Human monoclonal antibodies to programmed death ligand 1 (PD-L1)
The present disclosure provides isolated monoclonal antibodies, particularly human monoclonal antibodies that specifically bind to PD-L1 with high affinity. Nucleic acid molecules encoding the antibodies of this disclosure, expression vectors, host cells and methods for expressing the antibodies of this disclosure are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention are also provided. The disclosure also provides methods for detecting PD-L1, as well as methods for treating various diseases, including cancer and infectious diseases, using anti-PD-L1 antibodies.
1. A monoclonal anti-PD-L1 antibody, or an antigen-binding portion thereof, which cross-competes for binding to human PD-L1 with a reference antibody, wherein the reference antibody comprises:
(a) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:1 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:11;
(b) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:2 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:12;
(c) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:3 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:13;
(d) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:4 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:14;
(e) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:5 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:15;
(f) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:6 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:16;
(g) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:7 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:17;
(h) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:8 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:18;
(i) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:9 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:19; or
(j) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:10 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:20; and
wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a framework region exhibiting at least 90% sequence identity to a framework region of the heavy chain variable region of the reference antibody and/or the VL comprises a framework region exhibiting at least 90% sequence identity to a framework region of the light chain variable region of the reference antibody.
2. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , wherein the framework region of the VH exhibits at least 95% sequence identity to the framework region of the heavy chain variable region of the reference antibody and/or the framework region of the VL exhibits at least 95% sequence identity to the framework region of the light chain variable region of the reference antibody.
3. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , wherein the VL exhibits at least 90% sequence identity to:
(a) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:11;
(b) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:12;
(c) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:13;
(d) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:14;
(e) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:15;
(f) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:16;
(g) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:17;
(h) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:18;
(i) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:19; or
(j) the light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:20.
4. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , wherein the VL comprises a FR1 selected from:
(a) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:11 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:11 with one amino acid substitution;
(b) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:12 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:12 with one amino acid substitution;
(c) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:13 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:13 with one amino acid substitution;
(d) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:14 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:14 with one amino acid substitution;
(e) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:15 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:15 with one amino acid substitution;
(f) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:16 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:16 with one amino acid substitution;
(g) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:17 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:17 with one amino acid substitution;
(h) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:18 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:18 with one amino acid substitution;
(i) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:19 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:19 with one amino acid substitution; and
(j) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:20 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:20 with one amino acid substitution.
5. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , wherein the VL comprises a FR2 selected from:
(a) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:11 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:11 with one amino acid substitution;
(b) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:12 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:12 with one amino acid substitution;
(c) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:13 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:13 with one amino acid substitution;
(d) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:14 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:14 with one amino acid substitution;
(e) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:15 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:15 with one amino acid substitution;
(f) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:16 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:16 with one amino acid substitution;
(g) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:17 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:17 with one amino acid substitution;
(h) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:18 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:18 with one amino acid substitution;
(i) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:19 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:19 with one amino acid substitution; and
(j) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:20 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:20 with one amino acid substitution.
6. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , wherein the VL comprises a FR3 selected from:
(a) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:11 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:11 with one amino acid substitution;
(b) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:12 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:12 with one amino acid substitution;
(c) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:13 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:13 with one amino acid substitution;
(d) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:14 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:14 with one amino acid substitution;
(e) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:15 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:15 with one amino acid substitution;
(f) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:16 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:16 with one amino acid substitution;
(g) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:17 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:17 with one amino acid substitution;
(h) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:18 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:18 with one amino acid substitution;
(i) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:19 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:19 with one amino acid substitution; and
(j) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:20 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:20 with one amino acid substitution.
7. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , wherein the VL comprises a FR4 selected from:
(a) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:11 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:11 with one amino acid substitution;
(b) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:12 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:12 with one amino acid substitution;
(c) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:13 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:13 with one amino acid substitution;
(d) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:14 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO 14 with one amino acid substitution;
(e) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:15 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:15 with one amino acid substitution;
(f) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:16 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:16 with one amino acid substitution;
(g) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:17 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:17 with one amino acid substitution;
(h) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:18 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:18 with one amino acid substitution;
(i) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:19 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:19 with one amino acid substitution; and
(j) the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:20 or the FR4 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO:20 with one amino acid substitution.
8. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , wherein the VH comprises a FR1 selected from:
(a) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1 with one amino acid substitution;
(b) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2 with one amino acid substitution;
(c) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:3 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:3 with one amino acid substitution;
(d) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:4 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:4 with one amino acid substitution;
(e) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:5 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:5 with one amino acid substitution;
(f) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:6 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:6 with one amino acid substitution;
(g) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7 with one amino acid substitution;
(h) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8 with one amino acid substitution;
(i) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9 with one amino acid substitution; and
(j) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:10 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:10 with one amino acid substitution.
9. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , wherein the VH comprises a FR2 selected from:
(a) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1 with one amino acid substitution;
(b) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2 with one amino acid substitution;
(c) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:3 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:3 with one amino acid substitution;
(d) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:4 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:4 with one amino acid substitution;
(e) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:5 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:5 with one amino acid substitution;
(f) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:6 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:6 with one amino acid substitution;
(g) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7 with one amino acid substitution;
(h) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8 with one amino acid substitution;
(i) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9 with one amino acid substitution; and
(j) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:10 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:10 with one amino acid substitution.
10. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , wherein the VH comprises a FR3 selected from:
(a) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1 with one amino acid substitution;
(b) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2 with one amino acid substitution;
(c) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:3 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:3 with one amino acid substitution;
(d) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:4 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:4 with one amino acid substitution;
(e) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:5 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:5 with one amino acid substitution;
(f) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:6 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:6 with one amino acid substitution;
(g) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7 with one amino acid substitution;
(h) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8 with one amino acid substitution;
(i) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9 with one amino acid substitution; and
(j) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:10 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:10 with one amino acid substitution.
11. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , wherein the VH comprises a FR4 selected from:
(a) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1 with one amino acid substitution;
(b) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2 with one amino acid substitution;
(c) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:3 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:3 with one amino acid substitution;
(d) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:4 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:4 with one amino acid substitution;
(e) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:5 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:5 with one amino acid substitution;
(f) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:6 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:6 with one amino acid substitution;
(g) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7 with one amino acid substitution;
(h) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8 with one amino acid substitution;
(i) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:9 with one amino acid substitution; and
(j) the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:10 or the FR4 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:10 with one amino acid substitution.
12. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , wherein the VH is of a human IgG1, a human IgG2, a human IgG3, or a human IgG4 isotype.
13. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 12 , wherein the VH is of a human IgG4 isotype.
14. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 12 , wherein the VH is of a human IgG1 isotype and is modified by replacing at least one amino acid residue with a different amino acid residue to alter one or more effector functions of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof.
15. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , which binds to human PD-L1 with a KD of 5×10 −9 M or less.
16. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , which binds to human PD-L1 with a KD of 2×10 −9 M or less.
17. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , which binds to human PD-L1 with a KD of 1×10 −9 M or less.
18. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , wherein the reference antibody binds to human PD-L1 with a KD of about 5×10 −9 M.
19. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , wherein the reference antibody binds to human PD-L1 with a KD of 2×10 −9 M or less.
20. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , wherein the reference antibody binds to human PD-L1 with a KD of 1×10 −9 M or less.
21. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , which exhibits the following properties:
(a) binds with high affinity to human PD-L1 with a KD of about 2×10 −9 M or less as determined by surface plasmon resonance analysis using a Biacore system;
(b) inhibits binding of PD-L1 to a PD-1 receptor;
(c) augments T cell proliferation, IFN-γ and IL-2 secretion in mixed lymphocyte reaction assays;
(d) stimulates antibody responses; and
(e) reverses the suppressive effect of T regulatory cells on T cell effector cells, dendritic cells, or T cell effector cells and dendritic cells.
22. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , which is a human or a humanized antibody or a portion thereof.
23. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , comprising:
(a) the VH which comprises amino acids having the sequence set forth in SEQ ID NO:1 or a conservative sequence modification thereof and the VL which comprises amino acids having the sequence set forth in SEQ ID NO:11 or a conservative sequence modification thereof;
(b) the VH which comprises amino acids having the sequence set forth in SEQ ID NO:2 or a conservative sequence modification thereof and the VL which comprises amino acids having the sequence set forth in SEQ ID NO:12 or a conservative sequence modification thereof;
(c) the VH which comprises amino acids having the sequence set forth in SEQ ID NO:6 or a conservative sequence modification thereof and the VL which comprises amino acids having the sequence set forth in SEQ ID NO:16 or a conservative sequence modification thereof;
(d) the VH which comprises amino acids having the sequence set forth in SEQ ID NO:7 or a conservative sequence modification thereof and the VL which comprises amino acids having the sequence set forth in SEQ ID NO:17 or a conservative sequence modification thereof;
(e) the VH which comprises amino acids having the sequence set forth in SEQ ID NO:8 or a conservative sequence modification thereof and the VL which comprises amino acids having the sequence set forth in SEQ ID NO:18 or a conservative sequence modification thereof;
(f) the VH which comprises amino acids having the sequence set forth in SEQ ID NO:9 or a conservative sequence modification thereof and the VL which comprises amino acids having the sequence set forth in SEQ ID NO:19 or a conservative sequence modification thereof; or
(g) the VH which comprises amino acids having the sequence set forth in SEQ ID NO:10 or a conservative sequence modification thereof and the VL which comprises amino acids having the sequence set forth in SEQ ID NO:20 or a conservative sequence modification thereof,
wherein the conservative sequence modification comprises one or more additions, deletions, or conservative amino acid substitutions,
and wherein the antibodies comprising a conservative sequence modification retain the functional characteristics of unmodified antibodies.
24. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , comprising the VH which comprises amino acids having the sequence set forth in SEQ ID NO:2 or a conservative sequence modification thereof and the VL which comprises amino acids having the sequence set forth in SEQ ID NO:12 or a conservative sequence modification thereof, wherein the conservative sequence modification comprises one or more additions, deletions, or conservative amino acid substitutions.
25. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 23 , wherein the conservative sequence modification comprises a modification of one or more residues within one or more CDR regions, within one or more framework regions, or within one or more CDR regions and one or more framework regions.
26. The monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 23 , wherein no more than three amino acid residues within a CDR region are modified.
27. A composition comprising the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof of claim 1 , formulated together with a pharmaceutically acceptable carrier.
28. The composition of claim 27 , wherein the pharmaceutically acceptable carrier is suitable for intravenous administration.
29. A kit comprising the composition of claim 27 , a label indicating the intended use of the contents of the kit and instructions for use.
30. The kit of claim A, further comprising at least one additional anti-neoplastic agent.