Antibody molecules to pg-l1 and methods of treating cancer and infectious diseases

Patent metadata

Field	Value
Publication number	US-2024343808-A1
Application number	US-202318392954-A
Country	US
Kind code	A1
Filing date	Dec 21, 2023
Priority date	Oct 14, 2014
Publication date	Oct 17, 2024
Grant date	—

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.

First claim

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, C1-1040 (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;

Assignees

• Novartis Ag
• Dana Farber Cancer Inst Inc
• Harvard College

Inventors

• Freeman Gordon James
• Sharpe Arlene Helen
• Frey Gerhard Johann
• Chang Hwai Wen
• Mataraza Jennifer Marie
• Dranoff Glenn

Classifications

• G01N33/5759

  involving compounds localised on the membrane of tumour or cancer cells · CPC title

• G01N2333/70532

  B7 molecules, e.g. CD80, CD86 · CPC title

• C07K2317/567

  Framework region [FR] · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2317/56

  variable (Fv) region, i.e. VH and/or VL · CPC title