ADC payload design: Enhancing cytotoxic potency while reducing off-target toxicity
02 Sept 2026
ADC Cytotoxic Payload
- Are topoisomerase I inhibitor (TOP1i) payloads the default for solid tumor ADCs, or is the field over-converging on a single payload class with shared toxicity, resistance, and sequencing liabilities?
- How much of ADC therapeutic index is driven by raw cytotoxic potency versus payload behavior, including permeability, intracellular retention, catabolite properties, efflux susceptibility, and normal-tissue exposure?
- How should emerging evidence for extracellular and tissue-local payload release change how we think about bystander activity, efficacy in antigen-heterogeneous tumors, and off-tumor toxicities such as ILD?
- Can payload diversification, including next-generation TOP1i payload chemistries, dual-payload ADCs, conditionally-activated payloads, and degrader-antibody conjugates, improve antitumor activity without creating new safety liabilities?
- Which preclinical and translational assays can distinguish target-driven, linker-driven, and payload-driven toxicity early enough to guide payload selection before first-in-human studies?
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