An anti-CD39 antibody, or antigen-binding fragment thereof, comprising
- (i) at least one antigen binding domain that binds ectonucleoside triphosphate diphosphohydrolase-1 (CD39) at a site such that the anti-CD39 antibody forms a stable immune complex, and
- (ii) an FcγRIIIa binding moiety that binds FcγRIIIa receptor and confers antibody-dependent cellular cytotoxicity (ADCC) activity against CD39+ cells to the anti-CD39 antibody, optionally wherein
- a) the anti-CD39 antibody, or antigen-binding fragment thereof, promotes:
- (i) stable immune complex formation when incubated with HCC1739BL cells as characterized by loss of less than 30% of the immune complex after 24 hours, optionally wherein the immune complex formation is detected by fluorescent intensity using a fluorescently labeled secondary antibody;
- (ii) complement dependent cytotoxicity (CDC) activity against CD39+ cells;
- (iii) antibody-mediated target cytosis of CD39 on CD45+ immune cells;
- (iv) antibody-mediated target cytosis of CD39 from tumor vascular endothelium disruption or vasculature network collapse in a tumor;
- (v) binding to a CD39 epitope having a sequence selected from the group of CD39 amino acid epitope sequences listed in FIG. 33;
- and/or
- (vi) binding to CD39 in a manner that is non-competitive or only partially competitive with monoclonal antibody clone A1 binding to CD39;
- b) the FcγRIIIa binding moiety is selected from the group consisting of an Fc domain, an antibody or fragment thereof that binds to FcγRIIIa, and an FcγRIIIa binding peptide;
- c) the antigen binding domain is selected from the group consisting of a Fab, Fab′, F(ab′)2, Fv or single chain Fv (scFv), Fav, dsFv, sc(Fv)2, Fde, sdFv, single domain antibody (dAb), and diabodies fragments and/or wherein the anti-CD39 antibody, or antigen-binding fragment, is monoclonal;
- d) the anti-CD39 antibody, or antigen-binding fragment thereof, is conjugated to an agent, optionally wherein the agent is selected from the group consisting of a binding protein, an enzyme, a drug, a chemotherapeutic agent, a biologic agent, a toxin, a radionuclide, an immunomodulatory agent, a detectable moiety, and a tag;
- e) the anti-CD39 antibody, or antigen-binding fragment thereof, has a VH domain with an amino acid sequence that can be encoded by a nucleic acid that hybridizes under stringent conditions to the nucleic acid of SEQ ID No. 1 and a VL domain with an amino acid sequence that can be encoded by a nucleic acid that hybridizes under stringent conditions to the nucleic acid of SEQ ID No. 3;
- f) the anti-CD39 antibody, or antigen-binding fragment thereof, comprises a heavy chain having CDRs at least 60% identical to the CDRs of SEQ ID No. 2, 6, 10, 14, 18, 22, 26, 42, 46, 50, or 54, and a light chain having CDRs at least 60% identical to the CDRs of SEQ ID No. 4, 8, 12, 16, 20, 24, 28, 44, 48, 52, or 56;
- g) the anti-CD39 antibody, or antigen-binding fragment thereof, comprises a variable heavy (VH) chain at least 60% identical to SEQ ID No. 2, 6, 10, 14, 18, 22, 26, 42, 46, 50, or 54, and a variable light (VL) chain at least 60% identical to SEQ ID No. 4, 8, 12, 16, 20, 24, 28, 44, 48, 52, or 56;
- h) the anti-CD39 antibody, or antigen-binding fragment thereof, comprises:
- (i) a heavy chain having a CDR1 amino acid sequence at least 80% identical to SEQ ID No. 29, a CDR2 amino acid sequence at least 80% identical to SEQ ID No. 30, and a CDR3 amino acid sequence at least 80% identical to SEQ ID No. 31;
- and
- (ii) a light chain having a CDR1 amino acid sequence at least 80% identical to SEQ ID No. 32, a CDR2 amino acid sequence at least 80% identical to DAS, and a CDR3 amino acid sequence at least 80% identical to SEQ ID No. 34;
- i) the anti-CD39 antibody, or antigen-binding fragment thereof, comprises a heavy chain having CDRs selected from the group consisting of CDRs of SEQ ID No. 6, 10, 14, 18, 22, 26, 42, 46, 50, and 54, and a light chain having CDRs selected from the group consisting of CDRs of SEQ ID No. 8, 12, 16, 20, 24, 28, 44, 48, 52, and 56, and human framework sequences to form humanized heavy and light chains with an antigen binding site able to specifically bind human CD39;
- j) the anti-CD39 antibody, or antigen-binding fragment thereof, comprises an Fc domain of an IgG1 or IgG3 isotype, optionally wherein the Fc domain is human;
- k) the anti-CD39 antibody, or antigen-binding fragment thereof, is hypo-fucosylated or afucosylated;
- l) the anti-CD39 antibody, or antigen-binding fragment thereof, is human or is humanized;
- and/or
- m) the anti-CD39 antibody, or antigen-binding fragment thereof, is a bispecific including at least one additional antigen binding site for a tumor antigen, immune checkpoint, or costimulatory receptor, wherein if the additional antigen binding site is for an immune checkpoint it functions as a checkpoint inhibitor and wherein if the additional antigen binding site is for a costimulatory receptor it functions as a costimulatory agonist.