Human monoclonal antibodies to programmed death ligand 1 (pd-l1)

Abstract

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 - 67 . (canceled) 
     
     
         68 . A method for treating a cancer in a human subject comprising administering to the subject 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) a framework region exhibiting at least 90% sequence identity to a framework region of the heavy chain variable region of the reference antibody; (b) a framework region derived from a human VH 1-18 germline sequence; (c) a framework region derived from a human VH 1-69 germline sequence; (d) a framework region derived from a human VH 1-3 germline sequence; or (e) a framework region derived from a human VH 3-9 germline sequence, and/or   wherein the VL comprises: (a) a framework region exhibiting at least 90% sequence identity to a framework region of the light chain variable region of the reference antibody; (b) a framework region derived from a human VK L6 germline sequence; (c) a framework region derived from a human VK L15 germline sequence; (d) a framework region derived from a human VK A27 germline sequence; or (e) a framework region derived from a human VK L18 germline sequence.   
     
     
         69 . The method of  claim 68 , wherein the framework region of the VH of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof 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 of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof exhibits at least 95% sequence identity to the framework region of the light chain variable region of the reference antibody. 
     
     
         70 . The method of  claim 68 , wherein the VL of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof 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.   
     
     
         71 . The method of  claim 68 , wherein the VL of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof 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.   
     
     
         72 . The method of  claim 68 , wherein the VL of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof 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.   
     
     
         73 . The method of  claim 68 , wherein the VL of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof 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.   
     
     
         74 . The method of  claim 68 , wherein the VL of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof 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.   
     
     
         75 . The method of  claim 68 , wherein the VH of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof 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.   
     
     
         76 . The method of  claim 68 , wherein the VH of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof 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.   
     
     
         77 . The method of  claim 68 , wherein the VH of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof 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.   
     
     
         78 . The method of  claim 68 , wherein the VH of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof 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.   
     
     
         79 . The method of  claim 68 , wherein the framework region of the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof exhibits at least 90% sequence identity to the corresponding framework region of a heavy chain variable germline sequence selected from (a) a human VH 1-18 germline sequence; (b) a human VH 1-69 germline sequence; (c) a human VH 1-3 germline sequence; and (d) a human VH 3-9 germline sequence. 
     
     
         80 . The method of  claim 68 , wherein the framework region of the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof exhibits at least 95% sequence identity to the corresponding framework region of a heavy chain variable germline sequence selected from (a) a human VH 1-18 germline sequence; (b) a human VH 1-69 germline sequence; (c) a human VH 1-3 germline sequence; and (d) a human VH 3-9 germline sequence. 
     
     
         81 . The method of  claim 68 , wherein the framework region of the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises no more than 10 amino acid differences from the corresponding framework region of a heavy chain variable germline sequence selected from (a) a human VH 1-18 germline sequence; (b) a human VH 1-69 germline sequence; (c) a human VH 1-3 germline sequence; and (d) a human VH 3-9 germline sequence. 
     
     
         82 . The method of  claim 68 , wherein the framework region of the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof exhibits at least 90% sequence identity to the corresponding framework region of a light chain variable germline sequence selected from (a) a human VK L6 germline sequence, (b) a human VK L15 germline sequence, (c) a human VK A27 germline sequence, and (d) a human VK L18 germline sequence. 
     
     
         83 . The method of  claim 68 , wherein the framework region of the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof exhibits at least 95% sequence identity to the corresponding framework region of a light chain variable germline sequence selected from (a) a human VK L6 germline sequence, (b) a human VK L15 germline sequence, (c) a human VK A27 germline sequence, and (d) a human VK L18 germline sequence. 
     
     
         84 . The method of  claim 68 , wherein the framework region of the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises no more than 10 amino acid differences from the corresponding framework region of a light chain variable germline sequence selected from (a) a human VK L6 germline sequence, (b) a human VK L15 germline sequence, (c) a human VK A27 germline sequence, and (d) a human VK L18 germline sequence. 
     
     
         85 . The method of  claim 68 , wherein the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises amino acids having a sequence at least 90% identical to a light chain variable germline sequence selected from (a) a human VK L6 germline sequence, (b) a human VK L15 germline sequence, (c) a human VK A27 germline sequence, and (d) a human VK L18 germline sequence. 
     
     
         86 . The method of  claim 68 , wherein the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises amino acids having a sequence at least 95% identical to a light chain variable germline sequence selected from (a) a human VK L6 germline sequence, (b) a human VK L15 germline sequence, (c) a human VK A27 germline sequence, and (d) a human VK L18 germline sequence. 
     
     
         87 . The method of  claim 68 , wherein the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises amino acids having a sequence that differs by no more than 10 amino acids from a light chain variable germline sequence selected from (a) a human VK L6 germline sequence, (b) a human VK L15 germline sequence, (c) a human VK A27 germline sequence, and (d) a human VK L18 germline sequence. 
     
     
         88 . The method of  claim 68 , wherein the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises:
 (a) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:105;   (b) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:106;   (c) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:107; or   (d) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:108.   
     
     
         89 . The method of  claim 68 , wherein the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises:
 (a) FR1, FR2, and FR3 having amino acid sequences at least 95% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:105;   (b) FR1, FR2, and FR3 having amino acid sequences at least 95% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:106;   (c) FR1, FR2, and FR3 having amino acid sequences at least 95% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:107; or   (d) FR1, FR2, and FR3 having amino acid sequences at least 95% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:108.   
     
     
         90 . The method of  claim 68 , wherein the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises:
 (a) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:101;   (b) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:102;   (c) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:103; or   (d) FR1, FR2, and FR3 having amino acid sequences at least 90% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:104.   
     
     
         91 . The method of  claim 68 , wherein the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises:
 (a) FR1, FR2, and FR3 having amino acid sequences at least 95% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:101;   (b) FR1, FR2, and FR3 having amino acid sequences at least 95% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:102;   (c) FR1, FR2, and FR3 having amino acid sequences at least 95% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:103; or   (d) FR1, FR2, and FR3 having amino acid sequences at least 95% identical to the FR1, FR2, and FR3 amino acid sequences set forth in SEQ ID NO:104.   
     
     
         92 . The method of  claim 68 , wherein the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises an FR1 selected from:
 (a) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 105 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 105 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: 106 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 106 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: 107 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 107 with one amino acid substitution; and   (d) the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 108 or the FR1 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 108 with one amino acid substitution.   
     
     
         93 . The method of  claim 68 , wherein the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises an FR2 selected from:
 (a) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 105 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 105 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: 106 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 106 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: 107 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 107 with one amino acid substitution; and   (d) the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 108 or the FR2 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 108 with one amino acid substitution.   
     
     
         94 . The method of  claim 68 , wherein the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises an FR3 selected from:
 (a) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 105 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 105 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: 106 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 106 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: 107 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 107 with one amino acid substitution; and   (d) the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 108 or the FR3 of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 108 with one amino acid substitution.   
     
     
         95 . The method of  claim 68 , wherein the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises an FR1 selected from:
 (a) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 101 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 101 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: 102 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 102 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: 103 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 103 with one amino acid substitution; and   (d) the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 104 or the FR1 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 104 with one amino acid substitution.   
     
     
         96 . The method of  claim 68 , wherein the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises an FR2 selected from:
 (a) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 101 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 101 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: 102 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 102 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: 103 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 103 with one amino acid substitution; and   (d) the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 104 or the FR2 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 104 with one amino acid substitution.   
     
     
         97 . The method of  claim 68 , wherein the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises an FR3 selected from:
 (a) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 101 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 101 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: 102 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 102 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: 103 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 103 with one amino acid substitution; and   (d) the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 104 or the FR3 of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 104 with one amino acid substitution.   
     
     
         98 . The method of  claim 68 , wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof binds to human PD-L1 with a KD of 5×10 −9  M or less. 
     
     
         99 . The method of  claim 68 , wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof binds to human PD-L1 with a KD of 2×10 −9 M or less. 
     
     
         100 . The method of  claim 68 , wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof binds to human PD-L1 with a KD of 1×10 −9 M or less. 
     
     
         101 . The method of  claim 68 , wherein the reference antibody binds to human PD-L1 with a KD of about 5×10 −9 M. 
     
     
         102 . The method of  claim 68 , wherein the reference antibody binds to human PD-L1 with a KD of 2×10 −9 M or less. 
     
     
         103 . The method of  claim 68 , wherein the reference antibody binds to human PD-L1 with a KD of 1×10 −9 M or less. 
     
     
         104 . The method of  claim 68 , wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof exhibits the following properties:
 (a) binds with high affinity to human PD-L1 with a KD of about 2×10 −9 M or lower as determined by surface plasmon resonance analysis;   (b) augments T cell proliferation, IFN-γ and IL-2 secretion in mixed lymphocyte reactions;   (c) inhibits binding of PD-L1 to the PD-1 receptor;   (d) stimulates antibody responses; and   (e) reverses the suppressive effect of T regulatory cells on T cell effector cells and/or dendritic cells.   
     
     
         105 . The method of  claim 68 , wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof is a human or a humanized antibody or a portion thereof. 
     
     
         106 . The method of  claim 68 , wherein the cancer is selected from melanoma, lung cancer, renal cancer, colon cancer, colorectal cancer, prostate cancer, breast cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphocytic lymphoma, T-cell lymphoma, solid tumors of childhood, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, environmentally induced cancers including those induced by asbestos, a metastatic cancer, and combinations of said cancers. 
     
     
         107 . The method of  claim 68 , wherein the cancer is selected from melanoma, lung cancer, renal cancer, colon cancer, colorectal cancer, head or neck cancer, prostate cancer, breast cancer, or bladder cancer. 
     
     
         108 . The method of  claim 68 , further comprising administering to the subject a monoclonal anti-CTLA-4 antibody. 
     
     
         109 . A method for treating a cancer in a human subject comprising administering to the subject 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 antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 and a light chain variable region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4, wherein the FR1 of the light chain variable region is 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. 
   
     
     
         110 . The method of  claim 109 , wherein the FR2 of the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof is 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.   
     
     
         111 . The method of  claim 109 , wherein the FR3 of the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof is 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.   
     
     
         112 . The method of  claim 109 , wherein the FR4 of the light chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof is 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.   
     
     
         113 . The method of  claim 109 , wherein the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises an 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.   
     
     
         114 . The method of  claim 109 , wherein the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof comprises an 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.   
     
     
         115 . The method of  claim 109 , wherein the FR3 of the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof is 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.   
     
     
         116 . The method of  claim 109 , wherein the FR4 of the heavy chain variable region of the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof is 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.   
     
     
         117 . The method of  claim 109 , wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof binds to human PD-L1 with a KD of 5×10 −9  M or less. 
     
     
         118 . The method of  claim 109 , wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof binds to human PD-L1 with a KD of 2×10 −9  M or less. 
     
     
         119 . The method of  claim 109 , wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof binds to human PD-L1 with a KD of 1×10 −9  M or less. 
     
     
         120 . The method of  claim 109 , wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof exhibits the following properties:
 (a) binds with high affinity to human PD-L1 with a KD of about 2×10 −9  M or lower as determined by surface plasmon resonance analysis;   (b) augments T cell proliferation, IFN-γ and IL-2 secretion in mixed lymphocyte reactions;   (c) inhibits binding of PD-L1 to the PD-1 receptor;   (d) stimulates antibody responses; and   (e) reverses the suppressive effect of T regulatory cells on T cell effector cells and/or dendritic cells.   
     
     
         121 . The method of  claim 109 , wherein the monoclonal anti-PD-L1 antibody or antigen-binding portion thereof is a human or a humanized antibody or a portion thereof. 
     
     
         122 . The method of  claim 109 , wherein the cancer is selected from melanoma, lung cancer, renal cancer, colon cancer, colorectal cancer, prostate cancer, breast cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphocytic lymphoma, T-cell lymphoma, solid tumors of childhood, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, environmentally induced cancers including those induced by asbestos, a metastatic cancer, and combinations of said cancers. 
     
     
         123 . The method of  claim 109 , wherein the cancer is selected from melanoma, lung cancer, renal cancer, colon cancer, colorectal cancer, head or neck cancer, prostate cancer, breast cancer, or bladder cancer. 
     
     
         124 . The method of  claim 109 , further comprising administering to the subject a monoclonal anti-CTLA-4 antibody.