Abstract 2885: Discovery of a tripeptide-based camptothecin drug-linker for antibody-drug conjugates with potent antitumor activity and a broad therapeutic window

In efforts to bring forward antibody-drug conjugate (ADC) technologies that complement vedotin and enable new clinical-stage ADCs, we have investigated compounds that interact with topoisomerase 1, an enzyme involved in the unwinding of DNA. In connection with this, we developed a highly active and well-tolerated camptothecin drug-linker technology, in which the lead molecule consists of 7-aminomethyl-10,11-methylenedioxycamptothecin (AMDCPT) attached to a protease-cleavable valine-lysine-glycine (VKG) tripeptide linker unit. A hydrophilic and discrete polyethylene glycol unit was included to improve the properties of the drug-linker, enabling high ADC drug-loading, and reducing the propensity for aggregation. A VKG-AMDCPT ADC, with 8 drug-linkers/mAb (DAR8), displayed a pharmacokinetic profile coincident with parental unconjugated antibody, with a high degree of stability against retro-Michael reaction deconjugation. ADCs based on the VKG-AMDCPT were broadly active against cancer cells in vitro, and in mouse xenograft models, giving tumor regressions and complete responses with a single ≤3 mg/kg dose. These included both solid and hematologic tumor models, and models of bystander killing activity and multidrug resistance. A non-binding DAR8 ADC was well-tolerated in rats at 60 mg/kg, q7dx4. The VKG-AMDCPT drug-linker can be prepared from available materials in eight high-yielding steps, and this drug-linker is being employed in the anti-CD30 ADC, SGN-CD30C; an investigational new drug application is planned for 2020. Citation Format: Ryan Lyski, Lauren Bou, Margo Zaval, Kim Emmerton, Nicole Okeley, Jessica Simmons, Francisco Zapata, David Ortiz, Erica McKinney, David Meyer, Maureen Ryan, Peter Senter, Scott Jeffrey. Discovery of a tripeptide-based camptothecin drug-linker for antibody-drug conjugates with potent antitumor activity and a broad therapeutic window [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2885.