Antibody drug conjugates (ADCs) are changing the landscape of cancer therapy. These agents contain an antibody directed at a tumor cell surface antigen linked to a cytotoxic payload that is released following complex internalization and processing by the lysosome. To date, seven ADCs have been approved by the Federal Drug Administration for the treatment of solid tumors and an additional seven ADCs are approved in hematologic malignancies; because of the unique aspects of solid tumor therapy, this review will focus specifically on ADCs for solid malignancies. Review of the design of these solid tumor ADCs highlights the successful evolution of ADC treatment to date, including selection of antigen target, chemical linker features, and payload. In this review, we focus on how spatial and temporal intratumoral heterogeneity uniquely limits durable efficacy of ADC therapy. We consider strategies to overcome these hurdles, including improved characterization of clinical samples for optimal ADC selection, improvements in ADC design, and combinatorial therapy. These preclinical and clinical efforts seek to overcome the challenges of tumor heterogeneity to improve ADC options and outcomes in the treatment of solid tumor malignancies.

antibody drug conjugate, payload, tumor heterogeneity, tumor microenvironment, resistance, drug development, combination therapy