conditionally-activated anti-EpCAM antibody-drug conjugate CX-2051

An antibody-drug conjugate (ADC) composed of a monoclonal antibody directed against the tumor-associated antigen (TAA) human epithelial cell adhesion molecule (Ep-CAM; EpCAM; CD326), linked to a proprietary masking peptide through a protease-cleavable linker, and conjugated to a derivative of camptothecin, with potential antineoplastic activity. Upon administration of conditionally-activated anti-EpCAM ADC CX-2051, the linkage system is stable in the circulation and, upon extravasation into the tumor microenvironment (TME), the peptide mask is cleaved by tumor-associated proteases. These proteases are present in high concentrations and aberrantly activated in the TME, while expressed as inactive forms, at much lower concentrations, in normal, healthy tissue. Protease cleavage of the linker enables the binding of the unmasked, fully active anti-EpCAM antibody moiety of CX-2051 to EpCAM-expressing tumor cells. Upon binding and internalization, the camptothecin derivative is released. The camptothecin derivative inhibits DNA topoisomerase I activity, thereby inhibiting DNA replication and resulting in cell cycle arrest and tumor cell apoptosis. This inhibits the proliferation of EpCAM-expressing tumor cells. EpCAM, a cell surface protein upregulated on many tumor cell types, promotes the proliferation, migration and invasiveness of tumor cells.