Development of Antibody-Drug Conjugates

Antibody drug conjugates (ADCs) are a rapidly growing class of targeted cancer drugs in which a highly toxic small molecule (payload) is conjugated to a tumor-selective antibody. Over the past two decades, a total of 11 ADCs have been approved by the FDA in the United States; including: gemtuzumab ozogamicin (Mylotarg™), brentuximab vedotin (Adcetris™), ado-trastuzumab emtansine (Kadcyla™), inotuzumab ozogamicin (Besponsa™), polatuzumab vedotin (Polivy™), enfortumab vedotin (Padcev™), trastuzumab deruxtecan (Enhertu™), sacituzumab govitecan (Trodelvy™), belantamab mafodotin (Blenrep™), loncastuximab tesirine-lpyl (Zynlonta™), and tisotumab vedotin-tftv (Tivdak™). The path to commercial success for these ADCs has been challenging however, and new ADC approvals were rare prior to 2017 when only three ADCs had been approved by the FDA. Then in 2019 three more ADCs were approved, followed by two approvals in 2020 and two more in 2021. Dozens of ADCs are now in late-stage clinical trials and new approvals are expected to remain consistent for the near future. Following closely behind are over a hundred new ADCs in early clinical or preclinical development. This chapter will summarize the history of currently approved ADCs with emphasis on the challenges that were overcome during development and new technology that likely contributed to their success. The safety and efficacy of each ADC will be discussed from a critical but honest perspective based on personal experience. My intention in writing this chapter is to encourage readers to educate themselves about the real benefits and risks of ADC therapeutics so that informed decisions can be made by cancer patients in collaboration with their doctors.