CHAPTER 7: Traditional Cytotoxic Agents as Antibody–Drug Conjugate (ADC) Payloads

In the second half of the last century, when the antibody–drug conjugate (ADC) approach was still in its infancy, the choice of potential payloads was based on a small group of cytotoxic molecules already exploited clinically as cancer chemotherapeutic agents. The three best known agents to be investigated in this context were the DNA cross-linking agent mitomycin C, the DNA intercalating agent, doxorubicin and the antimetabolite methotrexate. The mechanisms of action, pre-clinical and clinical use and toxicity of these three agents and their analogues are described in this chapter, along with examples of ADCs that incorporate them as payloads. The new ADC payload Eribulin is also described. The vinca alkaloids and Taxol™ analogues have also been used as ADC payloads, but these are described in Chapter 6.