Abstract 2803: Novel auristatins with high activity on efflux-positive models and demonstrable bystander activity

Abstract

Abstract Auristatins are a class of clinically validated antimitotic agents utilized as payloads in antibody-drug conjugates (ADCs). Auristatins display many of the desirable properties necessary for ADC cytotoxins, such as low nanomolar potency, cell permeability, and activity across multidrug-resistant (MDR+) cell lines. Herein, we report the development of novel auristatins, which have a unique combination of these favorable properties. The hydrophilic monomethyl auristatin F (MMAF) was chosen as the parent structure, and a medicinal chemistry campaign was undertaken to functionalize various sites of the auristatin with hydrophobic moieties in an effort to improve membrane permeability. The structure-activity relationships (SAR) of the new auristatins demonstrated clear trends correlating hydrophobicity, structure, and polarity with permeability and in vitro cytotoxicity. The highest-performing molecules showed a preference for hydrophobic functionalization at the N-terminal dolavaline. The payloads were linked to the C-terminal position of the auristatin with a lysosomally cleavable maleimido-dipeptide linker. Examination of the ADCs revealed low ng/mL activity in CD30+ and CD19+ cell lines in vitro. Anti-CD70 ADCs demonstrated high in vivo efficacy in a 786-O xenograft and complete remissions (CRs) in the efflux-positive renal cell carcinoma model. Anti-CD30 ADCs were dosed in a CD30+ and CD30- admixed Karpas/Karpas-35R xenograft model to demonstrate proof-of-concept in vivo bystander activity. In summary, these novel auristatins showed potential across multiple indications as ADC payloads. Citation Format: Philip N. Moquist, Tim D. Bovee, Andrew B. Waight, Sarah Owen, Jamie A. Mitchell, Margo Zaval, Marsha Quick, Sharsti Sandall, Kim K. Emmerton, Nicole Blesie, Robert P. Lyon, Peter Senter, Svetlana Doronina. Novel auristatins with high activity on efflux-positive models and demonstrable bystander activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2803.