anti-5T4/D-2102 antibody-drug conjugate ACR246

An antibody-drug conjugate (ADC) composed of a humanized monoclonal antibody directed against the oncofetal antigen 5T4 and site-specifically conjugated, via a cleavable linker, to the cell penetrating cytotoxic agent and DNA topoisomerase I inhibitor D-2102, with potential antineoplastic activity. Upon administration of anti-5T4/D-2102 ADC ACR246, the anti-5T4 antibody moiety of ACR246 selectively binds to cells expressing 5T4. After internalization and cleavage within the tumor cell cytosol, the topoisomerase I inhibitor D-2102 is released and inhibits DNA topoisomerase I activity, thereby inhibiting DNA replication and resulting in DNA damage, cell cycle arrest and apoptosis in tumor cells overexpressing 5T4. In addition, ACR246 induces a bystander effect, thereby killing neighboring tumor cells in the tumor environment (TME). 5T4, a transmembrane glycoprotein, is overexpressed by a variety of cancer cell types while its expression is limited in normal adult tissues; its expression is correlated with increased invasiveness.