The art of innovation: clinical development of trastuzumab deruxtecan and redefining how antibody-drug conjugates target HER2-positive cancers

Antibody-drug conjugates (ADCs) first entered clinical development in the 1980s, and >80 ADCs have been evaluated in the clinic, yet only five have achieved regulatory approval.1–3 The efficacy of early, murine-based ADCs did not exceed that of traditional chemotherapy; furthermore, unstable linkers resulted in systemic exposure to the payload and unacceptable toxicity.1 At Daiichi Sankyo Co., Ltd (DS), an ADC research team led by Toshinori Agatsuma and Yuki Abe established in 2010 at Shinagawa R&D Center, Tokyo, Japan set out to rationally design a technologically advanced, unique, and effective ADC technology.