Anti-vista antibodies and fragments
The present invention relates to novel antibodies and fragments that bind to a V-domain Ig Suppressor of T cell Activation (VISTA), and methods of making and using same. Methods of use include methods of treatment of cancer, including leukemias, lymphomas, solid tumors and melanomas.
1. An isolated antibody or antibody fragment thereof comprising an antigen binding region that binds to a V-domain Ig Suppressor of T cell Activation (VISTA), wherein binding of the antibody or antibody fragment to VISTA modulates or enhances an immune response and which antibody:
(i) comprises a VH domain comprising a VH CDR1 having the amino acid sequence of SEQ ID NO: 19, a VH CDR2 having the amino acid sequence of SEQ ID NO:20 and a VH CDR3 having the amino acid sequence of SEQ ID NO:21, and further comprises a VL domain comprising a VL CDR1 having the amino acid sequence of SEQ ID NO:22, a VL CDR2 having the amino acid sequence of SEQ ID NO: 23 and a VL CDR3 having the amino acid sequence of SEQ ID NO:24; or
(ii) comprises a VH domain comprising a VH CDR1 having the amino acid sequence of SEQ ID NO: 25, a VH CDR2 having the amino acid sequence of SEQ ID NO:26 and a VH CDR3 having the amino acid sequence of SEQ ID NO:27, and which further comprises a VL domain comprising a VL CDR1 having the amino acid sequence of SEQ ID NO:28, a VL CDR2 having the amino acid sequence of SEQ ID NO: 29 and a VL CDR3 having the amino acid sequence of SEQ ID NO: 30.
2. The isolated antibody of claim 1 , which comprises a VH domain comprising a VH CDR1 having the amino acid sequence of SEQ ID NO: 19, a VH CDR2 having the amino acid sequence of SEQ ID NO:20 and a VH CDR3 having the amino acid sequence of SEQ ID NO:21, and further comprises a VL domain comprising a VL CDR1 having the amino acid sequence of SEQ ID NO:22, a VL CDR2 having the amino acid sequence of SEQ ID NO: 23 and a VL CDR3 having the amino acid sequence of SEQ ID NO:24.
3. The isolated antibody of claim 1 , which a VH domain comprising a VH CDR1 having the amino acid sequence of SEQ ID NO: 25, a VH CDR2 having the amino acid sequence of SEQ ID NO:26 and a VH CDR3 having the amino acid sequence of SEQ ID NO:27, and which further comprises a VL domain comprising a VL CDR1 having the amino acid sequence of SEQ ID NO:28, a VL CDR2 having the amino acid sequence of SEQ ID NO: 29 and a VL CDR3 having the amino acid sequence of SEQ ID NO: 30.
4. The isolated antibody of claim 2 , which comprises a variable heavy chain polypeptide having a sequence at least 90% identical to SEQ ID NO:40.
5. The isolated antibody of claim 2 , which comprises a variable heavy chain polypeptide having a sequence identical to SEQ ID NO:40.
6. The isolated antibody of claim 2 , which comprises a variable light chain polypeptide having a sequence at least 90% identical to SEQ ID NO:43.
7. The isolated antibody of claim 2 , which comprises a variable light chain polypeptide having a sequence identical to SEQ ID NO:43.
8. The isolated antibody of claim 2 , which comprises a variable light chain polypeptide having the sequence of SEQ ID NO:43 and a variable heavy chain polypeptide having the sequence of SEQ ID NO:40.
9. The isolated antibody of claim 3 , which comprises a variable heavy chain polypeptide having a sequence at least 90% identical to SEQ ID NO:37.
10. The isolated antibody of claim 3 , which comprises a variable heavy chain polypeptide having the sequence of SEQ ID NO:37.
11. The isolated antibody of claim 3 , which comprises a variable light chain polypeptide at least 90% identical to SEQ ID NO:44.
12. The isolated antibody of claim 3 , which comprises a variable light chain polypeptide identical to SEQ ID NO:44.
13. The isolated antibody of claim 3 , which comprises a variable light chain polypeptide having the sequence of SEQ ID NO:44 and a variable heavy chain polypeptide having the sequence of SEQ ID NO:37.
14. The isolated antibody of claim 1 , which comprises a human constant domain.
15. The isolated antibody of claim 1 , which comprises a human IgG1 constant domain.
16. The isolated antibody of claim 1 which comprises a human constant domain which comprises a mutation which impairs FcR binding or protease cleavage.
17. The isolated antibody of claim 1 , which comprises a human IgG1 constant domain which comprises a mutation which impairs FcR binding or protease cleavage.
18. The isolated antibody of claim 1 , which comprises a human IgG1 heavy constant domain having the sequence of SEQ ID NO:60 or SEQ ID NO:61.
19. The isolated antibody of claim 1 which comprises a human IgG1 light constant domain having the sequence of SEQ ID NO:56.
20. The isolated antibody of claim 1 , which comprises a human IgG1 heavy constant domain which comprises SEQ ID NO:60 or SEQ ID NO:61 and further comprises a human IgG1 light constant domain which comprises SEQ ID NO:56.
21. The isolated antibody of claim 2 , which comprises a heavy chain polypeptide having a sequence at least 90% identical to SEQ ID NO: 53 and a light chain polypeptide at least 90% identical to SEQ ID NO: 54.
22. The isolated antibody of claim 2 , which comprises a heavy chain polypeptide having a sequence identical to SEQ ID NO: 53 and a light chain polypeptide having a sequence at least 90% identical to SEQ ID NO: 54.
23. The isolated antibody of claim 3 , which comprises a heavy chain polypeptide having a sequence at least 90% identical to SEQ ID NO: 55 and a light chain polypeptide having a sequence at least 90% identical to SEQ ID NO: 56.
24. The isolated antibody of claim 3 , which comprises a heavy chain polypeptide having a sequence identical to SEQ ID NO: 55 and a light chain polypeptide having a sequence identical to SEQ ID NO: 56.
25. The antibody or antibody fragment of claim 1 , wherein the antibody fragment is a Fab, F(ab′)2, or scFv antibody fragment.
26. The antibody or antibody fragment of claim 1 , wherein the antibody is a monoclonal antibody.
27. The antibody or antibody fragment of claim 1 which is a human or humanized antibody.
28. The antibody or antibody fragment claim 1 , wherein the antibody or fragment binds to human VISTA with an affinity of at least 1×10 −9 liter/mole.
29. The antibody or antibody fragment of claim 1 , wherein the antibody binds to human VISTA with an affinity of at least 1×10 −8 liter/mole.
30. The antibody or antibody fragment of claim 1 , wherein the antibody binds to human VISTA with an affinity of at least 1×10 −7 liter/mole.
31. A composition comprising the antibody or antibody fragment of claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.
32. A composition comprising the antibody or antibody fragment of claim 4 and a pharmaceutically acceptable carrier, diluent, or excipient.
33. A composition comprising the antibody or antibody fragment of claim 5 and a pharmaceutically acceptable carrier, diluent, or excipient.
34. A composition comprising the antibody or antibody fragment of claim 6 and a pharmaceutically acceptable carrier, diluent, or excipient.
35. A composition comprising the antibody or antibody fragment of claim 7 and a pharmaceutically acceptable carrier, diluent, or excipient.
36. A composition comprising the antibody or antibody fragment of claim 8 and a pharmaceutically acceptable carrier, diluent, or excipient.
37. A composition comprising the antibody or antibody fragment of claim 9 and a pharmaceutically acceptable carrier, diluent, or excipient.
38. A composition comprising the antibody or antibody fragment of claim 10 and a pharmaceutically acceptable carrier, diluent, or excipient.
39. A composition comprising the antibody or antibody fragment of claim 11 and a pharmaceutically acceptable carrier, diluent, or excipient.
40. A composition comprising the antibody or antibody fragment of claim 12 and a pharmaceutically acceptable carrier, diluent, or excipient.
41. A composition comprising the antibody or antibody fragment of claim 13 and a pharmaceutically acceptable carrier, diluent, or excipient.
42. A composition comprising the antibody or antibody fragment of claim 22 and a pharmaceutically acceptable carrier, diluent, or excipient.
43. A composition comprising the antibody or antibody fragment of claim 24 and a pharmaceutically acceptable carrier, diluent, or excipient.
44. The composition of claim 31 which further comprises a tumor or viral antigen.