Binding molecules binding pd-l1 and lag-3

Abstract

The present invention relates to antibody molecules which bind to programmed death-ligand 1 (PD-L1) and lymphocyte-activation gene 3 (LAG-3). The antibody molecules preferably comprise a CDR-based antigen binding site for PD-L1, and a LAG-3 antigen binding site which may be located in two or more structural loops of a CH3 domain of the antibody molecule. The antibody molecules of the invention find application, for example, in cancer therapy.

1 .- 39 . (canceled) 
     
     
         40 . An antibody molecule which binds to programmed death-ligand 1 (PD-L1) and lymphocyte-activation gene 3 (LAG-3), wherein the antibody molecule comprises:
 (i) a CDR-based antigen binding site for PD-L1; and   (ii) a LAG-3 antigen binding site located in a CH3 domain of the antibody molecule, wherein the LAG-3 binding site comprises the amino acid sequences WDEPWGED (SEQ ID NO: 1) and PYDRWVWPDE (SEQ ID NO: 3).   
     
     
         41 . An antibody molecule according to  claim 40 , wherein the LAG-3 antigen biding site further comprises the amino acid sequence SNGQPENNY (SEQ ID NO: 2). 
     
     
         42 . An antibody molecule according to  claim 40 , wherein the LAG-3 antigen binding site comprises the amino acid sequence set forth in SEQ ID NO: 1 in the AB loop and the amino acid sequence set forth in SEQ ID NO: 3 in the EF loop of the CH3 domain. 
     
     
         43 . An antibody molecule according to  claim 41 , wherein the LAG-3 antigen binding site comprises the amino acid sequence set forth in SEQ ID NO: 1 in the AB loop, the amino acid sequence set forth in SEQ ID NO: 2 in the CD loop, and the amino acid sequence set forth in SEQ ID NO: 3 in the EF loop of the CH3 domain. 
     
     
         44 . An antibody molecule according to  claim 40 , wherein the antibody molecule is an immunoglobulin G1 (IgG1) molecule. 
     
     
         45 . An antibody molecule according to  claim 40 , wherein the antibody molecule comprises the CH3 domain set forth in SEQ ID NO: 5, 10, or 20. 
     
     
         46 . An antibody molecule according to  claim 41 , wherein the antibody molecule comprises a CH3 domain, wherein the CH3 domain comprises the sequence set forth in SEQ ID NO: 5, 10, or 20, and wherein the CH3 domain sequence further comprises a lysine residue (K) at the immediate C-terminus of the sequence shown in SEQ ID NO: 5, 10, or 20. 
     
     
         47 . An antibody molecule according to  claim 46 , wherein the antibody molecule comprises the CH3 domain set forth in SEQ ID NO: 135. 
     
     
         48 . An antibody molecule according to  claim 46 , wherein the antibody molecule comprises the sequence set forth in SEQ ID NO: 6, 7, 11, 12, 21, or 22. 
     
     
         49 . An antibody molecule according to  claim 46 , comprising the complementarity determining regions (CDRs) set forth in SEQ ID NOs: 86 to 91. 
     
     
         50 . An antibody molecule according to  claim 49 , wherein the antibody molecule comprises the VH and/or VL domains set forth in SEQ ID NOs: 92 and 93. 
     
     
         51 . An antibody molecule according to  claim 50 , wherein the antibody molecule comprises the heavy chain sequence set forth in any one of SEQ ID NOs: 94 to 97, 100, or 101. 
     
     
         52 . An antibody molecule according to  claim 51 , wherein the antibody molecule comprises the light chain sequence set forth in SEQ ID NO: 116. 
     
     
         53 . An antibody molecule according to  claim 40 , wherein the antibody molecule is conjugated to an immune system modulator, cytotoxic molecule, radioisotope, or detectable label. 
     
     
         54 . A nucleic acid encoding an antibody molecule according to  claim 52 . 
     
     
         55 . A vector comprising the nucleic acid of  claim 54 . 
     
     
         56 . A recombinant host cell comprising the nucleic acid of  claim 54 . 
     
     
         57 . A method of producing an antibody molecule, comprising culturing the recombinant host cell of  claim 56  under conditions for production of the antibody molecule. 
     
     
         58 . A pharmaceutical composition comprising an antibody molecule according to  claim 52  and a pharmaceutically acceptable excipient. 
     
     
         59 . A method of treating cancer in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of an antibody molecule according to  claim 52 . 
     
     
         60 . A method according to  claim 59 , wherein the cancer is selected from the group consisting of: Hodgkin's lymphoma, non-Hodgkin's lymphoma, ovarian cancer, prostate cancer, colorectal cancer, fibrosarcoma, renal cell carcinoma, melanoma, pancreatic cancer, breast cancer, glioblastoma multiforme, lung cancer, head and neck cancer, stomach cancer, bladder cancer, cervical cancer, uterine cancer, vulvar cancer, testicular cancer, penile cancer, leukemia, multiple myeloma, squamous cell cancer, testicular cancer, esophageal cancer, Kaposi's sarcoma, and central nervous system (CNS) lymphoma, hepatocellular carcinoma, Merkel cell carcinoma, nasopharyngeal cancer, and mesothelioma. 
     
     
         61 . An antibody molecule which binds to programmed death-ligand 1 (PD-L1) and lymphocyte-activation gene 3 (LAG-3), wherein the antibody molecule comprises the light chain sequence set forth in SEQ ID NO: 116, and the heavy chain sequence set forth in SEQ ID NO: 94. 
     
     
         62 . An antibody molecule which binds to programmed death-ligand 1 (PD-L1) and lymphocyte-activation gene 3 (LAG-3), wherein the antibody molecule comprises the light chain sequence set forth in SEQ ID NO: 116, and the heavy chain sequence set forth in SEQ ID NO: 94, and wherein the CH3 domain sequence in the heavy chain has the sequence set forth in SEQ ID NO: 135.