CHAPTER 15: Indolinobenzodiazepine Dimers (IGNs) as Antibody–Drug Conjugate (ADC) Payloads

The use of antibody–drug conjugates (ADCs) as a means to selectively deliver cytotoxic agents to cancer cells has become a clinically validated approach for cancer therapy with the recent approval of four ADCs. While the majority of ADCs in clinical use involve tubulin-interacting agents, there has been a shift towards developing payloads with alternative mechanisms of action, such as those that target DNA, exemplified by the use of the DNA cross-linking pyrrolobenzodiazepines (PBDs). While these agents have shown promising early clinical results, high systemic toxicity has been dose-limiting. In this chapter, we describe the development of a new class of DNA-interacting agents in which, by chemical design, we have altered the mechanism of action of our diimine indolinobenzodiazepine (IGN) DNA cross-linking agents to become DNA-alkylating agents. This modification, combined with further linker design, led to IGN ADCs that display similar in vitro potency to those containing DNA cross-linkers despite the different mechanism of action. More importantly, these DNA-alkylating ADCs produce improved bystander killing, in vivo efficacy and tolerability. Taken together these purposely-designed DNA-alkylating IGN ADCs have the potential to provide extended benefit, thus broadening the clinical application of ADC technology.