Anti-pd-1 antibodies and methods of use thereof

Abstract

The instant disclosure provides antibodies that specifically bind to human PD-1 and antagonize PD-1 function. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.

1 - 86 . (canceled) 
     
     
         87 . An isolated antibody that specifically binds to the amino acid sequence of SEQ ID NO: 77, 78, and 79. 
     
     
         88 . A method of increasing T cell activation in response to an antigen in a subject, the method comprising administering to the subject an effective amount of the antibody of  claim 87 . 
     
     
         89 . A method of treating cancer in a subject, the method comprising administering to the subject an effective amount of the antibody of  claim 87 . 
     
     
         90 . An isolated antibody that specifically binds to human PD-1, the antibody comprising:
 (a) a heavy chain variable region comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of the heavy chain variable region amino acid sequence of SEQ ID NO: 15, 17, 26, 27, 28, 29, 30, or 31; and/or   (b) a light chain variable region comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of the light chain variable region amino acid sequence of SEQ ID NO: 16.   
     
     
         91 . A pharmaceutical composition comprising the isolated antibody of  claim 90  and a pharmaceutically acceptable carrier or excipient. 
     
     
         92 . An isolated polynucleotide encoding:
 (a) a heavy chain variable region and/or a light chain variable region of the isolated antibody of  claim 90 ; or   (b) a heavy chain and/or a light chain of the isolated antibody of  claim 90 .   
     
     
         93 . A vector comprising the isolated polynucleotide of  claim 92 . 
     
     
         94 . A host cell comprising the isolated polynucleotide of  claim 92 . 
     
     
         95 . A method of producing an antibody that binds to human PD-1, the method comprising culturing the host cell of  claim 94  so that the polynucleotide is expressed and the antibody is produced. 
     
     
         96 . A method of increasing T cell activation in response to an antigen in a subject, the method comprising administering to the subject an effective amount of the antibody of  claim 90 . 
     
     
         97 . A method of treating cancer in a subject, the method comprising administering to the subject an effective amount of the antibody of  claim 90 . 
     
     
         98 . The method of  claim 97 , wherein the cancer is selected from the group consisting of acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, bladder cancer, bone cancer, brain stem glioma, breast cancer, cancer of the adrenal gland, cancer of the endocrine system, cancer of the kidney or ureter, cancer of the parathyroid gland, cancer of the small intestine, cancer of the thyroid gland, cancer of the urethra, cancers of the anus, cancers of the oropharynx, cancers of the penis, cancers of the rectum, cancers of the vagina, cancers of the vulva, cancers that express PD-L1, carcinoma of the cervix, carcinoma of the endometrium, carcinoma of the fallopian tubes, carcinoma of the renal pelvis, cervical cancer, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, endometrial cancer, environmentally induced cancers including those induced by asbestos, epidermoid cancer, esophageal cancer, glioblastoma multiforme, glioma, head and neck cancer, hepatocellular cancer, Hodgkin's Disease, HPV-associated cancers, Kaposi's sarcoma, leukemia, liver cancer, lung cancer, lymphocytic lymphoma, lymphoma, melanoma, metastatic cancers, multiple myeloma, neoplasm of the central nervous system (CNS), non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, pituitary adenoma, primary CNS lymphoma, prostate cancer, refractory or recurrent malignancies, renal cell carcinoma, sarcoma, sarcoma of soft tissue, skin cancer, solid tumors of childhood, spinal axis tumor, squamous cell cancer, stomach cancer, T-cell lymphoma, testicular cancer, and uterine cancer. 
     
     
         99 . The method of  claim 97 , wherein the antibody is administered subcutaneously, intratumorally, or intravenously. 
     
     
         100 . The method of  claim 97 , further comprising administering an additional therapeutic agent to the subject. 
     
     
         101 . The method of  claim 100 , wherein the additional therapeutic agent is a chemotherapeutic, radiotherapeutic, or checkpoint targeting agent. 
     
     
         102 . The method of  claim 101 , wherein the checkpoint targeting agent is selected from the group consisting of an antagonist anti-PD-1 antibody, an antagonist anti-PD-L1 antibody, an antagonist anti-PD-L2 antibody, an antagonist anti-CTLA-4 antibody, an antagonist anti-TIM-3 antibody, an antagonist anti-LAG-3 antibody, an antagonist anti-CEACAM1 antibody, an antagonist anti-TIGIT antibody, an agonist anti-CD137 antibody, an agonist anti-ICOS antibody, an agonist anti-GITR antibody, and an agonist anti-OX40 antibody. 
     
     
         103 . The method of  claim 100 , wherein the additional therapeutic agent is an inhibitor of indoleamine-2,3-di oxygenase (IDO). 
     
     
         104 . The method of  claim 103 , wherein the inhibitor is selected from the group consisting of epacadostat, F001287, indoximod, and LG919.