Beyond Cytotoxic Payloads for Antibody Drug Conjugates─A Medicinal Chemistry Perspective

Abstract Despite significant research and investment, antibody–drug conjugates (ADCs) primarily rely on a limited number of broadly cytotoxic payloads that contribute significantly to toxicity. More recently, there has been a migration toward mechanistically targeted payloads, pairing improved antibodies with small molecules that act on disease-specific biology, improving precision and tolerability. Designing these next-generation payloads means rethinking some of our design metrics and guidelines derived from traditional medicinal chemistry: properties such as LogD, pKa, permeability, efflux, and metabolic stability must be carefully balanced to ensure efficient intracellular release while limiting systemic exposure. Here we discuss our observations around these properties and suggest design rules and guidelines for the optimization of next-generation ADC payloads.