Compositions and methods for treating cancer

Abstract

The present invention relates to antigen-binding compounds that inhibit the enzymatic activity of soluble human CD39. The invention also relates to cells producing such compounds; methods of making such compounds, and antibodies, fragments, variants, and derivatives thereof; pharmaceutical compositions comprising the same; methods of using the compounds to diagnose, treat or prevent diseases, e.g., cancer.

1 - 47 . (canceled) 
     
     
         48 . A method for increasing T, NK and/or B cell activity in a subject having a cancer, and/or for relieving adenosine-mediated inhibition of T, NK and/or B cell activity in a subject having a cancer, the method comprising administering to said subject an effective amount of an antibody comprising a HCDR1 comprising an amino acid sequence DYNMH (SEQ ID NO: 8); a HCDR2 comprising an amino acid sequence YIVPLNGGSTFNQKFKG (SEQ ID NO: 9); a HCDR3 comprising an amino acid sequence GGTRFAY (SEQ ID NO: 10); a LCDR1 comprising an amino acid sequence RASESVDNFGVSFMY (SEQ ID NO: 11); a LCDR2 region comprising an amino acid sequence GASNQGS (SEQ ID NO: 12); and a LCDR3 region comprising an amino acid sequence QQTKEVPYT (SEQ ID NO: 13). 
     
     
         49 . A method for increasing the activation of dendritic cells in a subject having a cancer, and/or for restoring ATP-mediated activation of DC cells in a subject having a cancer, the method comprising administering to said subject an effective amount of an antibody. 
     
     
         50 . The method of  claim 48 , wherein the individual has detectable soluble CD39 protein. 
     
     
         51 . The method of  claim 50  wherein the individual has detectable soluble CD39 protein in circulation, in tumor tissue and/or in tumor adjacent tissue. 
     
     
         52 . The method of  claim 48 , wherein the method comprises administering to said individual an effective amount of the antibody comprising a HCDR1 comprising an amino acid sequence DYNMH (SEQ ID NO: 8); a HCDR2 comprising an amino acid sequence YIVPLNGGSTFNQKFKG (SEQ ID NO: 9); a HCDR3 comprising an amino acid sequence GGTRFAY (SEQ ID NO: 10); a LCDR1 comprising an amino acid sequence RASESVDNFGVSFMY (SEQ ID NO: 11); a LCDR2 region comprising an amino acid sequence GASNQGS (SEQ ID NO: 12); and a LCDR3 region comprising an amino acid sequence QQTKEVPYT (SEQ ID NO: 13), in combination with an antibody that neutralizes the inhibitory activity of human PD-1. 
     
     
         53 . The method of  claim 48 , wherein the method comprises administering to said individual an effective amount of the antibody comprising a HCDR1 comprising an amino acid sequence DYNMH (SEQ ID NO: 8); a HCDR2 comprising an amino acid sequence YIVPLNGGSTFNQKFKG (SEQ ID NO: 9); a HCDR3 comprising an amino acid sequence GGTRFAY (SEQ ID NO: 10); a LCDR1 comprising an amino acid sequence RASESVDNFGVSFMY (SEQ ID NO: 11); a LCDR2 region comprising an amino acid sequence GASNQGS (SEQ ID NO: 12); and a LCDR3 region comprising an amino acid sequence QQTKEVPYT (SEQ ID NO: 13), in combination with a composition comprising a cytotoxic agent. 
     
     
         54 . The method of  claim 53 , wherein the cytotoxic agent is a chemotherapeutic agent capable of causing tumor cell death. 
     
     
         55 . The method of  claim 53 , wherein the cytotoxic agent is a chemotherapeutic agent capable of causing extracellular release of ATP from tumor cells. 
     
     
         56 . A method for the treatment or prevention of a cancer in an individual in need thereof, the method comprising:
 a) detecting soluble CD39 protein in circulation and/or in the tumor environment, and   b) upon a determination that soluble CD39 protein is comprised in circulation and/or the tumor environment, optionally at a level that is increased compared to a reference level, administering to the individual an antibody comprising a HCDR1 comprising an amino acid sequence DYNMH (SEQ ID NO: 8); a HCDR2 comprising an amino acid sequence YIVPLNGGSTFNQKFKG (SEQ ID NO: 9); a HCDR3 comprising an amino acid sequence GGTRFAY (SEQ ID NO: 10); a LCDR1 comprising an amino acid sequence RASESVDNFGVSFMY (SEQ ID NO: 11); a LCDR2 region comprising an amino acid sequence GASNQGS (SEQ ID NO: 12); and a LCDR3 region comprising an amino acid sequence QQTKEVPYT (SEQ ID NO: 13).   
     
     
         57 . The method of  claim 56 , wherein detecting soluble CD39 protein comprises obtaining from the individual a biological sample, bringing said sample into contact with an antibody that binds soluble CD39 protein, and detecting soluble CD39 protein. 
     
     
         58 . The method of claim  45 , wherein the anti-CD39 antibody is administered at least once in an amount effective to achieve a concentration in blood (serum) and/or a tumor tissue that corresponds to at least the EC 50  for neutralization of the enzymatic activity of soluble CD39 protein. 
     
     
         59 . The method of claim  45 , wherein neutralization of the enzymatic activity of soluble CD39 protein is determined by assessing neutralization of ATPase activity of a CD39 extracellular domain protein in solution, by quantifying the reduction in ATP hydrolyzed when the CD39 protein is incubated with an anti-CD39 antibody. 
     
     
         60 . The method of claim  45 , wherein the tumor or cancer is a solid tumor. 
     
     
         61 . The method of claim  45 ,wherein the tumor or cancer is a leukemia, bladder cancer, glioma, glioblastoma, ovarian cancer, melanoma, prostate cancer, thyroid cancer, esophageal cancer or a breast cancer. 
     
     
         62 . A method for the identifying or selecting an antibody that binds CD39 and is capable of inhibiting the ATPase activity thereof, the method comprising:
 a) incubating one or a plurality of test antibody(ies) that binds CD39 with dendritic cells, in the presence of ATP,   b) assessing cell surface expression of the marker of activation on the dendritic cells, wherein a determination that an antibody causes an increase in a marker of activation on the surface of dendritic cells indicates that the antibody is suitable for inhibition of the ATPase activity CD39 (e.g., for treatment of cancer), and   c) optionally, selecting an antibody if it causes an increase in a marker of activation on the surface of dendritic cells.   
     
     
         63 . The method of  claim 62 , wherein the concentration of ATP is a concentration at which negative control (e.g., medium without test antibody) does not lead to an increase in cell surface expression of a marker of activation of dendritic cells. 
     
     
         64 . The method of  claim 62 , wherein the concentration of ATP is at least 0.125 mM. 
     
     
         65 . The method of  claim 54 , wherein the cytotoxic agent is a chemotherapeutic agent capable of causing extracellular release of ATP from tumor cells. 
     
     
         66 . The method of  claim 63 , wherein the concentration of ATP is at least 0.125 mM.