The next generation of antibody-drug conjugates

Antibody-drug conjugates (ADCs)-composed of a monoclonal antibody linked to a payload-were designed to deliver high concentrations of cytotoxic agents to cancer cells. Since their inception, a deeper understanding of the mechanisms of action and resistance to ADCs in patients has generated a wealth of advances in the chemistry of ADC constructs, together with rational therapeutic combinations. However, the pace of innovation now exceeds clinical trial capacity. Also, any single modification or combination is unlikely to generate clinically meaningful benefit on its own. In this context, there is a need to integrate multiple chemistry advances into individual ADCs and to develop frameworks, infrastructures and tools to accelerate and de-risk the preclinical and early clinical development of these agents. In addition, the development of multidimensional molecular tools to predict ADC sensitivity, together with the optimal use of new ADCs in early-stage cancers, should contribute to improved outcomes for patients. We discuss these opportunities and challenges and predict that in the longer term, the development of diversified ADC libraries incorporating distinct constructs and drug-to-antibody ratios will enable personalized treatment strategies aligned with individual tumor biology.