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