Targeting CD39 in cancer - a novel immune mechanism of action.. CD39

Here we have explored the mechanism of action of novel anti-mouse (B66) and anti-human (TTX-030) CD39 monoclonal antibodies (mAbs) that allosterically inhibit ecto-enzyme CD39 conversion of ATP to AMP and thus potentially augment ATP-P2-mediated pro-inflammatory responses. Using transplanted and de novo syngeneic mouse and humanized mouse models of tumor growth, we contrast the potency and mechanism of action of anti-CD39 mAbs compared with other agents targeting molecules in the adenosinergic pathway (eg. A2AR and CD73). We demonstrate the critical importance of an ATP-P2X7-ASC-NALP3-inflammasome pathway in the anti-tumor activity mediated by CD39 blockade, rather than simply reducing adenosine as mechanism of action. Anti-CD39 activity was shown to be underpinned by lymphocyte-myeloid cross-talk and a gene signature of early down regulation of immunosuppressive myeloid cells that facilitates the significant expansion of intratumor T cells with effector function. More importantly, anti-CD39 converted T cell poor tumors into T cell rich tumors and rescued anti-PD-1 resistance. TTX-030 enhanced human T cell proliferation and Th1 cytokine production and suppressed human B cell lymphoma in the context of autologous EBV-specific T cell transfer, where T cell transfer alone was insufficient.