Improving the Safety Profile of ADCs

Antibody–drug conjugates (ADCs) take advantage of the specificity of a monoclonal antibody to deliver cytotoxic agents directly into tumor cells. The plethora of ADCs investigated in clinical trials in recent years has enabled characterization of the major challenges faced by this therapeutic modality. With regard to safety, non-target-mediated toxicities, which are independent of the targeted antigens and similar for ADCs with the same linker-payloads, often drive dose-limiting events in patients and at the same time question the targeting efficiency of current ADCs. Development-limiting target-mediated toxicities have only been reported for a few ADCs. This manuscript will provide an overview of the major clinically relevant toxicities of ADCs with a presentation of key ADC attributes influencing these toxicities and discussion of potential mechanisms. Current research efforts to mitigate ADC-associated toxicities, including among others site-specific conjugation chemistry and prevention of normal tissue binding, will be presented and could be critical to future ADC endeavors.