Abstract 4640: Development of antibody-drug conjugate technology based on novel DNA-interacting agents and unique linker technology

Antibody-Drug Conjugation (ADC) is gaining momentum as a next generation antibody therapeutics approach in oncology. Tumor specific delivery of the cell-killing agent maximizes the agent9s potency while avoiding damage to healthy tissue resulting in a high therapeutic window. Synthon9s Potent Payload Technology comprises the combination of highly potent DNA-alkylating duocarmycin derivatives and unique releasable linker technology. Duocarmycin analogs and the CC-1065 derivatives represent a class of highly potent, cell-killing, DNA-alkylating, minor groove binding agents. This class is suitable to target solid tumors and has shown activity in a variety of Multi-Drug Resistant (MDR) models.Synthon SpaceLink technology is the only releasable linker technology for ADC that can couple the toxin via its hydroxyl group to the antibody, validated in vivo. Synthon has combined its linkers with duocarmycin derivatives that have a hydroxyl group crucial for biological activity. The data package to be presented supports that SpaceLink and duocarmycins form an excellent chemical match for ADC therapy, possessing an intrinsic complementarity. Strong in vivo Proof of Concept with Potent Payload ADCs has been obtained against multiple targets. In human tumor xenograft models, substantial efficacies have been obtained based on low, single dose treatments, with minimal or absent side effects. We discuss applicability and several other aspects of multiple, validated Potent Payload-based Antibody-Drug Conjugates (ADCs). Latest results of preclinical development progress (in vivo efficacy, safety, etc.) will be presented, including in vitro drug and ADC potencies, plasma stabilities, cathepsin cleavage kinetics, linker cyclization kinetics and in vivo therapeutic window aspects for ADCs directed against HER2 and potentially other (collaborator) targets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4640. doi:1538-7445.AM2012-4640