Anti-PD-L1 antibodies
The present disclosure relates to antibodies and antigen-binding fragments thereof that bind to PD-L1, and to methods of using such antibodies and antigen-binding fragments. For example, the present invention provides humanized anti-PD-L1 antibodies and methods of use thereof.
1. An isolated antibody or fragment thereof that binds to PD-L1, wherein the antibody or fragment thereof comprises
(i) a heavy chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NO: 81, 82, and 83, respectively, and a light chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NO: 84, 85, and 86, respectively;
(ii) a heavy chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NO: 93, 94, and 95, respectively, and a light chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NO: 96, 97, and 98, respectively;
(iii) a heavy chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NO: 99, 100, and 101, respectively, and a light chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NO: 102, 103, and 104, respectively;
(iv) a heavy chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NO: 111, 112, and 113, respectively, and a light chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NO: 114, 115, and 116, respectively; or
(v) a heavy chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NO: 123, 124, and 125, respectively, and a light chain CDR1, CDR2, and CDR3 sequence comprising SEQ ID NO: 126, 127, and 128, respectively.
2. The antibody or fragment of claim 1 , wherein the antibody or fragment thereof comprises a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID NOs: 81, 82, and 83, respectively; and a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID NOs: 84, 85, and 86, respectively.
3. The antibody or fragment of claim 1 , wherein the antibody or fragment thereof comprises a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID NOs: 93, 94, and 95, respectively; and a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID NOs: 96, 97, and 98, respectively.
4. The antibody or fragment of claim 1 , wherein the antibody or fragment thereof comprises a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID NOs: 99, 100, and 101, respectively; and a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID NOs: 102, 103, and 104, respectively.
5. The antibody or fragment of claim 1 , wherein the antibody or fragment thereof comprises a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID NOs: 111, 112, and 113, respectively; and a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID NOs: 114, 115, and 116, respectively.
6. The antibody or fragment of claim 1 , wherein the antibody or fragment thereof comprises a heavy chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID NOs: 123, 124, and 125, respectively; and a light chain CDR1, CDR2, and CDR3 comprising an amino acid sequence according to SEQ ID NOs: 126, 127, and 128, respectively.
7. The isolated antibody or fragment thereof of claim 1 , wherein the antibody or fragment thereof is chimeric or humanized.
8. The isolated antibody or fragment thereof of claim 1 , wherein the antibody or fragment thereof comprises:
(i) a heavy chain variable region comprising SEQ ID NO: 2 and a light chain variable region comprising SEQ ID NO: 4;
(ii) a heavy chain variable region comprising SEQ ID NO: 10 and a light chain variable region comprising SEQ ID NO: 12;
(iii) a heavy chain variable region comprising SEQ ID NO: 14 and a light chain variable region comprising SEQ ID NO: 16;
(iv) a heavy chain variable region comprising SEQ ID NO: 22 and a light chain variable region comprising SEQ ID NO: 24;
(v) a heavy chain variable region comprising SEQ ID NO: 30 and a light chain variable region comprising SEQ ID NO: 32; or
(vi) a heavy chain variable region comprising SEQ ID NO: 46 and a light chain variable region comprising SEQ ID NO: 48.
9. The isolated antibody or fragment thereof of claim 1 , wherein the antibody or fragment thereof comprises a heavy chain variable region according to SEQ ID NO: 42 and a light chain variable region according to SEQ ID NO: 44.
10. The isolated antibody or fragment thereof of claim 1 , wherein the antibody or fragment thereof comprises a heavy chain variable region according to SEQ ID NO: 46 and a light chain variable region according to SEQ ID NO: 48.
11. The isolated antibody or fragment thereof of claim 1 , wherein the antibody or fragment thereof comprises a heavy chain according to SEQ ID NO: 70 and a light chain according to SEQ ID NO: 74.
12. The isolated antibody or fragment thereof of claim 1 , wherein the antibody or fragment thereof comprises a heavy chain according to SEQ ID NO: 72 and a light chain according to SEQ ID NO: 74.
13. The isolated antibody or fragment thereof of claim 1 , wherein the antibody or fragment thereof comprises a heavy chain according to SEQ ID NO: 76 and a light chain according to SEQ ID NO: 80.
14. The isolated antibody or fragment thereof of claim 1 , wherein the antibody or fragment thereof comprises a heavy chain according to SEQ ID NO: 78 and a light chain according to SEQ ID NO: 80.
15. The isolated antibody or fragment thereof of claim 1 , wherein the antibody or fragment thereof is selected from the group consisting of a monoclonal antibody, an scFv, a Fab fragment, an Fab′ fragment, and an F(ab)′ fragment.
16. An antibody or fragment thereof according to claim 1 , wherein the antibody or fragment thereof is linked or conjugated to a therapeutic agent.
17. The antibody or fragment thereof according to claim 16 , wherein the therapeutic agent is a cytotoxic drug, a radioactive isotope, an immunomodulator, or an antibody.
18. The isolated antibody or fragment thereof according to claim 1 , wherein the antibody or fragment thereof has an affinity for PD-L1 of about 10 nM to about 0.01 nM.
19. The isolated antibody or fragment thereof according to claim 18 , wherein the antibody or fragment thereof as an affinity for PD-L1 of about 10 nM or less.
20. The isolated antibody or fragment thereof according to claim 18 , wherein the antibody or fragment thereof as an affinity for PD-L1 of about 1.0 nM or less.
21. The isolated antibody or fragment thereof according to claim 1 , wherein the antibody has a binding EC50 of about 5 ng/mL to about 1000 ng/mL.
22. The isolated antibody or fragment thereof of claim 1 , wherein the antibody blocks binding of PD-L1 to PD-1.
23. An isolated antibody or fragment thereof of claim 1 , wherein the antibody or fragment thereof blocks the binding of PD-L1 to PD-1 at an IC50 of about 5 ng/mL to about 1000 ng/mL.
24. The isolated antibody or fragment thereof of claim 1 , wherein the antibody or fragment increases T cell activation as measured by inflammatory cytokine production.
25. The isolated antibody or fragment thereof according to claim 24 , wherein the antibody or fragment thereof increases T cell production of IL-2 and IFNγ.
26. A composition comprising the antibody or fragment thereof according to claim 1 and a pharmaceutically acceptable carrier.
27. An isolated polynucleotide encoding the antibody or fragment thereof according to claim 1 .
28. An expression vector comprising the isolated polynucleotide according to claim 27 .
29. A host cell comprising the expression vector according to claim 28 .
30. A method for increasing T cell activation, the method comprising contacting T cells with an antibody or fragment thereof according to claim 1 .