Definition

A fusion protein composed of a monoclonal antibody directed against the cell surface receptor CD39 (cluster of differentiation 39; ectonucleoside triphosphate diphosphohydrolase-1; NTPDase1; ENTPD1) and fused to the transforming growth factor-beta receptor type II (TGF-beta RII) ectodomain, with potential immunomodulating and antineoplastic activities. Upon administration, anti-CD39/TGF-beta RII ectodomain fusion protein ES014 specifically and simultaneously targets and binds to the CD39 antigen and TGF-beta in the tumor microenvironment (TME), thereby preventing CD39- and TGF-beta-mediated signaling. By preventing CD39 activation, the conversion and degradation of adenosine triphosphate (ATP) to adenosine monophosphate (AMP) is abrogated as CD39 is the rate-limiting enzyme in the ATP-adenosine pathway. This leads to an increase in the extracellular levels of immunogenic ATP and a decrease in the levels of immunosuppressive adenosine within the TME. A high level of ATP increases pro-inflammatory cytokine levels and promotes both T-cell proliferation and the stimulation of dendritic and other myeloid-derived cells that are necessary for innate and adaptive immunity. The binding to TGF-beta prevents the activation of TGF-beta RII-mediated signaling pathways and also prevents the activation of CD39. This further reverses the immunosuppressive nature of the TME. This may further stimulate a T-cell-mediated anti-tumor immune response and may inhibit tumor cell proliferation. CD39, a cell surface ectonucleosidase, is upregulated on tumor cells as an immune evasion strategy; blocking its action may improve anti-tumor immune responses. TGF-beta is expressed by a number of cancer cell types and is involved in cancer cell proliferation, tumor progression, and immunosuppression. It suppresses T-cell activation and induces CD39 expression.