Antibody–Drug Conjugates: The Past, Present and Future

The concept of targeted delivery of anticancer agents using tumor-selective antibodies led to the evolution of antibody–drug conjugates (ADCs). Early efforts using traditional chemotherapy agents as ADC payloads were unsuccessful. The selectivity of antibodies was then leveraged to deliver potent cytotoxic agents that could not be administered systemically. The first two decades of exploration and approvals were with ADCs comprised of payloads that induce DNA damage (calicheamicins) or disrupt microtubule function (auristatins, maytansinoids) for treatment of both hematologic and solid tumor malignancies. More recently, ADCs with topoisomerase I inhibitor payloads have been successful for treating breast cancer and other solid tumors. Because ADCs show more toxicities than first anticipated, different approaches are under exploration for optimization of the antibody, linker, and drug components, with the goal of maintaining or increasing clinical activity while reducing associated toxicities. This review covers the history of ADC development, currently approved ADCs, and future efforts to improve ADC properties.