention provides humanized antibodies that recognize α v β 6 integrins, which antibodies comprise a variable region of nonhuman origin and at least a portion of an immunoglobulin of human origin. The invention also provides methods for preparation of such antibodies, pharmaceutical compositions comprising them, and methods of treating, diagnosing and/or preventing various diseases and disorders by administering the humanized anti-α v β 6 antibodies of the invention. The invention also relates to the identification of differential expression of the integrin α v β 6 on the surfaces of tumor cells and tissues, the use of this differential expression in determining the metastatic potential of tumor cells, and methods of diagnosis and treatment/prevention of tumor metastasis and for elimination of residual metastatic tumor cells using ligands, particularly antibodies, that bind to integrin α v β 6 .

1 .- 244 . (canceled) 
     
     
         245 . An antibody or antigen-binding fragment thereof that specifically binds to α v β 6 , comprising:
 (i) a heavy chain variable domain comprising heavy chain complementarity determining regions (CDRs) 1, 2, and 3 defined by RYVMS (amino acid residues 31-35 of SEQ ID NO:1), SISSGGRMYYPDTVKG (amino acid residues 50-65 of SEQ ID NO:1), and GSIYDGYYVFPY (amino acid residues 98-109 of SEQ ID NO:1), respectively; and 
 (ii) a light chain variable domain comprising light chain CDRs 1, 2, and 3 defined by SASSSVSSSYLY (amino acid residues 24-35 of SEQ ID NO:2), STSNLAS (amino acid residues 51-57 of SEQ ID NO:2), and HQWSTYPPT (amino acid residues of 90-98 SEQ ID NO:2), respectively. 
 
     
     
         246 . The antibody or antigen-binding fragment thereof of  claim 245 , wherein the heavy chain variable domain comprises framework regions 1, 2, 3, and 4 defined by amino acid residues 1-30, 36-49, 66-97, and 110-120, respectively, of SEQ ID NO:1. 
     
     
         247 . The antibody or antigen-binding fragment thereof of  claim 245 , wherein the light chain variable domain comprises framework regions 1, 2, 3, and 4 defined by amino acid residues 1-23, 36-50, 58-89, and 99-108, respectively, of SEQ ID NO:2. 
     
     
         248 . The antibody or antigen-binding fragment thereof of  claim 245 , wherein the antibody or antigen-binding fragment thereof is conjugated to a cytotoxic agent. 
     
     
         249 . The antibody or antigen-binding fragment thereof of  claim 246 , wherein the antibody or antigen-binding fragment thereof is conjugated to a cytotoxic agent. 
     
     
         250 . The antibody or antigen-binding fragment thereof of  claim 247 , wherein the antibody or antigen-binding fragment thereof is conjugated to a cytotoxic agent. 
     
     
         251 . A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of  claim 245 , and a pharmaceutically acceptable carrier. 
     
     
         252 . A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of  claim 246 , and a pharmaceutically acceptable carrier. 
     
     
         253 . A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of  claim 247 , and a pharmaceutically acceptable carrier. 
     
     
         254 . A method of treating a human subject having fibrosis, the method comprising administering to the human subject a therapeutically effective amount of the antibody or antigen-binding fragment thereof of  claim 245 . 
     
     
         255 . The method of  claim 254 , wherein the fibrosis is scleroderma. 
     
     
         256 . The method of  claim 254 , wherein the fibrosis is scarring. 
     
     
         257 . The method of  claim 254 , wherein the fibrosis is liver fibrosis. 
     
     
         258 . The method of  claim 254 , wherein the fibrosis is kidney fibrosis. 
     
     
         259 . The method of  claim 254 , wherein the fibrosis is lung fibrosis. 
     
     
         260 . The method of  claim 259 , wherein the lung fibrosis is idiopathic pulmonary fibrosis. 
     
     
         261 . The method of  claim 254 , wherein the fibrosis is bleomycin-induced fibrosis, asbestos-induced fibrosis, gut fibrosis, radiation-induced fibrosis, biliary duct injury-induced fibrosis, head and neck fibrosis, burn-induced fibrosis, surgical fibrosis, or spinal cord fibrosis. 
     
     
         262 . A method of treating a human subject having Alport's syndrome, the method comprising administering to the human subject a therapeutically effective amount of the antibody or antigen-binding fragment thereof of  claim 245 . 
     
     
         263 . A method of treating a human subject having acute lung injury, the method comprising administering to the human subject a therapeutically effective amount of the antibody or antigen-binding fragment thereof of  claim 245 . 
     
     
         264 . A method of treating a human subject having acute kidney injury, the method comprising administering to the human subject a therapeutically effective amount of the antibody or antigen-binding fragment thereof of  claim 245   
     
     
         265 . A nucleic acid molecule comprising a coding sequence for any one of SEQ ID NOs: 1-5.