Human monoclonal antibodies to programmed death ligand 1 (pd-l1)

Abstract

The present disclosure provides isolated monoclonal antibodies, particularly human monoclonal antibodies that specifically bind to PD-L1 with high affinity. Nucleic acid molecules encoding the antibodies of this disclosure, expression vectors, host cells and methods for expressing the antibodies of this disclosure are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention are also provided. The disclosure also provides methods for detecting PD-L1, as well as methods for treating various diseases, including cancer and infectious diseases, using anti-PD-L1 antibodies.

1 . A monoclonal antibody, or an antigen-binding portion thereof, wherein the antibody, or antigen-binding portion thereof, specifically binds to human PD-L1, and wherein the antibody exhibits at least one of the following properties:
 (a) binds to human PD-L1 with a K D  of 1×10 −7 M or less;   (b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;   (c) increases interferon-γ production in an MLR assay; or   (d) increases interleukin-2 (IL-2) secretion in an MLR assay.   
     
     
         2 - 22 . (canceled) 
     
     
         23 . The antibody, or antigen-binding portion thereof, of  claim 1 , comprising:
 (a) a heavy chain variable region CDR1 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30;   (b) a heavy chain variable region CDR2 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:31, 32, 33, 34 35, 36, 37, 38, 39, and 40;   (c) a heavy chain variable region CDR3 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47 48, 49, and 50;   (d) a light chain variable region CDR1 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60;   (e) a light chain variable region CDR2 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70;   (f) a light chain variable region CDR3 that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80.   
     
     
         24 - 26 . (canceled) 
     
     
         27 . The antibody, or antigen binding portion thereof, of  claim 1 , comprising:
 (a) a heavy chain variable region that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and   (b) a light chain variable region that comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.   
     
     
         28 - 42 . (canceled) 
     
     
         43 . A transgenic mouse comprising human immunoglobulin heavy and light chain transgenes, wherein the mouse expresses an antibody, or antigen-binding portion thereof, that specifically binds to human PD-L1, and wherein the antibody exhibits at least one of the following properties:
 (a) binds to human PD-L1 with a K D  of 1×10 −7 M or less;   (b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;   (c) increases interferon-γ production in an MLR assay; or   (d) increases interleukin-2 (IL-2) secretion in an MLR assay.   
     
     
         44 . (canceled) 
     
     
         45 . A method of modulating an immune response in a subject comprising administering to the subject an antibody, or antigen-binding portion thereof, that specifically binds to human PD-L1, such that the immune response in the subject is modulated, wherein the antibody exhibits at least one of the following properties:
 (a) binds to human PD-L1 with a K D  of 1×10 −7 M or less;   (b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;   (c) increases interferon-γ production in an MLR assay; or   (d) increases interleukin-2 (IL-2) secretion in an MLR assay.   
     
     
         46 . A method of inhibiting growth of tumor cells in a subject, comprising administering to the subject an antibody, or antigen-binding portion thereof, that specifically binds to human PD-L1, such that growth of tumor cells in the subject is inhibited, wherein the antibody exhibits at least one of the following properties:
 (a) binds to human PD-L1 with a K D  of 1×10 −7 M or less;   (b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;   (c) increases interferon-γ production in an MLR assay; or   (d) increases interleukin-2 (IL-2) secretion in an MLR assay.   
     
     
         47 - 49 . (canceled) 
     
     
         50 . The method of  claim 46 , wherein the tumor cells are of a cancer selected from the group consisting of melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, and lung cancer. 
     
     
         51 . The method of  claim 46 , wherein the tumor cells are of a cancer selected from the list consisting of bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. 
     
     
         52 . (canceled) 
     
     
         53 . A method of treating an infectious disease in a subject comprising administering to the subject an antibody, or antigen-binding portion thereof, that specifically binds to human PD-L1, such that the subject is treated for the infectious disease, wherein the antibody exhibits at least one of the following properties:
 (a) binds to human PD-L1 with a K D  of 1×10 −7 M or less;   (b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;   (c) increases interferon-γ production in an MLR assay; or   (d) increases interleukin-2 (IL-2) secretion in an MLR assay.   
     
     
         54 . The method of  claim 53 , wherein the infectious disease is selected from the list consisting of: HIV, Influenza, Herpes,  Giardia , Malaria,  Leishmania , the pathogenic infection by the virus Hepatitis (A, B, & C), herpes virus, adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus, pathogenic infection by the bacteria  Chlamydia , rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci,  Klebsiella, Proteus, Serratia, Pseudomonas, Legionella , diphtheria,  Salmonella , bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria, pathogenic infection by the fungi  Candida, Cryptococcus neoformans, Aspergillus , Genus  Mucorales, Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis  and  Histoplasma capsulatum , and pathogenic infection by the parasites  Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba  sp.,  Giardia lambia, Cryptosporidium  sp.,  Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylus brasiliensis.    
     
     
         55 . A method of enhancing an immune response to an antigen in a subject, comprising administering to the subject: (i) the antigen; and (ii) the antibody, or antigen-binding portion thereof, that specifically binds to human PD-L1, such that an immune response to the antigen in the subject is enhanced, wherein the antibody exhibits at least one of the following properties:
 (a) binds to human PD-L1 with a K D  of 1×10 −7 M or less;   (b) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay;   (c) increases interferon-γ production in an MLR assay; or   (d) increases interleukin-2 (IL-2) secretion in an MLR assay.   
     
     
         56 . The method of  claim 55 , wherein the antigen is a tumor antigen, a viral antigen, a bacterial antigen or an antigen from a pathogen. 
     
     
         57 . A method of treating or preventing an inflammatory disease in a subject comprising administering to the subject the antibody, or antigen-binding portion thereof, of  claim 1  such that the subject is treated for the inflammatory disease. 
     
     
         58 . (canceled) 
     
     
         59 . A method for preparing an anti-PD-L1 antibody comprising:
 (a) providing a nucleic acid encoding an antibody, or antigen-binding portion thereof, comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 domains; and a light chain variable region comprising CDR1, CDR2, and CDR3 domains, wherein the heavy chain variable region CDR1 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:21, 22, 23, 24, 25, 26, 27, 28, 29, and 30; the heavy chain variable CDR2 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:31, 32, 33, 34, 35, 36, 37, 38, 39, and 40; the heavy chain variable region CDR3 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:41, 42, 43, 44, 45, 46, 47, 48, 49, and 50; the light chain variable region CDR1 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:51, 52, 53, 54, 55, 56, 57, 58, 59, and 60; the light chain variable region CDR2 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:61, 62, 63, 64, 65, 66, 67, 68, 69, and 70; and the light chain variable region CDR3 comprises amino acids having a sequence selected from the group consisting of SEQ ID NOs:71, 72, 73, 74, 75, 76, 77, 78, 79, and 80;   (b) altering the nucleic acid encoding at least one amino acid residue within at least one variable region to create a nucleic acid encoding an altered antibody sequence or antigen-binding portion thereof comprising at least one amino acid alteration; and   (c) expressing the altered antibody sequence or antigen-binding portion thereof as a protein.   
     
     
         60 - 67 . (canceled) 
     
     
         68 . The antibody, or antigen-binding portion thereof, of  claim 1 , which is a chimeric antibody or antigen-binding portion thereof, a humanized antibody or antigen-binding portion thereof, or a fully human antibody or antigen-binding portion thereof.