Human CTLA-4 antibodies and their uses
The present invention provides novel human sequence antibodies against human CTLA-4 and methods of treating human diseases, infections and other conditions using these antibodies.
1. An isolated nucleic acid encoding a heavy chain variable region of an anti-CTLA-4 monoclonal antibody, or antigen-binding portion thereof, comprising CDR1, CDR2, and CDR3 domains, wherein the CDR3 domain comprises amino acids having a sequence selected from the group consisting of: SEQ ID NO: 37 and SEQ ID NO: 38.
2. The isolated nucleic acid of claim 1 , wherein the CDR3 and CDR2 domains are selected from the group consisting of:
(a) a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 37, and a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 32;
(b) a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 37, and a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 33; and
(c) a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 38, and a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 34.
3. The isolated nucleic acid of claim 2 , wherein the CDR3, CDR2, and CDR1 domains are selected from the group consisting of:
(a) a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 37, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 32, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 27;
(b) a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 37, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 33, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 27; and
(c) a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 38, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 34, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 28.
4. An isolated nucleic acid encoding a light chain variable region of an anti-CTLA-4 monoclonal antibody, or antigen-binding portion thereof, comprising CDR1, CDR2, and CDR3 domains, wherein the CDR3 domain comprises amino acids having a sequence selected from the group consisting of: SEQ ID NO: 35 and SEQ ID NO: 36.
5. The isolated nucleic acid of claim 4 , wherein the CDR3 and CDR2 domains are selected from the group consisting of: (a) (a) a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 35, and a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 29;
(b) a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 35, and a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 30; and
(c) a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 36, and a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 31.
6. The isolated nucleic acid of claim 5 , wherein the CDR3, CDR2, and CDR1 domains are selected from the group consisting of:
(a) a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 35, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 29, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 24;
(b) a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 35, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 30, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 25; and
(c) a CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 36, a CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 31, and a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 26.
7. An isolated nucleic acid encoding an anti-CTLA-4 monoclonal antibody, or antigen-binding portion thereof, comprising:
(a) the nucleic acid of claim 3 ;
(b) the nucleic acid of claim 6 ; and
(c) one or more nucleic acids encoding one or more constant domains, operatively linked together.
8. An isolated nucleic acid encoding a heavy chain variable region and a light chain variable region of an anti-CTLA-4 monoclonal antibody, or antigen-binding portion thereof, said variable regions selected from the group consisting of:
a) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 17; and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 7;
b) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 19; and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 9; and
c) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 23; and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 13.
9. The isolated nucleic acid of claim 8 , wherein the heavy chain variable region comprises amino acids having the sequence set forth in SEQ ID NO: 17; and the light chain variable region comprises amino acids having the sequence set forth in SEQ ID NO: 7.
10. The isolated nucleic acid of claim 8 , wherein the heavy chain variable region comprises amino acids having the sequence set forth in SEQ ID NO: 19; and the light chain variable region comprises amino acids having the sequence set forth in SEQ ID NO: 9.
11. The isolated nucleic acid of claim 8 , wherein the heavy chain variable region comprises amino acids having the sequence set forth in SEQ ID NO: 23; and the light chain variable region comprises amino acids having the sequence set forth in SEQ ID NO: 13.
12. An isolated nucleic acid encoding a heavy chain variable region comprising amino acids having a sequence selected from the group consisting of: SEQ ID NO: 17, SEQ ID NO: 19, and SEQ ID NO: 23.
13. An isolated nucleic acid encoding a light chain variable region comprising amino acids having a sequence selected from the group consisting of: SEQ ID NO: 7, SEQ ID NO: 9, and SEQ ID NO: 13.
14. An isolated nucleic acid encoding a heavy chain variable region, said nucleic acid comprising nucleotides having a sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 22.
15. An isolated nucleic acid encoding a light chain variable region, said nucleic acid comprising nucleotides having a sequence selected from the group consisting of: SEQ ID NO: 6, SEQ ID NO: 8, and SEQ ID NO: 12.
16. An isolated nucleic acid molecule encoding a monoclonal antibody, or an antigen-binding portion thereof, comprising:
(a) a heavy chain variable region that comprises amino acids having a sequence derived from a human V H 3-30.3 germline sequence; and a light chain variable region that comprises-amino acids having a sequence derived from a human V K A27 germline sequence; or
(b) a heavy chain variable region that comprises amino acids having a sequence derived from a human V H 3-33 germline sequence; and a light chain variable region that comprises amino acids having a sequence derived from a human V K L15 germline sequence;
wherein the antibody or antigen-binding portion specifically binds to CTLA-4.
17. An expression vector comprising the nucleic acids of claim 1 and claim 4 .
18. A host cell containing the expression vector of claim 17 .
19. A process for producing an anti-CTLA-4 antibody, or antigen-binding portion thereof, comprising culturing a host cell transfected with the expression vector of claim 17 .
20. An expression vector comprising the nucleic acid of claim 1 or claim 4 .
21. A host cell containing the expression vector of claim 20 .
22. A process for producing an anti-CTLA-4 antibody, or antigen-binding portion thereof, comprising culturing a host cell transfected with the expression vector of claim 20 .
23. An expression vector comprising the nucleic acids of claim 3 and claim 6 .
24. A host cell containing the expression vector of claim 23 .
25. A process for producing an anti-CTLA-4 antibody, or antigen-binding portion thereof, comprising culturing a host cell transfected with the expression vector of claim 23 .
26. An expression vector comprising the nucleic acid of claim 3 or claim 6 .
27. A host cell containing the expression vector of claim 26 .
28. A process for producing an anti-CTLA-4 antibody, or antigen-binding portion thereof, comprising culturing a host cell transfected with the expression vector of claim 26 .
29. A host cell containing the nucleic acid of claims 12 and 13 , wherein the nucleic acid encodes amino acids having the sequences set forth in SEQ ID NO:17 and SEQ ID NO:7.
30. A host cell containing the nucleic acid of claims 12 and 13 , wherein the nucleic acid encodes amino acids having the sequences set forth in SEQ ID NO:19 and SEQ ID NO:9.
31. A host cell containing the nucleic acid of claims 12 and 13 , wherein the nucleic acid encodes amino acids having the sequences set forth in SEQ ID NO:23 and SEQ ID NO:13.
32. An isolated nucleic acid encoding a heavy chain of an anti-CTLA-4 monoclonal antibody, or antigen-binding portion thereof, comprising a CDR3 domain comprising amino acids having the sequence set forth in SEQ ID NO:37; a CDR2 domain comprising amino acids having a sequence set forth in SEQ ID NO:32; and a CDR1 domain comprising amino acids having the sequence set forth in SEQ ID NO:27.
33. An isolated nucleic acid encoding a light chain of an anti-CTLA-4 monoclonal antibody, or antigen-binding portion thereof, comprising a CDR3 domain comprising amino acids having the sequence set forth in SEQ ID NO:35; a CDR2 domain comprising amino acids having a sequence set forth in SEQ ID NO:29; and a CDR1 domain comprising amino acids having the sequence set forth in SEQ ID NO:24.
34. An isolated nucleic acid encoding a CTLA-4-binding portion of an immunoglobulin comprising a CDR3 domain comprising amino acids having the sequence set forth in SEQ ID NO:37, a CDR2 domain comprising amino acids having the sequence set forth in SEQ ID NO:32, and a CDR1 domain comprising amino acids having the sequence set forth in SEQ ID NO:27.
35. An isolated nucleic acid encoding a CTLA-4-binding portion of an immunoglobulin comprising a CDR3 domain comprising amino acids having the sequence set forth in SEQ ID NO:35, a CDR2 domain comprising amino acids having the sequence set forth in SEQ ID NO:29, and a CDR1 domain comprising amino acids having the sequence set forth in SEQ ID NO:24.
36. An isolated nucleic acid encoding an anti-CTLA-4 monoclonal antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR1 domain comprising amino acids having the sequence set forth in SEQ ID NO: 27, a CDR2 domain comprising amino acids having the sequence set forth in SEQ ID NO: 32, and a CDR3 domain comprising amino acids having the sequence set forth in SEQ ID NO: 37; and a light chain variable region comprising a CDR1 domain comprising amino acids having the sequence set forth in SEQ ID NO: 24, a CDR2 domain comprising amino acids having the sequence set forth in SEQ ID NO: 29, and a CDR3 domain comprising amino acids having the sequence set forth in SEQ ID NO: 35.
37. An isolated nucleic acid encoding an anti-CTLA-4 monoclonal antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising a CDR1domain comprising amino acids having the sequence set forth in SEQ ID NO: 27, a CDR2 domain comprising amino acids having the sequence set forth in SEQ ID NO: 33, and a CDR3 domain comprising amino acids having the sequence set forth in SEQ ID NO: 37; and a light chain variable region comprising a CDR1 domain comprising amino acids having the sequence set forth in SEQ ID NO: 25, a CDR2 domain comprising amino acids having the sequence set forth in SEQ ID NO: 30, and a CDR3 domain comprising amino acids having the sequence set forth in SEQ ID NO: 35.
38. An isolated nucleic acid encoding an anti-CTLA-4 monoclonal antibody, or antigen-binding portion thereof; comprising a heavy chain variable region comprising a CDR1domain comprising amino acids having the sequence set forth in SEQ ID NO: 28, a CDR2 domain comprising amino acids having the sequence set forth in SEQ ID NO: 34, and a CDR3 domain comprising amino acids having the sequence set forth in SEQ ID NO: 38; and a light chain variable region comprising a CDR1 domain comprising amino acids having the sequence set forth in SEQ ID NO: 26, a CDR2 domain comprising amino acids having the sequence set forth in SEQ ID NO: 31, and a CDR3 domain comprising amino acids having the sequence set forth in SEQ ID NO: 36.