Repurposing payloads: next generation of antibody–drug conjugates

Antibody-drug conjugates (ADCs) are reshaping solid tumor therapy, yet most programs converge on a narrow set of ultrapotent payloads. Trastuzumab deruxtecan demonstrates that cytotoxics abandoned due to systemic toxicity can achieve substantial benefit when redesigned for targeted delivery, controlled release, and tuned bystander effects. This perspective argues that future ADC development should prioritize pharmacologic precision, proliferation-restricted mechanisms, soft-drug pharmacokinetics, and sustained intracellular target engagement over maximal in vitro potency. Using topoisomerase I inhibitors as a blueprint, we propose a five-pillar framework for rational payload repurposing and identify legacy cytotoxins whose historical liabilities become advantages under ADC delivery. Systematic rescue of these agents can expand mechanistic diversity and delay class-wide resistance in solid tumors.