Anti-pd-l1 antibodies and diagnostic uses thereof

Abstract

The invention provides programmed death-ligand 1 (PD-L1) antibodies and methods of using the same.

1 . An isolated antibody that specifically binds to PD-L1, wherein the antibody binds to an epitope comprising amino acid residues 279-290 of human PD-L1 polypeptide (SEQ ID NO: 1). 
     
     
         2 . The antibody of  claim 1 , wherein the antibody comprises the following hypervariable regions (HVRs):
 (a) an HVR-H1 comprising the amino acid sequence of SNGLT (SEQ ID NO: 2);   (b) an HVR-H2 comprising the amino acid sequence of TINKDASAYYASWAKG (SEQ ID NO: 3); and   (c) an HVR-H3 comprising the amino acid sequence of IAFKTGTSI (SEQ ID NO: 4).   
     
     
         3 . The antibody of  claim 2 , further comprising the following heavy chain variable domain framework regions (FRs):
 (a) FR-H1 comprising the amino acid sequence of QSLEESGGRLVKPDETLTITCTVSGIDLS (SEQ ID NO: 5);   (b) FR-H2 comprising the amino acid sequence of WVRQAPGEGLEWIG (SEQ ID NO: 6);   (c) FR-H3 comprising the amino acid sequence of RLTISKPSSTKVDLKITSPTTEDTATYFCGR (SEQ ID NO: 7); and   (d) FR-H4 comprising the amino acid sequence of WGPGTLVTVSS (SEQ ID NO: 8).   
     
     
         4 . The antibody of  claim 2 , further comprising the following HVRs:
 (a) an HVR-L1 comprising the amino acid sequence of QASESVYSNNYLS (SEQ ID NO: 9);   (b) an HVR-L2 comprising the amino acid sequence of LASTLAS (SEQ ID NO: 10); and   (c) an HVR-L3 comprising the amino acid sequence of IGGKSSSTDGNA (SEQ ID NO: 11).   
     
     
         5 . The antibody of  claim 4 , further comprising the following light chain variable domain FRs:
 (a) FR-L1 comprising the amino acid sequence of AIVMTQTPSPVSAAVGGTVTINC (SEQ ID NO: 12);   (b) FR-L2 comprising the amino acid sequence of WFQQKPGQPPKLLIY (SEQ ID NO: 13);   (c) FR-L3 comprising the amino acid sequence of GVPSRFKGSGSGTQFTLTISGVQCDDAATYYC (SEQ ID NO: 14); and   (d) FR-L4 comprising the amino acid sequence of FGGGTEVVVR (SEQ ID NO: 15   
     
     
         6 . The antibody of  claim 1 , wherein the antibody comprises the following HVRs:
 (a) an HVR-L1 comprising the amino acid sequence of QASESVYSNNYLS (SEQ ID NO: 9);   (b) an HVR-L2 comprising the amino acid sequence of LASTLAS (SEQ ID NO: 10); and   (c) an HVR-L3 comprising the amino acid sequence of IGGKSSSTDGNA (SEQ ID NO: 11).   
     
     
         7 . The antibody of  claim 6 , further comprising the following light chain variable domain FRs:
 (a) FR-L1 comprising the amino acid sequence of AIVMTQTPSPVSAAVGGTVTINC (SEQ ID NO: 12);   (b) FR-L2 comprising the amino acid sequence of WFQQKPGQPPKLLIY (SEQ ID NO: 13);   (c) FR-L3 comprising the amino acid sequence of GVPSRFKGSGSGTQFTLTISGVQCDDAATYYC (SEQ ID NO: 14); and   (d) FR-L4 comprising the amino acid sequence of FGGGTEVVVR (SEQ ID NO: 15).   
     
     
         8 . The antibody of  claim 1 , comprising (a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16; (b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17; or (c) a VH sequence as in (a) and a VL sequence as in (b). 
     
     
         9 - 10 . (canceled) 
     
     
         11 . An isolated antibody that specifically binds PD-L1, wherein the antibody comprises the following HVRs:
 (a) an HVR-H1 comprising the amino acid sequence of SNGLT (SEQ ID NO: 2);   (b) an HVR-H2 comprising the amino acid sequence of TINKDASAYYASWAKG (SEQ ID NO: 3);   (c) an HVR-H3 comprising the amino acid sequence of IAFKTGTSI (SEQ ID NO: 4);   (d) an HVR-L1 comprising the amino acid sequence of QASESVYSNNYLS (SEQ ID NO: 9);   (e) an HVR-L2 comprising the amino acid sequence of LASTLAS (SEQ ID NO: 10); and   (f) an HVR-L3 comprising the amino acid sequence of IGGKSSSTDGNA (SEQ ID NO: 11).   
     
     
         12 . The antibody of  claim 11 , wherein the antibody further comprises the following heavy chain variable domain and light chain variable domain FRs:
 (a) FR-H1 comprising the amino acid sequence of QSLEESGGRLVKPDETLTITCTVSGIDLS (SEQ ID NO: 5);   (b) FR-H2 comprising the amino acid sequence of WVRQAPGEGLEWIG (SEQ ID NO: 6);   (c) FR-H3 comprising the amino acid sequence of RLTISKPSSTKVDLKITSPTTEDTATYFCGR (SEQ ID NO: 7);   (d) FR-H4 comprising the amino acid sequence of WGPGTLVTVSS (SEQ ID NO: 8);   (e) FR-L1 comprising the amino acid sequence of AIVMTQTPSPVSAAVGGTVTINC (SEQ ID NO: 12);   (f) FR-L2 comprising the amino acid sequence of WFQQKPGQPPKLLIY (SEQ ID NO: 13);   (g) FR-L3 comprising the amino acid sequence of GVPSRFKGSGSGTQFTLTISGVQCDDAATYYC (SEQ ID NO: 14); and   (h) FR-L4 comprising the amino acid sequence of FGGGTEVVVR (SEQ ID NO: 15).   
     
     
         13 . The antibody of  claim 11 , wherein the antibody comprises a VH sequence of SEQ ID NO: 16 and a VL sequence of SEQ ID NO: 17. 
     
     
         14 . An isolated antibody that competes for binding to PD-L1 with the antibody of  claim 1 . 
     
     
         15 . An isolated antibody that binds to the same epitope as the antibody of  claim 1 . 
     
     
         16 . The antibody of  claim 1 , wherein the antibody is a monoclonal antibody. 
     
     
         17 . (canceled) 
     
     
         18 . The antibody of  claim 1 , wherein the antibody is an IgG antibody. 
     
     
         19 . The antibody of  claim 1 , wherein the antibody is an antibody fragment that specifically binds PD-L1. 
     
     
         20 . The antibody of  claim 19 , wherein the antibody fragment is selected from the group consisting of Fab, single chain variable fragment (scFv), Fv, Fab′, Fab′-SH, F(ab′) 2 , and diabody. 
     
     
         21 . An isolated nucleic acid encoding an isolated antibody of  claim 1 . 
     
     
         22 . A vector comprising the nucleic acid of  claim 21 . 
     
     
         23 . A host cell comprising the vector of  claim 22 . 
     
     
         24 . An immunoconjugate comprising the antibody of  claim 1 . 
     
     
         25 . The antibody of  claim 1  for use in detecting the presence or expression level of PD-L1 in a biological sample. 
     
     
         26 . The antibody of  claim 25 , wherein the detecting is by immunohistochemistry (IHC), immunofluorescence (IF), flow cytometry, Enzyme-Linked Immunosorbant Assay (ELISA), or immunoblotting. 
     
     
         27 . (canceled) 
     
     
         28 . The antibody of  claim 25 , wherein the sample comprises a fixed tissue. 
     
     
         29 . (canceled) 
     
     
         30 . The antibody of  claim 25 , wherein the sample is from a subject having, or at risk of, a cancer or an immune dysfunction. 
     
     
         31 - 32 . (canceled) 
     
     
         33 . A method of detecting the presence or expression level of PD-L1 in a biological sample comprising contacting the biological sample with the antibody of  claim 1  and detecting the presence of the bound antibody. 
     
     
         34 . The method of  claim 33 , wherein the detecting is by IHC, IF, flow cytometry, ELISA, or immunoblotting. 
     
     
         35 . (canceled) 
     
     
         36 . The method of  claim 33 , wherein the sample comprises a fixed tissue. 
     
     
         37 . (canceled) 
     
     
         38 . The method of  claim 33 , wherein the sample is from a subject having, or at risk of, a cancer or an immune dysfunction. 
     
     
         39 . The method of  claim 38 , wherein the immune dysfunction is a T-cell dysfunctional disorder. 
     
     
         40 - 41 . (canceled) 
     
     
         42 . The method of  claim 33 , wherein the presence or expression level of PD-L1 in the sample indicates that the subject is likely to respond to treatment with an anti-cancer therapy. 
     
     
         43 - 44 . (canceled) 
     
     
         45 . The method of  claim 42 , wherein the method further comprises selecting an anti-cancer therapy for the subject based on the presence or expression level of PD-L1 in the sample. 
     
     
         46 . The method of  claim 42 , wherein the method further comprises administering a therapeutically effective amount of an anti-cancer therapy to the subject. 
     
     
         47 . The method of  claim 38 , wherein the cancer is selected from the group consisting of non-small cell lung cancer, squamous cell cancer, small-cell lung cancer, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, leukemia, and head and neck cancer. 
     
     
         48 . The method of  claim 47 , wherein the cancer is non-small cell lung cancer (NSCLC). 
     
     
         49 . (canceled) 
     
     
         50 . The method of  claim 38 , wherein the sample is a tumor sample. 
     
     
         51 . The method of  claim 50 , wherein the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, or any combination thereof. 
     
     
         52 . The method of  claim 51 , wherein the tumor sample has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 1% or more of the tumor sample by area. 
     
     
         53 . The method of  claim 52 , wherein the tumor sample has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 5% or more of the tumor sample by area. 
     
     
         54 . The method of  claim 53 , wherein the tumor sample has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 10% or more of the tumor sample by area. 
     
     
         55 . The method of  claim 50 , wherein the tumor sample has a detectable expression level of PD-L1 in about 1% or more of the tumor cells in the tumor sample. 
     
     
         56 . The method of  claim 55 , wherein the tumor sample has a detectable expression level of PD-L1 in about 5% or more of the tumor cells in the tumor sample. 
     
     
         57 . The method of  claim 56 , wherein the tumor sample has a detectable expression level of PD-L1 in about 10% or more of the tumor cells in the tumor sample. 
     
     
         58 . The method of  claim 46 , wherein the anti-cancer therapy comprises a PD-1 axis binding antagonist. 
     
     
         59 . The method of  claim 58 , wherein the PD-1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist. 
     
     
         60 . The method of  claim 59 , wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist. 
     
     
         61 . The method of  claim 60 , wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners. 
     
     
         62 - 63 . (canceled) 
     
     
         64 . The method of  claim 61 , wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 or B7-1. 
     
     
         65 . The method of  claim 60 , wherein the PD-L1 binding antagonist is an antibody. 
     
     
         66 . The method of  claim 65 , wherein the antibody is selected from the group consisting of: YW243.55.S70, MPDL3280A (atezolizumab), MDX-1105, and MED14736 (durvalumab), and MSB0010718C (avelumab). 
     
     
         67 . The method of  claim 59 , wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist. 
     
     
         68 . The method of  claim 67 , wherein the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners. 
     
     
         69 - 70 . (canceled) 
     
     
         71 . The method of  claim 68 , wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 or PD-L2. 
     
     
         72 . The method of  claim 67 , wherein the PD-1 binding antagonist is an antibody. 
     
     
         73 . The method of  claim 72 , wherein the antibody is selected from the group consisting of: MDX 1106 (nivolumab), MK-3475 (pembrolizumab), CT-011 (pidilizumab), MEDI-0680 (AMP-514), PDR001, REGN2810, and BGB-108. 
     
     
         74 . The method of  claim 67 , wherein the PD-1 binding antagonist is an Fc-fusion protein. 
     
     
         75 . The method of  claim 74 , wherein the Fc-fusion protein is AMP-224. 
     
     
         76 . The method  claim 46 , further comprising administering to the patient an effective amount of a second therapeutic agent. 
     
     
         77 . The method of  claim 76 , wherein the second therapeutic agent is selected from the group consisting of a cytotoxic agent, a growth-inhibitory agent, a radiation therapy agent, an anti-angiogenic agent, and combinations thereof. 
     
     
         78 . The method of  claim 33 , wherein the subject is a human.