Human antibodies to pd-l1

Abstract

The present invention provides antibodies that bind to the T-cell co-inhibitor ligand programmed death-ligand1 (PD-L1) protein, and methods of use. In various embodiments of the invention, the antibodies are fully human antibodies that bind to PD-L1. In certain embodiments, the present invention provides multi-specific antigen-binding molecules comprising a first binding specificity that binds to PD-L1 and a second binding specificity that binds to a tumor cell antigen, an infected cell-specific antigen, or a T-cell co-inhibitor. In some embodiments, the antibodies of the invention are useful for inhibiting or neutralizing PD-L1 activity, thus providing a means of treating a disease or disorder such as cancer or viral infection.

What is claimed is: 
     
         1 . An isolated antibody or antigen-binding fragment thereof that competes for binding to human programmed death-ligand 1 (PD-L1) protein with a reference antibody comprising the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR), wherein the HCVR has an amino acid sequence selected from the group consisting of HCVR sequences listed in Table 1; and the CDRs of a light chain variable region (LCVR), wherein the LCVR has an amino acid sequence selected from the group consisting of LCVR sequences listed in Table 1 and wherein the antibody has one or more of the following properties:
 (a) binds monomeric PD-L1 with a binding dissociation equilibrium constant (K D ) of less than about 310 pM as measured in a surface plasmon resonance assay at 37° C.;   (b) binds monomeric human PD-L1 with a K D  less than about 180 pM in a surface plasmon resonance assay at 25° C.;   (c) binds dimeric human PD-L1 with a K D  of less than about 15 pM as measured in a surface plasmon resonance assay at 37° C.; and   (d) binds dimeric human PD-L1 with a K D  less than about 8 pM in a surface plasmon resonance assay at 25° C.   
     
     
         2 . The isolated antibody or antigen-binding fragment of  claim 1 , wherein the reference antibody or antigen-binding fragment thereof comprises an HCVR/LCVR amino acid sequence pair as set forth in Table 1. 
     
     
         3 . The isolated antibody or antigen-binding fragment of  claim 2 , wherein the reference antibody comprises an HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 82/90, 98/106, 146/154, 162/170, 290/274, 306/274, 314/274 and 330/274. 
     
     
         4 . An isolated human monoclonal antibody or antigen-binding fragment thereof that binds specifically to human PD-L1, wherein the antibody or antigen-binding fragment thereof comprises a HCVR having an amino acid sequence selected from the group consisting of HCVR sequences listed in Table 1. 
     
     
         5 . An isolated human monoclonal antibody or antigen-binding fragment thereof that binds specifically to human PD-L1, wherein the antibody or antigen-binding fragment thereof comprises a LCVR having an amino acid sequence selected from the group consisting of LCVR sequences listed in Table 1. 
     
     
         6 . An isolated human monoclonal antibody or antigen-binding fragment thereof that binds specifically to human PD-L1, wherein the antibody or antigen-binding fragment thereof comprises (a) a HCVR having an amino acid sequence selected from the group consisting of HCVR sequences listed in Table 1; and (b) a LCVR having an amino acid sequence selected from the group consisting of LCVR sequences listed in Table 1. 
     
     
         7 . The isolated antibody or antigen-binding fragment thereof of  claim 6 , wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within any one of the HCVR sequences listed in Table 1; and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within any one of the LCVR sequences listed in Table 1. 
     
     
         8 . The isolated antibody or antigen-binding fragment thereof of  claim 7 , comprising:
 (a) a HCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 20, 36, 52, 68, 84, 100, 116, 132, 148, 164, 180, 188, 204, 220, 236, 252, 268, 284, 292, 300, 308, 316, 324, 332, and 340;   (b) a HCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 22, 38, 54, 70, 86, 102, 118, 134, 150, 166, 182, 190, 206, 222, 238, 254, 270, 286, 294, 302, 310, 318, 326, 334, and 342;   (c) a HCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 24, 40, 56, 72, 88, 104, 120, 136, 152, 168, 184, 192, 208, 224, 240, 256, 272, 288, 296, 304, 312, 320, 328, 336, and 344;   (d) a LCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 28, 44, 60, 76, 92, 108, 124, 140, 156, 172, 196, 212, 228, 244, 260, and 276;   (e) a LCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 30, 46, 62, 78, 94, 110, 126, 142, 158, 174, 198, 214, 230, 246, 262, and 278; and   (f) a LCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 32, 48, 64, 80, 96, 112, 128, 144, 160, 176, 200, 216, 232, 248, 264, and 280.   
     
     
         9 . The isolated antibody or antigen-binding fragment of  claim 8 , comprising a HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 82/90, 98/106, 146/154, 162/170, 290/274, 306/274, 314/274 and 330/274. 
     
     
         10 . An isolated antibody or antigen-binding fragment thereof that blocks PD-L1 binding to one of PD-1 or B7-1, the isolated antibody or antigen-binding fragment thereof comprising the CDRs of a HCVR, wherein the HCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 34, 50, 82, 98, 146, 162, 178, 186, 234, 250, 266, 290, 306, 314, and 330; and the CDRs of a LCVR, wherein the LCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 42, 58, 90, 106, 154, 170, 194, 242, 258, and 274. 
     
     
         11 . An isolated antibody or antigen-binding fragment thereof that binds PD-L1, wherein the antibody or antigen-binding fragment thereof enhances PD-L1 binding to one of PD-1 or B7-1. 
     
     
         12 . The isolated antibody or antigen-binding fragment thereof of  claim 11 , wherein the antibody comprises the CDRs of a HCVR, wherein the HCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 66, 114, 130, 202, 218, 282, 298, 322, and 338; and the CDRs of a LCVR, wherein the LCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 74, 122, 138, 210, 226, and 274. 
     
     
         13 . The isolated antibody or antigen-binding fragment thereof of  claim 11  or  12 , wherein the antibody comprises an HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 18/26, 66/74, 114/122, 130/138, 202/210, 218/226, 282/274, 298/274, 322/274, and 338/274. 
     
     
         14 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 13 , wherein the antibody is a multi-specific antigen-binding molecule. 
     
     
         15 . A pharmaceutical composition comprising an isolated antibody or antigen-binding fragment thereof that binds to PD-L1 according to any one of  claims 1 - 14  and a pharmaceutically acceptable carrier or diluent. 
     
     
         16 . An isolated polynucleotide molecule comprising a polynucleotide sequence that encodes a HCVR of an antibody as set forth in any one of  claims 1 - 7  or  9 - 14 . 
     
     
         17 . An isolated polynucleotide molecule comprising a polynucleotide sequence that encodes a LCVR of an antibody as set forth in any one of  claims 1 - 6  or  8 - 14 . 
     
     
         18 . A vector comprising the polynucleotide sequence of  claim 16  or  17 . 
     
     
         19 . A cell expressing the vector of  claim 18 . 
     
     
         20 . A multi-specific antigen-binding molecule or fragment thereof comprising a first antigen-binding specificity that binds specifically to PD-L1 and a second antigen-binding specificity that binds specifically to an antigen selected from the group consisting of a tumor-cell-specific antigen, an antigen specific to a virally-infected cell, and a T-cell co-inhibitor. 
     
     
         21 . The multi-specific antigen-binding molecule or fragment thereof of  claim 20 , wherein the first antigen-binding specificity comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within any one of the heavy chain variable region (HCVR) sequences listed in Table 1; and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within any one of the light chain variable region (LCVR) sequences listed in Table 1. 
     
     
         22 . The multi-specific antigen-binding molecule or fragment thereof of  claim 21 , wherein the first antigen-binding specificity comprises a HCVR having an amino acid sequence selected from the group consisting of HCVR sequences listed in Table 1; and a LCVR having an amino acid sequence selected from the group consisting of LCVR sequences listed in Table 1. 
     
     
         23 . The multi-specific antigen-binding molecule or fragment thereof of  claim 22 , wherein the first antigen-binding specificity comprises a HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 82/90, 98/106, 146/154, 162/170, 290/274, 306/274, 314/274 and 330/274. 
     
     
         24 . The multi-specific antigen-binding molecule or fragment thereof of  claim 20 , wherein the first antigen-binding specificity comprises an extracellular domain of one of PD-1 or B7-1, or fragment thereof. 
     
     
         25 . The multi-specific antigen-binding molecule or fragment thereof of  claim 20 , wherein the second antigen-binding specificity binds specifically to a T-cell co-inhibitor selected from the group consisting of LAG3, TIM3, B7-1, CTLA-4, BTLA, CD28, 2B4, LY108, TIGIT, ICOS, and CD160. 
     
     
         26 . The multi-specific antigen-binding molecule or fragment thereof of any one of  claims 20 - 24 , wherein the second antigen-binding specificity binds specifically to a tumor cell-specific antigen selected from the group consisting of CA9, CA125, melanoma-associated antigen (MAGE), carcinoembryonic antigen (CEA), vimentin, tumor-M2-PK, prostate-specific antigen (PSA), MART-1, and CA19-9. 
     
     
         27 . The multi-specific antigen-binding molecule or fragment thereof of any one of  claims 20 - 24 , wherein the second antigen-binding specificity binds specifically to an antigen from a cell infected with a virus selected from the group consisting of human immunodeficiency virus (HIV), hepatitis C virus (HCV), human papilloma virus (HPV), lymphocytic choriomeningitis virus (LCMV), and simian immunodeficiency virus (SIV). 
     
     
         28 . The multi-specific antigen-binding molecule or fragment thereof of any one of  claims 20 - 26  for use in the treatment of a cancer selected from the group consisting of renal cell carcinoma, colorectal cancer, ovarian cancer, prostate cancer, breast cancer, colon cancer, non-small-cell lung cancer and melanoma. 
     
     
         29 . The multi-specific antigen-binding molecule or fragment thereof any one of  claim 20 - 25  or  27  for use in the treatment of a chronic viral infection caused by a virus selected from the group consisting of HIV, HPV, HBV, HCV, LCMV and SIV. 
     
     
         30 . A multi-specific antigen-binding molecule or antigen-binding fragment thereof comprising a first binding specificity that binds specifically to PD-L1 and a second binding specificity that comprises an extracellular domain of PD-1 or B7-1, or fragment thereof. 
     
     
         31 . The multi-specific antigen-binding molecule or fragment thereof of  claim 30  for use in the treatment of a cancer selected from the group consisting of renal cell carcinoma, colorectal cancer, ovarian cancer, prostate cancer, breast cancer, colon cancer, non-small-cell lung cancer and melanoma. 
     
     
         32 . The multi-specific antigen-binding molecule or fragment thereof of  claim 30  for use in the treatment of a chronic viral infection caused by a virus selected from the group consisting of HIV, HPV, HBV, HCV, LCMV and SIV. 
     
     
         33 . A method of enhancing an immune response in a subject, the method comprising administering a pharmaceutical composition comprising an isolated antibody or antigen-binding fragment thereof according to any one of  claims 1 - 14 ; or a multi-specific antigen-binding molecule or fragment thereof according to any one of  claim 20 - 27  or  30 . 
     
     
         34 . A method of inhibiting a T-regulatory (Treg) cell in a subject comprising administering a pharmaceutical composition comprising an isolated human antibody or antigen-binding fragment thereof according to any one of  claims 1 - 14 ; or a multi-specific antigen-binding molecule or fragment thereof according to any one of  claim 20 - 27  or  30 . 
     
     
         35 . A method of enhancing T-cell activation in a subject, the method comprising administering a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof according to any one of  claims 1 - 14 ; or a multi-specific antigen-binding molecule or fragment thereof according to any one of  claim 20 - 27  or  30 . 
     
     
         36 . The method of any one of  claims 33 - 35 , wherein the subject has a disease or disorder selected from the group consisting of renal cell carcinoma, ovarian cancer, prostate cancer, non-small-cell lung cancer, colorectal cancer, and melanoma. 
     
     
         37 . The method of any one of  claims 33 - 35 , wherein the subject has a chronic viral infection caused by a virus selected from the group consisting of HIV, HCV, HBV, HPV, LCMV and SIV. 
     
     
         38 . A method of inhibiting growth of a tumor or a tumor cell, the method comprising contacting the tumor or tumor cell with a therapeutically effective amount of the antibody of any one of  claim 1 - 14  or  20 - 26 . 
     
     
         39 . The method of any one of  claims 33 - 38 , wherein the antibody or antigen-binding fragment thereof, or the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, is administered to the subject in combination with a second therapeutic agent. 
     
     
         40 . The method of  claim 39 , wherein the second therapeutic agent is selected from the group consisting of a NSAID, a corticosteroid, an antibody to a T-cell co-inhibitor, an antibody to a tumor specific antigen, an antibody to an autoimmune tissue antigen, an antibody to a virally-infected-cell antigen, an antibody to PD-1, a dietary supplement such an antioxidant, a VEGF antagonist, a chemotherapeutic agent, a cytotoxic agent, and an anti-viral drug. 
     
     
         41 . The method of any one of  claims 33 - 40 , wherein the antibody or antigen-binding fragment thereof is administered subcutaneously, intravenously, intradermally, intraperitoneally, orally, intramuscularly or intracranially. 
     
     
         42 . The method of any one of  claims 33 - 41 , wherein the antibody or antigen-binding fragment is administered at a dose of about 0.1 mg/kg of body weight to about 60 mg/kg of body weight of the subject.