Anti-CTLA-4 antibodies and methods of use thereof
The instant disclosure provides antibodies that specifically bind to CTLA-4 (e.g., human CTLA-4) and antagonize CTLA-4 function. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.
1. An isolated antibody that specifically binds to human CTLA-4 protein, comprising: a heavy chain variable region comprising the CDRH1, CDRH2 and CDRH3 amino acid sequences of SEQ ID NOs: 10, 12, and 14, respectively; and a light chain variable region comprising the CDRL1, CDRL2 and CDRL3 amino acid sequences of SEQ ID NOs: 15, 16, and 17, respectively.
2. The isolated antibody of claim 1 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 8.
3. The isolated antibody of claim 1 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 9.
4. The isolated antibody of claim 1 , wherein the antibody comprises a human IgG 1 heavy chain constant region comprising S239D/A330L/I332E mutations, numbered according to the EU numbering system.
5. The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 30.
6. The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 25.
7. The isolated antibody of claim 1 , wherein the antibody comprises a light chain constant region comprising the amino acid sequence of SEQ ID NO: 32.
8. The isolated antibody of claim 1 , wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 27.
9. An isolated antibody that specifically binds to human CTLA-4 protein, comprising: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 9.
10. The isolated antibody of claim 9 , wherein the antibody comprises a human IgG 1 heavy chain constant region comprising S239D/A330L/I332E mutations, numbered according to the EU numbering system.
11. The isolated antibody of claim 9 , wherein the antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 30.
12. The isolated antibody of claim 9 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 25.
13. The isolated antibody of claim 9 , wherein the antibody comprises a light chain constant region comprising the amino acid sequence of SEQ ID NO: 32.
14. The isolated antibody of claim 9 , wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 27.
15. An isolated antibody that specifically binds to human CTLA-4 protein, comprising: a heavy chain comprising the amino acid sequence of SEQ ID NO: 25; and a light chain comprising the amino acid sequence of SEQ ID NO: 27.
16. The isolated antibody of claim 15 , wherein the amino acid sequence of the heavy chain consists of the amino acid sequence of SEQ ID NO: 25.
17. The isolated antibody of claim 15 , wherein the amino acid sequence of the light chain consists of the amino acid sequence of SEQ ID NO: 27.
18. The isolated antibody of claim 15 , wherein the amino acid sequence of the heavy chain consists of the amino acid sequence of SEQ ID NO: 25, and the amino acid sequence of the light chain consists of the amino acid sequence of SEQ ID NO: 27.
19. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier or excipient.
20. A pharmaceutical composition comprising the antibody of claim 4 and a pharmaceutically acceptable carrier or excipient.
21. A pharmaceutical composition comprising the antibody of claim 9 and a pharmaceutically acceptable carrier or excipient.
22. A pharmaceutical composition comprising the antibody of claim 10 and a pharmaceutically acceptable carrier or excipient.
23. A pharmaceutical composition comprising the antibody of claim 15 and a pharmaceutically acceptable carrier or excipient.
24. A pharmaceutical composition comprising the antibody of claim 16 and a pharmaceutically acceptable carrier or excipient.
25. A pharmaceutical composition comprising the antibody of claim 17 and a pharmaceutically acceptable carrier or excipient.
26. A pharmaceutical composition comprising the antibody of claim 18 and a pharmaceutically acceptable carrier or excipient.