Human CTLA-4 antibodies and their uses

1. A method for increasing an immune response to an antigen in a subject, the method comprising administering to the subject an anti-CTLA-4 antibody or antigen-binding portion thereof, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region that comprises CDR1, CDR2, and CDR3 domains; and a light chain variable region that comprises CDR1, CDR2, and CDR3 domains, wherein the heavy chain variable region and light chain variable region CDR3 domains are selected from the group consisting of:

(a) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:37; and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:35; and

(b) a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:38; and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO:36; and

binds to human CTLA-4 with a binding affinity of about 10 8 M −1 or greater.

2. The method of claim 1 , wherein the antibody or antigen-binding portion thereof comprises:

(a) a heavy chain variable region comprising CDR3 and CDR2 sequences set forth in SEQ ID NOs:37 and 32, respectively; and a light chain variable region comprising CDR3 and CDR2 sequences set forth in SEQ ID NOs:35 and 29, respectively;

(b) a heavy chain variable region comprising CDR3 and CDR2 sequences set forth in SEQ ID NOs: 37 and 33, respectively; and a light chain variable region comprising CDR3 and CDR2 sequences set forth in SEQ ID NOs: 35 and 30, respectively; or

(c) a heavy chain variable region comprising CDR3 and CDR2 sequences set forth in SEQ ID NOs:38 and 34, respectively; and a light chain variable region comprising CDR3 and CDR2 sequences set forth in SEQ ID NOs:36 and 31, respectively.

3. The method of claim 2 , wherein the antibody or antigen-binding portion thereof comprises:

(a) a heavy chain variable region comprising CDR3, CDR2 and CDR1 sequences set forth in SEQ ID NOs:37, 32 and 27, respectively; and a light chain variable region comprising CDR3, CDR2 and CDR1 sequences set forth in SEQ ID NOs:35, 29 and 24, respectively;

(b) a heavy chain variable region comprising CDR3, CDR2 and CDR1 sequences set forth in SEQ ID NOs:37, 33 and 27, respectively; and a light chain variable region comprising CDR3, CDR2 and CDR1 sequences set forth in SEQ ID NOs:35, 30 and 25, respectively; or

(c) a heavy chain variable region comprising CDR3, CDR2 and CDR1 comprising sequences set forth in SEQ ID NOs:38, 34 and 28, respectively; and a light chain variable region comprising CDR3, CDR2 and CDR1 sequences set forth in SEQ ID NOs:36, 31 and 26, respectively.

4. The method of claim 1 , wherein the antibody or antigen-binding portion thereof comprises: (a) a heavy chain variable region derived from a human V H 3-30.3 gene; and (b) a light chain variable region derived from a human V K A-27 gene.

5. The method of claim 1 , wherein the antibody or antigen-binding portion thereof comprises: (a) a heavy chain variable region derived from a human V H 3-33 gene; and (b) a light chain variable region derived from a human V K L-15 gene.

6. The method of claim 4 , wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region CDR3 sequence set forth in SEQ ID NO: 37, and a light chain variable region CDR3 sequence set forth in SEQ ID NO: 35.

7. The method of claim 5 , wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region CDR3 sequence set forth in SEQ ID NO: 38, and a light chain variable region CDR3 sequence set forth in SEQ ID NO: 36.

8. The method of claim 1 , wherein the antibody or antigen-binding portion thereof comprises at least one heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 17, 19 and 23.

9. The method of claim 1 , wherein the antibody or antigen-binding portion thereof comprises at least one light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 7, 9 and 13.

10. The method of claim 1 , wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 7.

11. The method of claim 1 , wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 19 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 9.

12. The method of claim 1 , wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 23 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13.

13. The method of claim 1 , wherein the antibody or antigen-binding portion thereof comprises: (a) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 27, 32 and 37, respectively; and (b) a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 24, 29 and 35, respectively.

14. The method of claim 1 , wherein the antibody or antigen-binding portion thereof comprises: (a) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 27, 33 and 37, respectively; and (b) a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 25, 30 and 35, respectively.

15. The method of claim 1 , wherein the antibody or antigen-binding portion thereof comprises: (a) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 28, 34 and 38, respectively; and (b) a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 26, 31 and 36, respectively.

16. A method for increasing an immune response to an antigen in a subject, the method comprising administering to the subject an antibody or antigen-binding portion thereof, wherein the antibody or antigen-binding portion thereof competes for binding to a human CTLA-4 polypeptide with a reference antibody comprising the amino acid sequence set forth in SEQ ID NO: 17, and the amino acid sequence set forth in SEQ ID NO: 7; and has a binding affinity of about 10 8 M −1 or greater.

17. A method for increasing an immune response to an antigen in a subject, the method comprising administering to the subject an anti-CTLA-4 antibody or antigen-binding portion thereof, comprising: (a) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 27, 32 and 37, respectively; and (b) a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 24, 29 and 35, respectively.

18. A method for increasing an immune response to an antigen in a subject, the method comprising administering to the subject an anti-CTLA-4 antibody or antigen-binding portion thereof, comprising: (a) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 27, 33 and 37, respectively; and (b) a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 25, 30 and 35, respectively.

19. A method for increasing an immune response to an antigen in a subject, the method comprising administering to the subject an anti-CTLA-4 antibody or antigen-binding portion thereof, comprising: (a) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 28, 34 and 38, respectively; and (b) a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOS: 26, 31 and 36, respectively.

20. A method for increasing an immune response to an antigen in a subject, the method comprising administering to the subject an anti-CTLA-4 antibody or antigen-binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 7.

21. A method for increasing an immune response to an antigen in a subject, the method comprising administering to the subject an anti-CTLA-4 antibody or antigen-binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 19 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 9.

22. A method for increasing an immune response to an antigen in a subject, the method comprising administering to the subject an anti-CTLA-4 antibody or antigen-binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 23 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13.

23. The method of any one of claims 1 and 16 - 22 , wherein the antibody is a human antibody.

24. The method of any one of claims 1 and 16 - 22 , wherein the antibody is a monoclonal antibody.

25. The method of any one of claims 1 and 16 - 22 , wherein the antibody or antigen-binding portion thereof inhibits binding of human CTLA-4 to B7-1 or B7-2.

26. The method of any one of claims 1 and 16 - 22 , wherein the antigen is a tumor antigen.

27. The method of claim 26 , wherein the tumor antigen is selected from the group consisting of a prostate tumor antigen, a melanoma tumor antigen, an epithelial tumor antigen, and a combination thereof.

28. The method of any one of claims 1 and 16 - 22 , further comprising administering an antigen, or a fragment or an analog thereof, to the subject, wherein administration of the antigen in combination with the antibody, or antigen-binding portion thereof, increases the immune response to the antigen.

29. The method of claim 28 , wherein the antigen is a tumor antigen.