Antibodies against cd73 and uses thereof

Abstract

The present invention provides isolated monoclonal antibodies, particularly human antibodies, that bind to human Cluster of Differentiation 73 (CD73) with high affinity, and inhibit the activity of CD73, and optionally mediate antibody dependent CD73 internalization. Nucleic acid molecules encoding the antibodies of the invention, expression vectors, host cells and methods for expressing the antibodies of the invention are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention are also provided. The invention also provides methods for inhibiting the growth of a tumor cell expressing CD73 using the antibodies of the invention, including methods for treating various cancers.

1 - 62 . (canceled) 
     
     
         63 . A method of decreasing adenosine levels in a tumor of a human subject, comprising administering to the subject an antibody, or antigen binding portion thereof, that binds to human CD73, wherein the antibody, or antigen binding portion thereof, comprises a heavy chain comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences of SEQ ID NOs: 5, 6, and 7, respectively, and a light chain comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively. 
     
     
         64 . A method of stimulating an immune response against a tumor in a human subject in need thereof, comprising administering to the subject an effective amount of an antibody, or antigen binding portion thereof, that binds to human CD73, wherein the antibody, or antigen binding portion thereof, comprises a heavy chain comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences of SEQ ID NOs: 5, 6, and 7, respectively, and a light chain comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively. 
     
     
         65 . A method of stimulating an immune response in a human subject comprising administering to the subject an antibody, or antigen binding portion thereof, that binds to CD73, to the subject, wherein the antibody, or antigen binding portion thereof, comprises a heavy chain comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences of SEQ ID NOs: 5, 6, and 7, respectively, and a light chain comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively. 
     
     
         66 . A method for inhibiting the growth of a tumor in a human subject comprising administering to the subject an antibody, or antigen binding portion thereof, that binds to human CD73, wherein the antibody, or antigen binding portion thereof, comprises a heavy chain comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences of SEQ ID NOs: 5, 6, and 7, respectively, and a light chain comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively. 
     
     
         67 . A method of treating cancer in a human subject, comprising administering to the subject a therapeutically effective amount of an antibody, or antigen binding portion thereof, that binds to human CD73, to the subject, wherein the antibody, or antigen binding portion thereof, comprises a heavy chain comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences of SEQ ID NOs: 5, 6, and 7, respectively, and a light chain comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively. 
     
     
         68 . The method of  claim 67 , wherein the cancer is selected from the group consisting of: bladder cancer, breast cancer, uterine/cervical cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, lung cancer, stomach cancer, germ cell cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, and virus-related cancer. 
     
     
         69 . The method of  claim 67 , further comprising administering to the subject one or more additional therapeutic agents. 
     
     
         70 . The method of  claim 69 , wherein the additional therapeutic agent is a PD-1 antagonist, a PD-L1 antagonist, a CTLA-4 antagonist, or a LAG-3 antagonist. 
     
     
         71 . The method of  claim 67 , wherein the antibody, or antigen binding portion thereof, comprises heavy and light chain variable regions comprising the amino acid sequences of SEQ ID NOs: 135 and 12, respectively. 
     
     
         72 . The method of  claim 71 , wherein the antibody, or antigen binding portion thereof, comprises a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 133 or 189 and a light chain sequence comprising the amino acid sequence of SEQ ID NO: 102. 
     
     
         73 . The method of  claim 67 , wherein the heavy chain is a full-length heavy chain and the light chain is a full-length light chain. 
     
     
         74 . The method of  claim 71 , wherein the heavy chain is a full-length heavy chain and the light chain is a full-length light chain. 
     
     
         75 . The method of  claim 67 , wherein the antibody, or antigen binding portion thereof, is an IgG antibody. 
     
     
         76 . The method of  claim 72 , wherein the antibody, or antigen binding portion thereof, comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO: 133 and a light chain consisting of the amino acid sequence of SEQ ID NO: 102. 
     
     
         77 . The method of  claim 72 , wherein the antibody, or antigen binding portion thereof, comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO: 189 and a light chain consisting of the amino acid sequence of SEQ ID NO: 102. 
     
     
         78 . The method of  claim 67 , wherein the antibody, or antigen binding portion thereof, binds to human CD73 with a K D  of 0.1 nM to 10 nM, as determined by Surface Plasmon Resonance (SPR). 
     
     
         79 . The method of  claim 67 , wherein the antibody, or antigen binding portion thereof, inhibits the activity of human CD73. 
     
     
         80 . The method of  claim 67 , wherein the antibody, or antigen binding portion thereof, comprises mediates internalization of human CD73. 
     
     
         81 . The method of  claim 67 , wherein the antibody, or antigen binding portion thereof, has reduced effector function relative to a wild type IgG1 antibody. 
     
     
         82 . The method of  claim 67 , wherein the antibody, or antigen binding portion thereof, binds to human CD73 with a K D  of 0.1 nM to 10 nM, as determined by Surface Plasmon Resonance (SPR).