Arming antibodies with DNA cross-linking agents derived from the duocarmycins

Abstract

Antibody drug conjugates (ADCs) are composed of an antibody covalently linked to a therapeutic agent in such a way that the agent (or ‘payload’) is released selectively by antigen-presenting cells. Two ADCs armed with cytotoxic microtubule-binding agents have recently been approved for the treatment of HER2-positive breast cancer and CD30-positive lymphoma, prompting much work on the development of alternative ADCs as anticancer agents. An active area of exploration concerns the search for suitable payloads outside the class of microtubule-binding agents. The duocarmycins are a small group of natural products that alkylate adenine in the minor groove of DNA. They possess several properties that make them attractive as ADC payloads, including high cytotoxic potency, activity against many multidrug-resistant cell lines, and activity against both cycling and non-cycling cells. Simplified and more synthetically accessible variants of the alkylating subunit have been reported which retain the cytotoxic potency of the natural products. This potency can be further enhanced by the preparation of dimeric analogues which cross-link DNA, providing, in some examples, remarkably toxic compounds with IC50s in the fM range. This presentation will report on the synthesis and properties of homo- and heterodimers incorporating duocarmycin analogues, the preparation and antibody-conjugation of drug-linker constructs of the same, and the properties of these new ADC candidates.