Antibodies That Bind CD39 and Uses Thereof

Abstract

The present disclosure relates to anti-CD39 antibodies, and antigen binding portions thereof and their use in treating cancer.

1 . An isolated anti-CD39 antibody, or an antigen binding portion thereof, wherein the antibody or antigen binding portion thereof exhibits one or more of the following properties:
 a. binds to recombinant human CD39 and/or to membrane-bound human CD39;   b. binds to human CD39 with an equilibrium dissociation constant (K D ) of less than 10 nM;   c. inhibits or reduces an enzymatic activity of human CD39;   d. inhibits or reduces conversion by human CD39 of extracellular adenosine triphosphate (eATP) or extracellular adenosine diphosphate (eADP) to extracellular adenosine monophosphate (eAMP);   e. increases or enhances a level of eATP;   f. decreases or reduces extracellular adenosine;   g. maintains, increases or enhances an immunostimulatory level of eATP;   h. increases or enhances proliferation of a lymphocyte;   i. increases or enhances expression of one or more dendritic cell activation markers;   j. increases or enhances secretion of one or more cytokines from dendritic cells;   k. increases or enhances macrophage infiltration in tumors;   l. increases or enhances secretion of macrophage attracting chemokines;   m. antagonizes human CD39 in a tumor microenvironment of a tissue;   n. cross-reacts with cynomolgus CD39; and   o. a combination of any one of (a)-(n).   
     
     
         2 . The isolated anti-CD39 antibody, or antigen binding portion thereof, of  claim 1 , wherein the antibody or antigen binding portion thereof comprises, consists, or consists essentially of:
 i) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 1, 2 and 3, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 11, 12, and 13, respectively; or   ii) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 4, 5, and 6, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 15, 16, and 17, respectively; or   iii) a variable heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7, and a variable light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7; or   iv) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 9, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19; or   v) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 21, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19; or   vi) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 23, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19; or   vii) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 25, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19; or   viii) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 27, 28, and 29, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 37, 38, and 39, respectively; or   ix) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 30, 31, and 32, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 40, 41, and 42, respectively; or   x) a variable heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 33, and a variable light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 43; or   xi) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 35, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 45; or   xii) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 47, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 45; or   xiii) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 49, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 45; or   xiv) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 51, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 45; or   xv) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 53, 54, and 55, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 63, 64, and 65, respectively; or   xvi) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 56, 57, and 58, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 66, 67, and 68, respectively; or   xvii) a variable heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 59, and a variable light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 69; or   xviii) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 61, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 71; or   xix) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 73, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 71; or   xx) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 75, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 71; or   xxi) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 77, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 71; or   xxii) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 79, 80, and 81, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 89, 90, and 91, respectively; or   xxiii) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 82, 83, and 84, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 92, 93, and 94, respectively; or   xxiv) a variable heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 85, and a variable light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 95; or   xxv) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 87, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 97; or   xxvi) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 99, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 97; or   xxvii) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 101, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 97; or   xxviii) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 103, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 97; or   xxix) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 105, 106, and 107, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 115, 116, and 117, respectively; or   xxx) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 108, 109, 110, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 118, 119, and 120, respectively; or   xxxi) a variable heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 111, and a variable light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 121; or   xxxii) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 113, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 123; or   xxxiii) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 125, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 123; or   xxxiv) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 127, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 123; or   xxxv) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 129, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 123.   
     
     
         3 . The isolated anti-CD39 antibody, or antigen binding portion thereof, of any one of the preceding claims, wherein the antibody or antigen binding portion thereof increases proliferation of a lymphocyte, optionally wherein the lymphocyte is a tumor-infiltrating lymphocyte, or CD4+ T cell. 
     
     
         4 . The isolated anti-CD39 antibody, or antigen binding portion thereof, of any one of the preceding claims, wherein the antibody or antigen binding portion thereof enhances expression of one or more dendritic cell activation markers, optionally wherein the dendritic cell activation marker is CD86, HLA-DR, or a both CD86 and HLA-DR. 
     
     
         5 . The isolated anti-CD39 antibody, or antigen binding portion thereof of any one of the preceding claims, wherein the antibody or antigen binding portion thereof enhances secretion of one or more cytokines from dendritic cells, optionally wherein the cytokine is IL-16, IL-12/IL-23p40, VEGFA, or any combination thereof. 
     
     
         6 . The isolated anti-CD39 antibody, or antigen binding portion thereof, of any one of the preceding claims, wherein the antagonism of human CD39 occurs in a tumor microenvironment, optionally wherein the antagonism is non-competitive and/or allosteric. 
     
     
         7 . The isolated anti-CD39 antibody, or antigen binding portion thereof, of any one of the preceding claims, wherein the antibody or antigen binding portion thereof cross-reacts with cynomolgus CD39. 
     
     
         8 . The isolated anti-CD39 antibody, or antigen binding portion thereof, of any one of the preceding claims, wherein the antibody is an IgG1, an IgG2, an IgG3, an IgG4, an IgM, an IgA1, an IgA2, an IgD, or an IgE antibody. 
     
     
         9 . The isolated anti-CD39 antibody, or antigen binding portion thereof, of any one of the preceding claims, wherein the antibody is a wild type or mutant IgG1 or IgG4 antibody. 
     
     
         10 . The isolated anti-CD39 antibody, or antigen binding portion thereof, of any one of the preceding claims, comprising a mutant IgG4 heavy chain constant region, wherein the mutation i) reduces the ability of the IgG4 to form half-molecules; and/or ii) minimizes binding to Fc receptors. 
     
     
         11 . The isolated anti-CD39 antibody, or antigen binding portion thereof, of any one of the preceding claims, comprising a mutant IgG4 heavy chain constant region comprising an S228P mutation. 
     
     
         12 . The isolated anti-CD39 antibody, or antigen binding portion thereof, of any one of the preceding claims, comprising a mutant IgG4 heavy chain constant region comprising S228P and L235E mutations. 
     
     
         13 . The isolated anti-CD39 antibody, or antigen binding portion thereof, of any one of the preceding claims, wherein the antibody or antigen binding portion thereof comprises the heavy chain CDR3 sequence set forth in SEQ ID NO: 3. 
     
     
         14 . The isolated anti-CD39 antibody, or antigen binding portion thereof, of any one of the preceding claims, wherein the antibody or antigen binding portion thereof binds to substantially the same epitope as a reference antibody or antigen binding portion thereof comprising the heavy chain CDR3 sequence set forth in SEQ ID NO: 3. 
     
     
         15 . The isolated anti-CD39 antibody, or antigen binding portion thereof, of any one of the preceding claims, wherein the antibody or antigen binding portion thereof binds to substantially the same epitope as a reference antibody or antigen binding portion thereof comprising:
 i) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 1, 2 and 3, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 11, 12, and 13, respectively; or   ii) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 4, 5, and 6, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 15, 16, and 17, respectively; or   iii) a variable heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7, and a variable light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7; or   iv) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 9, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19; or   v) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 21, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19; or   vi) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 23, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19; or   vii) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 25, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19; or   viii) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 27, 28, and 29, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 37, 38, and 39, respectively; or   ix) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 30, 31, and 32, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 40, 41, and 42, respectively; or   x) a variable heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 33, and a variable light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 43; or   xi) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 35, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 45; or   xii) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 47, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 45; or   xiii) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 49, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 45; or   xiv) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 51, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 45; or   xv) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 53, 54, and 55, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 63, 64, and 65, respectively; or   xvi) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 56, 57, and 58, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 66, 67, and 68, respectively; or   xvii) a variable heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 59, and a variable light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 69; or   xviii) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 61, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 71; or   xix) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 73, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 71; or   xx) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 75, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 71; or   xxi) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 77, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 71; or   xxii) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 79, 80, and 81, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 89, 90, and 91, respectively; or   xxiii) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 82, 83, and 84, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 92, 93, and 94, respectively; or   xxiv) a variable heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 85, and a variable light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 95; or   xxv) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 87, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 97; or   xxvi) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 99, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 97; or   xxvii) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 101, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 97; or   xxviii) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 103, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 97; or   xxix) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 105, 106, and 107, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 115, 116, and 117, respectively; or   xxx) heavy chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 108, 109, 110, respectively, and light chain CDR1, CDR2 and CDR3 sequences comprising SEQ ID NOs: 118, 119, and 120, respectively; or   xxxi) a variable heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 111, and a variable light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 121; or   xxxii) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 113, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 123; or   xxxiii) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 125, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 123; or   xxxiv) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 127, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 123; or   xxxv) a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 129, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 123.   
     
     
         16 . A nucleic acid encoding the anti-CD39 antibody, or antigen binding portion thereof, of any one of the preceding claims. 
     
     
         17 . An expression vector comprising the nucleic acid of  claim 16 . 
     
     
         18 . A cell transformed with an expression vector of  claim 17 . 
     
     
         19 . A pharmaceutical composition comprising an isolated anti-CD39 antibody or antigen binding portion thereof, of any one of  claims 1 - 15 , or the nucleic acid of  claim 16 , and a pharmaceutically acceptable carrier. 
     
     
         20 . A method of treating a cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the isolated anti-CD39 antibody, or antigen binding portion thereof, of any one  claims 1 - 15  or the pharmaceutical composition of  claim 19 . 
     
     
         21 . The method of  claim 21 , wherein the cancer is selected from the group consisting of: lung cancer (e.g., non-small cell lung cancer), ovarian cancer, kidney cancer, testicular cancer, pancreas cancer, breast cancer (e.g., triple-negative breast cancer), melanoma, head and neck cancer (e.g., squamous head and neck cancer), colorectal cancer, bladder cancer, endometrial cancer, prostate cancer, thyroid cancer, hepatocellular carcinoma, gastric cancer, brain cancer, lymphoma an renal cancer (e.g., renal cell carcinoma). 
     
     
         22 . The method of any one of  claims 20 - 21 , wherein the isolated anti-CD39 antibody, or antigen binding portion thereof, is administered in combination with one or more additional therapeutic agents or procedure, wherein the additional therapeutic agent or procedure is selected from the group consisting of: a chemotherapy, a targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, an immune-based therapy, a cytokine, surgical procedure, a radiation procedure, an activator of a costimulatory molecule, an inhibitor of an inhibitory molecule, a vaccine, or a cellular immunotherapy, or a combination thereof. 
     
     
         23 . The method of  claim 22 , wherein the one or more additional therapeutic agents is a PD-1 antagonist, an adenosine A2AR antagonist, a CD73 inhibitor, a CTLA-4 inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor, chimeric antigen receptor (CAR) cell therapy, an anthracycline, or a combination thereof. 
     
     
         24 . A method of detecting human CD39 in vivo or ex vivo in a biological sample comprising (i) contacting the sample (and optionally, a reference/control sample or subject) with the antibody of any one of  claims 1 - 15 , or the pharmaceutical composition of  claim 19 , under conditions that allow interaction of the antibody molecule and human CD39 to occur, and (ii) detecting formation of a complex between the antibody molecule and the sample or the subject (and optionally, the reference sample or subject). 
     
     
         25 . A kit comprising the isolated anti-CD39 antibody, or antigen binding portion thereof, of any one of  claims 1 - 15 , the nucleic acid of  claim 16 , or the pharmaceutical composition of  claim 19  and instructions for use in treating cancer in a subject, optionally with instructions for use in combination with one or more additional therapeutic agents or procedure.