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 . (canceled) 
     
     
         2 . An isolated monoclonal antibody, or antigen binding portion thereof, which binds to human CD73 and comprises heavy and light chain variable regions, wherein the heavy chain variable region comprises an amino acid sequence which is at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 135 and the light chain variable region comprises an amino acid sequence which is at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 
     
     
         12 . 
     
     
         3 . The antibody, or antigen binding portion thereof, of  claim 2 , wherein the heavy chain variable region comprises an amino acid sequence which is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 135 and the light chain variable region comprises an amino acid sequence which is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 12. 
     
     
         4 . The antibody, or antigen binding portion thereof, of  claim 2 , wherein the heavy chain variable region comprises an amino acid sequence which is at least 97% identical to the amino acid sequence set forth in SEQ ID NO: 135 and the light chain variable region comprises an amino acid sequence which is at least 97% identical to the amino acid sequence set forth in SEQ ID NO: 12. 
     
     
         5 . The antibody, or antigen binding portion thereof, of  claim 2 , wherein the heavy chain variable region comprises an amino acid sequence which is at least 98% or 99% identical to the amino acid sequence set forth in SEQ ID NO: 135 and the light chain variable region comprises an amino acid sequence which is at least 98% or 99% identical to the amino acid sequence set forth in SEQ ID NO: 12. 
     
     
         6 . The antibody, or antigen binding portion thereof, of  claim 2 , wherein the heavy chain is a full-length heavy chain and the light chain is a full-length light chain. 
     
     
         7 . The antibody of  claim 6 , which is an IgG antibody. 
     
     
         8 . The antibody, or antigen binding portion thereof, of  claim 2 , wherein the antibody:
 (a) binds to human CD73 with a K D  of 0.1 nM to 10 nM, as determined by Surface Plasmon Resonance (SPR);   (b) inhibits the activity of human CD73; and/or   (c) mediates internalization of human CD73.   
     
     
         9 . A composition comprising the antibody, or antigen binding portion thereof, of  claim 2  and a pharmaceutically acceptable carrier. 
     
     
         10 . The composition of  claim 9 , further comprising one or more additional therapeutic agents. 
     
     
         11 . The composition of  claim 10 , wherein the additional therapeutic agent is a programmed cell death protein 1 (PD-1) antagonist, a programmed death-ligand 1 (PD-L1) antagonist, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antagonist, or a lymphocyte activation gene-3 (LAG-3) antagonist. 
     
     
         12 . A method of decreasing adenosine levels in a tumor of a human subject, comprising administering to the subject the antibody, or antigen binding portion thereof, of  claim 2 . 
     
     
         13 . A method of stimulating an immune response against a tumor in a human subject in need thereof, comprising administering to the subject the antibody, or antigen binding portion thereof, of  claim 2 . 
     
     
         14 . A method of stimulating an immune response in a human subject, comprising administering to the subject the antibody, or antigen binding portion thereof, of  claim 2 . 
     
     
         15 . A method for inhibiting the growth of a tumor in a human subject comprising administering to the subject the antibody, or antigen binding portion thereof, of  claim 2 . 
     
     
         16 . The method of  claim 15 , wherein the tumor is selected from the group consisting of breast, lung, colon, ovary, and prostate cancer tumors. 
     
     
         17 . A method of treating cancer in a human subject, comprising administering to the subject the antibody, or antigen binding portion thereof, of  claim 2 . 
     
     
         18 . The method of  claim 17 , wherein the cancer is selected from the group consisting of breast, lung, colon, ovary, and prostate cancer. 
     
     
         19 . The method of  claim 17 , further comprising administering to the subject one or more additional therapeutic agents. 
     
     
         20 . The method of  claim 19 , wherein the additional therapeutic agent is a PD-1 antagonist, a PD-L1 antagonist, a CTLA-4 antagonist, and/or a LAG-3 antagonist.