The Future of Antibody–Drug Conjugate (ADC) Payloads

Historically, the dominance of tubulin inhibitors as the payload of choice for antibody–drug conjugate (ADC) development is probably due to a combination of (1) their tractability as highly potent cytotoxics with the synthetic flexibility required for successful conjugation, (2) an early commitment to their potential by ADC innovators and (3) their intrinsic selectivity for proliferating cells, thus directly contributing to the therapeutic index for an ADC. While regulatory approvals for this class of payload have been achieved, with more hopefully on the way, concerns about the clinical effectiveness of tubulin-targeting agents has led to an expansion in efforts to develop ADC payloads with alternative mechanisms of action. Substantial efforts have been focused on DNA-targeting payloads, with a variety of topoisomerase inhibitors, DNA mono-alkylators and DNA cross-linkers being evaluated pre-clinically and in clinical trials. A wide array of payloads with mechanisms of action beyond targeting tubulin or DNA are also being investigated. This chapter looks across the entire spectrum of payloads under evaluation, attempting to connect where ADC payload development has come from in the past, and where it is going now. Expanding efforts using prodrug approaches to improve tolerability, and the potential for some payloads to synergize with immuno-oncology agents are also highlighted.