Antibody molecules to pd-l1 and uses thereof

Abstract

Antibody molecules that specifically bind to PD-L1 are disclosed. Combination therapies comprising the anti-PD-L1 antibody molecules are also disclosed. The anti-PD-L1 antibody molecules can be used to treat, prevent and/or diagnose cancerous or infectious conditions and disorders.

1 .- 141 . (canceled) 
     
     
         142 . A method of treating a cancer or an infectious disease, comprising administering to a subject in need thereof, an isolated antibody molecule capable of binding to human Programmed Death-Ligand 1 (PD-L1) in combination with an AKT inhibitor in an amount effective to treat the cancer or infectious disease; wherein the antibody molecule comprises:
 (a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 4; a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14;   (b) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 9, a VLCDR2 amino acid sequence of SEQ ID NO: 10, and a VLCDR3 amino acid sequence of SEQ ID NO: 11;   (c) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 195; a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14; or   (d) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 195; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 9, a VLCDR2 amino acid sequence of SEQ ID NO: 10, and a VLCDR3 amino acid sequence of SEQ ID NO: 11, wherein the cancer expresses PD-L1.   
     
     
         143 . The method of  claim 142 , wherein the cancer is chosen from a solid tumor, a lung cancer, a skin cancer, a renal cancer, a liver cancer, a prostate cancer, a breast cancer, a colorectal cancer, a gastric cancer, a pancreatic cancer, a thyroid cancer, a brain cancer, a uterine cancer, a nasopharyngeal cancer, a head and neck cancer, an ovarian cancer, an endometrial cancer, an endocrine cancer, a bladder cancer, a urothelial cancer, and a hematological cancer, and a metastatic lesion of the cancer. 
     
     
         144 . The method of  claim 143 , wherein
 (a) the lung cancer is chosen from a non-small cell lung cancer (NSCLC), a lung adenocarcinoma, a squamous cell lung carcinoma, and a small cell lung cancer;   (b) the skin cancer is a melanoma or a Merkel cell carcinoma;   (c) the renal cancer is chosen from a renal cell carcinoma (RCC), a metastatic renal cell carcinoma, and a clear cell renal cell carcinoma (CCRCC);   (d) the hematologic cancer is chosen from a lymphoma, a myeloma, and a leukemia;   (e) the brain cancer is a glioblastoma;   (f) the breast cancer is a triple negative breast cancer;   (g) the liver cancer is a hepatocellular carcinoma; or   (h) the cancer is a MSI-high (high microsatellite instability) cancer.   
     
     
         145 . The method of  claim 142 , wherein the combination of the antibody molecule and AKT inhibitor is administered further in combination with one or more therapeutic agents or procedures. 
     
     
         146 . The method of  claim 145 , wherein the one or more therapeutic agents or procedures is chosen from one or more of chemotherapy, a targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, an immune-based therapy, a cytokine, surgical procedure, a radiation procedure, an activator of a costimulatory molecule, an inhibitor of an inhibitory molecule, a vaccine, and a cellular immunotherapy. 
     
     
         147 . The method of  claim 145 , wherein the one or more therapeutic agents is
 (a) an agonist of a costimulatory molecule chosen from one or more of GITR, OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, and CD83 ligand; or   (b) an inhibitor of an immune checkpoint molecule chosen from one or more of PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM-1, CEACAM-5, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and TGFR.   
     
     
         148 . The method of  claim 145 , wherein the one or more therapeutic agents is
 (a) an inhibitor of PD-1;   (b) an inhibitor of LAG-3;   (c) an inhibitor of TIM-3;   (d) an agonist of GITR;   (e) an interleukin;   (f) a MEK inhibitor;   (g) an FGFR inhibitor,   (h) a chemotherapy to treat a lung cancer;   (i) an indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor to treat a lung cancer;   (j) an inhibitor of CTLA-4 to treat a lung cancer or a melanoma;   (k) a cancer vaccine;   (l) one or more of: an immune-based therapy, a targeting agent, a VEGF tyrosine kinase inhibitor, an RNAi inhibitor, or an inhibitor of a downstream mediator of VEGF signaling, to treat a renal cancer;   (m) one, two or all of oxaliplatin, leucovorin, or 5-FU, to treat a melanoma, a colorectal cancer, a non-small cell lung cancer, an ovarian cancer, a breast cancer, a prostate cancer, a pancreatic cancer, a hematological cancer, or a renal cell carcinoma; or   (n) a tyrosine kinase inhibitor to treat a renal cancer.   
     
     
         149 . The method of  claim 148 , wherein
 (a) the inhibitor of PD-1 is an anti-PD-1 antibody molecule, or is chosen from Nivolumab, Pembrolizumab, Pidilizumab, AMP-224, or AMP 514, to treat a thyroid cancer, a non-small cell lung cancer, a triple negative breast cancer, an endometrial cancer, a uterine cancer, and a lymphoma;   (b) the inhibitor of LAG-3 is an anti-LAG-3 antibody molecule, to treat an NSCLC, a melanoma, an RCC, or a hematologic cancer;   (c) the inhibitor of TIM-3 is an anti-TIM-3 antibody molecule, to treat a melanoma or a renal cell carcinoma;   (d) the agonist of GITR is an anti-GITR antibody molecule or a GITR fusion protein, to treat a non-small cell lung cancer;   (e) the interleukin is IL-15, to treat a solid tumor;   (f) the MEK inhibitor is chosen from ARRY-142886, G02442104 (GSK1120212), RDEA436, RDEA119/BAY 869766, AS703026, G00039805 (AZD-6244 or selumetinib), BIX 02188, BIX 02189, CI-1040 (PD-184352), PD0325901, PD98059, U0126, GDC-0973 (Methanone or [3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl][3-hydroxy-3-(25)-2-piperidinyl-1-azetidinyl]-), G-38963, G02443714 (AS703206), and a pharmaceutically acceptable salt or solvate thereof, to treat a triple negative breast cancer, an NSCLC, or a colorectal cancer;   (g) the chemotherapy is a platinum doublet therapy;   (h) the IDO inhibitor is INCB24360;   (i) the inhibitor of CTLA-4 is an anti-CTLA-4 antibody or a soluble ligand of CTLA-4, wherein the antibody molecule is further used in combination with a BRAF inhibitor;   (j) the immune-based therapy comprises interleukin-2 or interferon-α.   (k) the targeting agent is a VEGF inhibitor;   (l) the VEGF tyrosine kinase inhibitor is chosen from sunitinib, sorafenib, axitinib, and pazopanib; or   (m) the inhibitor of a downstream mediator of VEGF signaling is an inhibitor of the mammalian target of rapamycin (mTOR).   
     
     
         150 . The method of  claim 142 , wherein the antibody molecule is administered at a dose of about 1 to 30 mg/kg. 
     
     
         151 . The method of  claim 142 , wherein the antibody molecule is administered once a week to once every 2, 3, or 4 weeks. 
     
     
         152 . The method of  claim 142 , wherein the antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 18, 30, 38, 46, 50, 54, 62, 70, or 78, a VL comprising the amino acid sequence of SEQ ID NO: 22, 26, 34, 42, 58, 66, 74, 82, or 86, or both. 
     
     
         153 . The method of  claim 142 , wherein the antibody molecule comprises:
 (a) a VH comprising the amino acid sequence of SEQ ID NO: 18 and a VL comprising the amino acid sequence of SEQ ID NO: 22;   (b) a VH comprising the amino acid sequence of SEQ ID NO: 18 and a VL comprising the amino acid sequence of SEQ ID NO: 26;   (c) a VH comprising the amino acid sequence of SEQ ID NO: 18 and a VL comprising the amino acid sequence of SEQ ID NO: 86;   (d) a VH comprising the amino acid sequence of SEQ ID NO: 30 and a VL comprising the amino acid sequence of SEQ ID NO: 34;   (e) a VH comprising the amino acid sequence of SEQ ID NO: 30 and a VL comprising the amino acid sequence of SEQ ID NO: 66;   (f) a VH comprising the amino acid sequence of SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ ID NO: 42;   (g) a VH comprising the amino acid sequence of SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ ID NO: 74;   (h) a VH comprising the amino acid sequence of SEQ ID NO: 46 and a VL comprising the amino acid sequence of SEQ ID NO: 42;   (i) a VH comprising the amino acid sequence of SEQ ID NO: 50 and a VL comprising the amino acid sequence of SEQ ID NO: 42;   (j) a VH comprising the amino acid sequence of SEQ ID NO: 50 and a VL comprising the amino acid sequence of SEQ ID NO: 22;   (k) a VH comprising the amino acid sequence of SEQ ID NO: 50 and a VL comprising the amino acid sequence of SEQ ID NO: 86;   (l) a VH comprising the amino acid sequence of SEQ ID NO: 54 and a VL comprising the amino acid sequence of SEQ ID NO: 58;   (m) a VH comprising the amino acid sequence of SEQ ID NO: 54 and a VL comprising the amino acid sequence of SEQ ID NO: 86;   (n) a VH comprising the amino acid sequence of SEQ ID NO: 62 and a VL comprising the amino acid sequence of SEQ ID NO: 66;   (o) a VH comprising the amino acid sequence of SEQ ID NO: 62 and a VL comprising the amino acid sequence of SEQ ID NO: 86;   (p) a VH comprising the amino acid sequence of SEQ ID NO: 70 and a VL comprising the amino acid sequence of SEQ ID NO: 66; or   (q) a VH comprising the amino acid sequence of SEQ ID NO: 78 and a VL comprising the amino acid sequence of SEQ ID NO: 82.   
     
     
         154 . The method of  claim 142 , wherein the antibody molecule comprises:
 (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 20 and a light chain comprising the amino acid sequence of SEQ ID NO: 24;   (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 20 and a light chain comprising the amino acid sequence of SEQ ID NO: 28;   (c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 20 and a light chain comprising the amino acid sequence of SEQ ID NO: 88;   (d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 32 and a light chain comprising the amino acid sequence of SEQ ID NO: 36;   (e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 32 and a light chain comprising the amino acid sequence of SEQ ID NO: 68;   (f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 44;   (g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 76;   (h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 48 and a light chain comprising the amino acid sequence of SEQ ID NO: 44;   (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 44;   (j) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 24   (k) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 88;   (l) a heavy chain comprising the amino acid sequence of SEQ ID NO: 56 and a light chain comprising the amino acid sequence of SEQ ID NO: 60;   (m) a heavy chain comprising the amino acid sequence of SEQ ID NO: 56 and a light chain comprising the amino acid sequence of SEQ ID NO: 88;   (n) a heavy chain comprising the amino acid sequence of SEQ ID NO: 64 and a light chain comprising the amino acid sequence of SEQ ID NO: 68;   (o) a heavy chain comprising the amino acid sequence of SEQ ID NO: 64 and a light chain comprising the amino acid sequence of SEQ ID NO: 88;   (p) a heavy chain comprising the amino acid sequence of SEQ ID NO: 72 and a light chain comprising the amino acid sequence of SEQ ID NO: 68;   (q) a heavy chain comprising the amino acid sequence of SEQ ID NO: 80 and a light chain comprising the amino acid sequence of SEQ ID NO: 84;   (r) a heavy chain comprising the amino acid sequence of SEQ ID NO: 197 and a light chain comprising the amino acid sequence of SEQ ID NO: 36;   (s) a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 44;   (t) a heavy chain comprising the amino acid sequence of SEQ ID NO: 96 and a light chain comprising the amino acid sequence of SEQ ID NO: 68;   (u) a heavy chain comprising the amino acid sequence of SEQ ID NO: 247 and a light chain comprising the amino acid sequence of SEQ ID NO: 84; or   (v) a heavy chain comprising the amino acid sequence of SEQ ID NO: 260 and a light chain comprising the amino acid sequence of SEQ ID NO: 44.   
     
     
         155 . The method of  claim 142 , wherein the antibody molecule is a Fab, F(ab′) 2 , Fv, or a single chain Fv fragment (scFv). 
     
     
         156 . The method of  claim 142 , wherein the antibody molecule comprises a heavy chain constant region of IgG1, IgG2, IgG3, or IgG4 and/or a light chain constant region of kappa or lambda. 
     
     
         157 . The method of  claim 142 , wherein the antibody molecule comprises a kappa light chain constant region and:
 (a) a human IgG4 heavy chain constant region comprising SEQ ID NO: 188 or 190 or a human IgG4 heavy chain constant region comprising Proline at the position corresponding to amino acid 108 of SEQ ID NO: 188 or 190;   (b) a human IgG1 heavy chain constant region comprising SEQ ID NO: 192 or a human IgG1 heavy chain constant region comprising Alanine at the position corresponding to amino acid 180 of SEQ ID NO: 191;   (c) a human IgG1 heavy chain constant region comprising SEQ ID NO: 193 or a human IgG1 heavy chain constant region comprising Alanine at the positions corresponding to amino acids 148 and 212 of SEQ ID NO: 191; or   (d) a human IgG1 heavy chain constant region comprising SEQ ID NO: 194 or a human IgG1 heavy chain constant region comprising Alanine at the positions corresponding to amino acid 117 and 118 of SEQ ID NO: 191.   
     
     
         158 . The method of  claim 142 , wherein the antibody molecule has one or more of the following properties:
 (a) is capable of binding to human PD-L1 with a dissociation constant (KD) of less than about 0.2 nM;   (b) binds an extracellular domain of PD-L1;   (c) is capable of reducing binding of PD-1 to PD-L1; or   (d) is capable of enhancing an antigen-specific T cell response.   
     
     
         159 . The method of  claim 142 , wherein said antibody molecule is a humanized antibody molecule, a monospecific antibody molecule, or a bispecific antibody molecule. 
     
     
         160 . The method of  claim 159 , wherein said antibody molecule is a bispecific antibody molecule and has a first binding specificity for PD-L1 and a second binding specificity for TIM-3, LAG-3, CEACAM-1, CEACAM-5, PD-1 or PD-L2. 
     
     
         161 . The method of  claim 142 , wherein
 (a) the VH comprises the amino acid sequence of SEQ ID NO: 30 and the VL comprises the amino acid sequence of SEQ ID NO: 66; or   (b) the VH comprises the amino acid sequence of SEQ ID NO: 78 and the VL comprising the amino acid sequence of SEQ ID NO: 82.   
     
     
         162 . The method of  claim 142 , wherein the antibody molecule comprises
 (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 96 and a light chain comprising the amino acid sequence of SEQ ID NO: 68; or   (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 80 and a light chain comprising the amino acid sequence of SEQ ID NO: 84.   
     
     
         163 . The method of  claim 142 , wherein the AKT inhibitor is RX-0201 or MK-2206. 
     
     
         164 . The method of  claim 142 , wherein the combination is administered in sequentially or simultaneously.