Anti-pd-1 antibodies and methods of use thereof

Abstract

The present invention provides antagonizing antibodies that bind to programmed cell death protein 1 (PD-1) and methods of using same. The anti-PD-1 antibodies can be used therapeutically alone or in combination with other therapeutics to treat cancer and other diseases.

1 . An isolated antagonist antibody that specifically binds to PD-1 and comprises:
 a heavy chain variable region (VH) comprising a VH complementarity determining region one (CDR1), VH CDR2, and VH CDR3 of the VH having an amino acid sequence SEQ ID NO: 6; and   a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3 of the VL having an amino acid sequence SEQ ID NO: 8.   
     
     
         2 . The isolated antagonist antibody of  claim 1 , wherein the antibody comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 13, 14, or 15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 27 or 28, a VH CDR3 comprising the amino acid sequence shown in SEQ ID NO: 18, a VL CDR1 comprising the amino acid sequence shown in SEQ ID NO:10, a VL CDR2 comprising the amino acid sequence shown in SEQ ID NO: 20, a VL CDR3 comprising the amino acid sequence shown in SEQ ID NO: 21. 
     
     
         3 . The isolated antagonist antibody of  claim 1 , wherein the antibody comprises a VH comprising the amino acid sequence shown in SEQ ID NO: 6, or a variant thereof with one or several conservative amino acid substitutions in residues that are not within a CDR. 
     
     
         4 . The isolated antagonist antibody of  claim 3 , wherein the antibody comprises a VL comprising the amino acid sequence shown in SEQ ID NO: 8, or a variant thereof with one or several amino acid substitutions in amino acids that are not within a CDR. 
     
     
         5 . The isolated antagonist antibody of  claim 1 , wherein the antibody comprises a VH comprising the amino acid sequence shown in SEQ ID NO: 6, and a VL comprising the amino acid sequence shown in SEQ ID NO: 8. 
     
     
         6 . (canceled) 
     
     
         7 . The isolated antagonist antibody of  claim 1 , wherein the antibody comprises a constant region. 
     
     
         8 . The isolated antagonist antibody of  claim 7 , wherein the antibody has an isotype that is selected from the group consisting of IgG 2 , IgG 2Δa , IgG 4 , IgG 4Δb , IgG 4Δc , IgG 4  S228P, IgG 4Δb  S228P and IgG 4Δc  S228P. 
     
     
         9 . The isolated antagonist antibody of  claim 7 , wherein the constant region is IgG 4  S228P. 
     
     
         10 . The isolated antagonist antibody of  claim 1 , wherein each CDR of the antibody is defined in accordance with the Kabat definition, the Chothia definition, the combination of the Kabat definition and the Chothia definition, the AbM definition, or the contact definition of CDR. 
     
     
         11 . (canceled) 
     
     
         12 . An isolated anti-PD-1 antibody, wherein the antibody comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 13, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 28, a VH CDR3 comprising the amino acid sequence shown in SEQ ID NO: 18, a VL CDR1 comprising the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 comprising the amino acid sequence shown in SEQ ID NO: 20, and a VL CDR3 comprising the amino acid sequence shown in SEQ ID NO: 21. 
     
     
         13 . The isolated antibody of  claim 1 , wherein the antibody promotes IFNγ and/or TNF secretion from T cells. 
     
     
         14 . The isolated antibody of  claim 1 , wherein the antibody promotes proliferation of T cells. 
     
     
         15 . The isolated antibody of  claim 1 , wherein the antibody inhibits tumor growth. 
     
     
         16 . The isolated antibody of  claim 1 , wherein the antibody binds human PD-1 and mouse PD-1. 
     
     
         17 . The isolated antibody of  claim 16 , wherein the antibody binds human PD-1 with an affinity of about 0.73 nM at 25° C. as measured by surface plasmon resonance. 
     
     
         18 . An isolated cell line that produces the antibody of  claim 1 . 
     
     
         19 . An isolated nucleic acid encoding the antibody of  claim 1 . 
     
     
         20 . A recombinant expression vector comprising the nucleic acid of  claim 19 . 
     
     
         21 . A host cell comprising the expression vector of  claim 20 . 
     
     
         22 . A hybridoma capable of producing the antibody of  claim 1 . 
     
     
         23 . A method of producing an anti-PD-1 antagonist antibody, the method comprising: culturing a cell line that recombinantly produces the antibody of  claim 1  under conditions wherein the antibody is produced; and recovering the antibody. 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . A pharmaceutical composition comprising the antibody of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         28 . (canceled) 
     
     
         29 . A method for treating cancer in a subject in need thereof, the method comprising administering to the individual an effective amount of the anti-PD-1 antibody of  claim 1  such that one or more symptoms associated with the cancer is ameliorated in the individual. 
     
     
         30 . The method of  claim 29 , wherein the cancer is selected from the group consisting of gastric cancer, sarcoma, lymphoma, Hodgkin's lymphoma, leukemia, head and neck cancer, squamous cell head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, colon cancer, oral cancer, skin cancer, and melanoma. 
     
     
         31 . The method of  claim 29  wherein the individual is a previously treated adult patient with locally advanced or metastatic melanoma, squamous cell head and neck cancer (SCHNC), ovarian carcinoma, sarcoma, or relapsed or refractory classic Hodgkin's Lymphoma (cHL). 
     
     
         32 . The method of  claim 29 , wherein the anti-PD-1 antibody is administered at a dosage of about 0.5 mg/kg, about 1.0 mg/kg, about 3.0 mg/kg, or about 10 mg/kg. 
     
     
         33 . The method of  claim 29 , wherein the anti-PD-1 antibody is administered once every 7, 14, 21, or 28 days. 
     
     
         34 . The method of  claim 29 , wherein the anti-PD-1 antibody is administered intravenously or subcutaneously. 
     
     
         35 . The method of  claim 29 , wherein the method further comprises administering an effective amount of a second therapeutic agent. 
     
     
         36 . The method of  claim 35 , wherein the second therapeutic agent is selected from the group consisting of an anti-CTLA4 antibody, an anti-4-1BB antibody, a second PD-1 antagonist, an anti-PD-L1 antibody, an anti-TIM3 antibody, an anti-LAG3 antibody, an anti-TIGIT antibody, an anti-OX40 antibody, an anti-GITR antibody, a tyrosine kinase inhibitor, and an ALK inhibitor. 
     
     
         37 . The method of  claim 36 , wherein the tyrosine kinase inhibitor is axitinib or palbociclib. 
     
     
         38 . The method of  claim 36 , wherein the ALK inhibitor is sunitinib or crizotinib. 
     
     
         39 - 46 . (canceled)