The Highs, Lows, and Resurgence of Antibody-drug Conjugates

Antibody-drug conjugates (ADCs) offer a way to deliver a cytotoxic or an immuno-stimulatory payload directly to tumors to maximize the anti-tumor efficacy of the payload with reduced systemic toxicities. Over several decades, the development of ADCs has cycled through highs and lows in which substantial excitement over the promise of ADCs was followed by disinterest when disappointing clinical results were announced. This has resulted in several companies abandoning their internal ADC development efforts. To date, 13 ADCs have been approved to treat hematologic or solid tumors, with 11 granted FDA approvals. Several ADC deals have been announced, which has reinvigorated interest and investments in ADCs. The renewed interest in ADCs is due, in part, to the recent clinical success of Daiichi Sankyo’s HER2-targeting ADC, trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo/AstraZeneca), which uses their proprietary topoisomerase I inhibitor payload, DXd. Enhertu is the first ADCs to gain US Food and Drug Administration’s (FDA) approval as a tissue-agnostic ADC, which provides optimism that more ADCs will be able to follow the success of trastuzumab deruxtecan.