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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.

Publication details

Print publication date
15 Jul 2019
Copyright year
Print ISBN
ePub eISBN

From the book series:
Drug Discovery