Monoclonal antibodies that specifically bind to M.96. Also included are methods of using these antibodies to treat mammals having or at risk of having 006-mediated diseases, or to diagnose % Qmediated diseases.
1. A monoclonal antibody that is an αvβ6 blocking antibody or antigen binding fragment thereof that (a) specifically binds to αvβ6 and not other αv integrins or non-specific integrins; (b) inhibits the binding of αvβ6 to latency associated peptide (LAP) with an IC50 value lower than that of 10D5 and (c) binds αvβ6 in either cation independent manner or a cation dependent manner that does not distinguish between the use of Ca 2+ /Mg 2+ and Mn 2+ for cation-dependent binding to soluble αvβ6.
2. The antibody of claim 1 , wherein the antibody comprises the same heavy and light chain polypeptide sequences as an antibody produced by hybridoma 6.1A8 (ATCC accession number PTA-3647).
3. An antibody which comprises the same heavy and light chain polypeptide sequences as an antibody produced by hybridoma 6.3G9 (ATCC accession number PTA-3649).
4. The antibody of claim 1 , wherein the antibody comprises the same heavy and light chain polypeptide sequences as an antibody produced by hybridoma 6.8G6 (ATCC accession number PTA-3645).
5. An antibody which comprises the same heavy and light chain polypeptide sequences as an antibody produced by hybridoma 6.2B1 (ATCC accession number PTA-3646).
6. An antibody which comprises the same heavy and light chain polypeptide sequences as an antibody produced by hybridoma 7.1G10 (ATCC accession number PTA-3898).
7. The antibody of claim 1 , wherein the antibody comprises the same heavy and light chain polypeptide sequences as an antibody produced by hybridoma 7.7G5 (ATCC accession number PTA-3899).
8. An antibody which comprises the same heavy and light chain polypeptide sequences as an antibody produced by hybridoma 7.1C5 (ATCC accession number PTA-3900).
9. The antibody of claim 1 , wherein the binding between the antibody and α v β 6 is divalent cation-independent.
10. An anti-α v β 6 antibody whose heavy chain complementarity determining regions (CDR) 1, 2 and 3 comprise the sequences of SEQ ID NOs: 1, 4 and 7, respectively, and whose light chain CDRs 1, 2 and 3 comprise the sequences of SEQ ID NOs:10, 13 and 15, respectively.
11. An anti-α v β 6 antibody whose heavy chain complementarity determining regions (CDR) 1, 2 and 3 comprise the sequences of SEQ ID NOs:3, 5 and 8, respectively, and whose light chain CDRs 1, 2 and 3 comprise the sequences of SEQ ID NOs:11, 14 and 17, respectively.
12. An anti-α v β 6 antibody whose heavy chain complementarity determining regions (CDR) 1, 2 and 3 comprise the sequences of SEQ ID NOs:3, 6 and 9, respectively, and whose light chain CDRs 1, 2 and 3 comprise the sequences of SEQ ID NOs:12, 14 and 18, respectively.
13. An anti-α v β 6 antibody whose heavy chain complementarity determining regions (CDR) 1, 2 and 3 comprise the sequences of SEQ ID NOs:2, 46 and 47, respectively, and whose light chain CDRs 1, 2 and 3 comprise the sequences of SEQ ID NOs:48, 13 and 16, respectively.
14. An anti-α v β 6 antibody whose heavy chain complementarity determining regions (CDR) 1, 2 and 3 comprise the sequences of SEQ ID NOs:49, 51, and 53, respectively, and whose light chain CDRs 1, 2 and 3 comprise the sequences of SEQ ID NOs:55, 57 and 59, respectively.
15. An anti-α v β 6 antibody whose heavy chain complementarity determining regions (CDR) 1, 2 and 3 comprise the sequences of SEQ ID NOs:50, 52, and 54, respectively, and whose light chain CDRs 1, 2 and 3 comprise the sequences of SEQ ID NOs:56, 58 and 60, respectively.
16. An anti-α v β 6 antibody comprising a heavy chain variable domain sequence of any one of SEQ ID NOs:19-36 or SEQ ID NOS: 61-62.
17. An anti-αvβ6 antibody or antigen binding fragment thereof comprising the heavy chain variable domain sequence of SEQ ID NO:19 and the light chain variable domain sequence of SEQ ID NO:37.
18. An anti-αvβ6 antibody or antigen binding fragment thereof comprising the heavy chain variable domain sequence of SEQ ID NO:20 or 21, and the light chain variable domain sequence of SEQ ID NO:38.
19. An anti-αvβ6 antibody or antigen binding fragment thereof comprising the heavy chain variable domain sequence of SEQ ID NO:22 and the light chain variable domain sequence of SEQ ID NO:43.
20. An anti-αvβ6 antibody or antigen binding fragment thereof comprising the heavy chain variable domain sequence of SEQ ID NO:23 and the light chain variable domain sequence of SEQ ID NO:44.
21. An anti-αvβ6 antibody or antigen binding fragment thereof comprising the heavy chain variable domain sequence of SEQ ID NO:24 and the light chain variable domain sequence of SEQ ID NO:45.
22. An anti-αvβ6 antibody or antigen binding fragment thereof comprising the heavy chain variable domain sequence of SEQ ID NO:25 or 26 and the light chain variable domain sequence of SEQ ID NO:42.
23. An anti-αvβ6 antibody or antigen binding fragment thereof comprising the heavy chain variable domain sequence of SEQ ID NO:27, 28, or 29, and the light chain variable domain sequence of SEQ ID NO:39.
24. An anti-αvβ6 antibody or antigen binding fragment thereof comprising the heavy chain variable domain sequence of SEQ ID NO:34 or 35, and the light chain variable domain sequence of SEQ ID NO:40.
25. An anti-αvβ6 antibody or antigen binding fragment thereof comprising the heavy chain variable domain sequence of SEQ ID NO:36, and the light chain variable domain sequence of SEQ ID NO:41.
26. An anti-αvβ6 antibody or antigen binding fragment thereof comprising the heavy chain variable domain sequence of SEQ ID NO:61, and the light chain variable domain sequence of SEQ ID NO:63.
27. An anti-αvβ6 antibody or antigen binding fragment thereof comprising the heavy chain variable domain sequence of SEQ ID NO:62, and the light chain variable domain sequence of SEQ ID NO:64.
28. An anti-αvβ6 antibody or antigen binding fragment thereof which comprises the same heavy and light chain polypeptide sequences as an antibody produced by hybridoma 6.2A1 (ATCC accession number PTA-3896).
29. An anti-αvβ6 antibody or antigen binding fragment thereof which comprises the same heavy and light chain polypeptide sequences as an antibody produced by hybridoma 6.2E5 (ATCC accession number PTA-3897).
30. A composition for treating a disease mediated by αvβ6 in a mammal, comprising the antibody of any one of 1, 3, 9, 12, 16 or 21, and a pharmaceutically acceptable carrier.
31. The composition of claim 30 , wherein the antibody is conjugated to a cytotoxic agent.
32. A cell of hybridoma 6.1A8 (ATCC accession number PTA-3647).
33. A cell of hybridoma 6.2B10 (ATCC accession number PTA-3648).
34. A cell of hybridoma 6.3G9 (ATCC accession number PTA-3649).
35. A cell of hybridoma 6.8G6 (ATCC accession number PTA-3645).
36. A cell of hybridoma 6.2B1 (ATCC accession number PTA-3646).
37. A cell of hybridoma 6.2A1 (ATCC accession number PTA-3896).
38. A cell of hybridoma 6.2E5 (ATCC accession number PTA-3897).
39. A cell of hybridoma 7.1G10 (ATCC accession number PTA-3898).
40. A cell of hybridoma 7.7G5 (ATCC accession number PTA-3899).
41. A cell of hybridoma 7.1 C5 (ATCC accession number PTA-3900).
42. An anti-αvβ6 antibody comprising an amino acid sequence of any one of SEQ ID NOs:19-45 and 61-64.
43. A monoclonal antibody comprising the same heavy and light chain polypeptide sequences as an antibody produced by hybridoma 6.2B10 (ATCC accession number PTA-3648).
44. The monoclonal antibody of claim 1 , wherein the antibody comprises heavy chain complementarity determining regions 1, 2, and 3 and light chain complementarity determining regions 1, 2, and 3 wherein the heavy chain complementarity determining regions (CDR) 1, 2 and 3 comprising the sequences of SEQ ID NOs:3, 6 and 9, respectively and wherein the light chain CDRs comprising the SEQ ID NOs:12, 14 and 18, respectively.
45. The monoclonal antibody of claim 1 , wherein said antibody binds soluble αvβ6 but does not bind the β6 subunit.
46. The monoclonal antibody of claim 1 , wherein said antibody prevents the activation of TGF-β.
47. The monoclonal antibody of claim 9 wherein the antibody comprises heavy chain complementarity determining regions 1, 2, and 3 and light chain complementarity determining regions 1, 2, and 3, wherein said antibody competes with 6.8G6 (ATCC accession number PTA-3645) for binding to αvβ6 and contains an FXY motif in CDR3 of the heavy chain.
48. The monoclonal antibody of claim 1 , wherein said antibody contains a mutation at an amino acid residue that is a site for glycosylation such that the glycosylation site is eliminated.
49. An antibody produced by hybridoma 6.1A8 (ATCC accession number PTA-3647) or an antigen binding fragment of an antibody produced by hybridoma 6.1A8 (ATCC accession number PTA-3647).
50. An antibody produced by hybridoma 6.2B10 (ATCC accession number PTA-3648) or an antigen binding fragment of an antibody produced by hybridoma 6.2B10 (ATCC accession number PTA-3648).
51. An antibody produced by hybridoma 6.3G9 (ATCC accession number PTA-3649) or an antigen binding fragment of an antibody produced by hybridoma 6.3G9 (ATCC accession number PTA-3649).
52. An antibody produced by hybridoma 6.8G6 (ATCC accession number PTA-3645) or an antigen binding fragment of an antibody produced by hybridoma 6.8G6 (ATCC accession number PTA-3645).
53. An antibody produced by hybridoma 6.2B1 (ATCC accession number PTA-3646) or an antigen binding fragment of an antibody produced by hybridoma 6.2B1 (ATCC accession number PTA-3646).
54. An antibody produced by hybridoma 6.2A1 (ATCC accession number PTA-3896) or an antigen binding fragment of an antibody produced by hybridoma 6.2A1 (ATCC accession number PTA-3896).
55. An antibody produced by hybridoma 6.2E5 (ATCC accession number PTA-3897) or an antigen binding fragment of an antibody produced by hybridoma 6.2L5 (ATCC accession number PTA-3897).
56. An antibody produced by hybridoma 7.1G10 (ATCC accession number PTA-3898) or an antigen binding fragment of an antibody produced by hybridoma 7.1G10 (ATCC accession number PTA-3898).
57. An antibody produced by hybridoma 7.7G5 (ATCC accession number PTA-3899) or an antigen binding fragment of an antibody produced by hybridoma 7.7G5 (ATCC accession number PTA-3899).
58. An antibody produced by hybridoma 7.1C5 (ATCC accession number PTA-3900) or an antigen binding fragment of an antibody produced by hybridoma 7.1 C5 (ATCC accession number PTA-3900).