Discovery of Trastuzumab Deruxtecan (T-DXd, DS-8201a) as Next-Generation ADC

Abstract

An antibody-drug conjugate (ADC) is a biologics that binds a drug to a monoclonal antibody. ADCs use antibodies to selectively deliver a potent cytotoxic agent to tumor cells, thus drastically improving the therapeutic index of chemotherapeutic agents. We discovered trastuzumab deruxtecan (T-DXd, DS-8201a) with the study of ADC drug-linker technology as the next-generation ADC drug that applied a camptothecin derivative, which is a DNA topoisomerase I inhibitor, to an anti-HER2 antibody. T-DXd achieves a high drug-to-antibody-ratio with homogeneous conjugation and has strong potency on heterogeneous tumors by the bystander effect and considers safety concerns in systemic circulation by drug-linker stability. T-DXd could provide a valuable therapy with a great potential to respond to breast cancer and other HER2-expression cancers in clinical settings. Phase II and III is ongoing for HER2-positive breast cancer, HER2-low breast cancer, HER2-positive gastric cancer and the other HER2-expressing cancers.