Antibodies to human programmed death receptor pd-1

Abstract

Antibodies which block binding of hPD-1 to hPD-L1 or hPD-L2 and their variable region sequences are disclosed. A method of increasing the activity (or reducing downmodulation) of an immune cell through the PD-1 pathway is also disclosed.

1 - 23 . (canceled) 
     
     
         24 . A method of increasing the activity of an immune cell, comprising contacting the immune cell with a monoclonal antibody which binds to human programmed death receptor 1 (hPD-1), wherein the antibody blocks the binding of human PD-L1 and human PD-L2 to hPD-1 and comprises:
 a. three light chain CDRs having the amino acid sequences set forth in SEQ ID NOs: 9, 10 and 11 and   b. three heavy chain CDRs having the amino acid sequences set forth in SEQ ID NOs: 12, 13 and 14.   
     
     
         25 . A method of increasing the activity of an immune cell for the treatment of cancer in a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of a monoclonal antibody which binds to human programmed death receptor 1 (hPD-1), wherein the antibody blocks the binding of human PD-L1 and human PD-L2 to hPD-1 and comprises:
 a. three light chain CDRs having the amino acid sequences set forth in SEQ ID Nos: 9, 10 and 11 and   b. three heavy chain CDRs having the amino acid sequences set forth in SEQ ID Nos: 12, 13 and 14.   
     
     
         26 . The method of  claim 25 , wherein the cancer is melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, esophageal cancer, squamous cell carcinoma of the head and neck, liver cancer, ovarian cancer, cervical cancer, thyroid cancer, glioblastoma, or lymphoma. 
     
     
         27 . The method of  claim 25 , wherein the antibody is used in combination with an anti-neoplastic agent or immunogenic agent. 
     
     
         28 . The method of  claim 25 , wherein the antibody is used in combination with chemotherapy, radiotherapy, or surgery. 
     
     
         29 . The method of  claim 25 , wherein the antibody is used in combination with an antibody that binds to VEGF, an antibody that binds to EGFR, an antibody that binds to Her2/neu, an antibody that binds to a VEGF receptor, an antibody that binds to CTLA-4, an antibody that binds to OX-40, an antibody that binds to 4-1BB, an antibody that binds to ICOS, an antibody that binds to CD20, or an antibody that binds to CD40. 
     
     
         30 . The method of  claim 25 , wherein the antibody blocks binding of human PD-L1 and human PD-L2 to human PD-1 with an IC50 of about 1 nM or lower, wherein the IC50 is measured using an FMAT competition assay. 
     
     
         31 . The method of  claim 25 , wherein the antibody binds PD-1 with a K D  of about 30 μM or lower, wherein the binding is determined using bio-light interferometry. 
     
     
         32 . The method of  claim 25 , wherein the antibody is an IgG4 isotype. 
     
     
         33 . The method of  claim 25 , wherein the wherein the antibody is a human antibody, a humanized antibody or a chimeric antibody. 
     
     
         34 . The method of  claim 25 , wherein the antibody blocks binding of human PD-L1 and human PD-L2 to human PD-1 with an IC50 of about 1 nM or lower, wherein the IC50 is measured using a FACS assay. 
     
     
         35 . The method of  claim 25 , wherein the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:6 and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:5. 
     
     
         36 . The method of  claim 35 , wherein the cancer is melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, esophageal cancer, squamous cell carcinoma of the head and neck, liver cancer, ovarian cancer, cervical cancer, thyroid cancer, glioblastoma, or lymphoma. 
     
     
         37 . The method of  claim 35 , wherein the antibody is used in combination with an anti-neoplastic agent or immunogenic agent. 
     
     
         38 . The method of  claim 35 , wherein the antibody is used in combination with chemotherapy, radiotherapy, or surgery. 
     
     
         39 . The method of  claim 35 , wherein the antibody is used in combination with an antibody that binds to VEGF, an antibody that binds to EGFR, an antibody that binds to Her2/neu, an antibody that binds to a VEGF receptor, an antibody that binds to CTLA-4, an antibody that binds to OX-40, an antibody that binds to 4-1BB, an antibody that binds to ICOS, an antibody that binds to CD20, or an antibody that binds to CD40. 
     
     
         40 . The method of  claim 35 , wherein the antibody blocks binding of human PD-L1 and human PD-L2 to human PD-1 with an IC50 of about 1 nM or lower, wherein the IC50 is measured using an FMAT competition assay. 
     
     
         41 . The method of  claim 35 , wherein the antibody binds PD-1 with a K D  of about 30 μM or lower, wherein the binding is determined using bio-light interferometry. 
     
     
         42 . The method of  claim 35 , wherein the antibody is an IgG4 isotype. 
     
     
         43 . The method of  claim 35 , wherein the antibody is a human antibody, a humanized antibody or a chimeric antibody.