Abstract 4476: Novel auristatins with improved tolerability and unique bystander activity profile

Abstract Auristatins are a class of clinically validated payloads used extensively in antibody-drug conjugate (ADC) technology. There are currently 4 FDA approved ADCs utilizing the vedotin drug linker to treat an array of solid tumors and lymphomas and several more in clinical trials. Auristatin payloads have several desirable properties, including strong anticancer cytotoxicity, bystander activity, and induction of immunologic cell death. While auristatin-based ADCs have been remarkably successful, there remain opportunities to further understand and improve payload properties. Bystander activity is one such property that can greatly impact the balance between efficacy and tolerability. Herein, we present a medicinal chemistry investigation into a series of auristatins with similar tubulin binding and biochemical potency that differ in lipophilicity and ability to cross the cell membrane. This design enabled us to focus on and characterize the impact of bystander activity while maintaining all other parameters. Ultimately, this effort resulted in ADCs with similar on-target in vitro cytotoxicity but differed in the extent of off-target bystander activity. Evaluation of in vivo efficacy, in vivo bystander activity, and rodent tolerability afforded a lead drug linker that was well-tolerated as an ADC and exhibited strong antitumor growth delay. Citation Format: Philip N. Moquist, Nicole M. Eng-Duncan, Tim Bovee, Katie Snead, Jenn Wright, Kaleb Smith, Teri Blevins, Brittney Blackburn, Michelle Ulrich, Forgivemore Magunda, Jessica Simmons, Peter D. Senter, Svetlana O. Doronina. Novel auristatins with improved tolerability and unique bystander activity profile abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4476.