Beyond Cytotoxic Potency: Disposition Features Required to Design ADC Payload

Antibody-drug conjugates (ADCs) have demonstrated impressive clinical usefulness in treating several types of cancer, with the notion of widening of the therapeutic index of the cytotoxic payload through the minimization of the systemic toxicity. Therefore, choosing the most appropriate payload molecule is a particularly important part of the early design phase of ADC development, especially given the highly competitive environment ADCs find themselves in today. The focus of the current review is to describe critical attributes/considerations needed in the discovery and ultimately development of cytotoxic payloads in support of ADC design. In addition to potency, several key dispositional characteristics including solubility, permeability and bystander effect, pharmacokinetics, metabolism, and drug-drug interactions, are described as being an integral part of the integrated activities required in the design of clinically safe and useful ADC therapeutic agents.