Auristatin S: An Auristatin Payload with Improved Tolerability and Modified Bystander Activity

Auristatins are a class of antibody-drug conjugate (ADC) payloads employed in anticancer therapies. Auristatin payloads are clinically validated and effective, but opportunities remain to improve their clinical benefit. Here, we describe the development and characterization of a new auristatin payload, Auristatin S, that demonstrates robust efficacy and improved off-target toxicity. This effort focused on the optimization of bystander activity, which is a key property that modulates the efficacy and tolerability of the ADC payloads. In vitro screening of tubulin binding, free drug cytotoxicity, and ADC activity were utilized to characterize the bystander activity profile. The corresponding peptide-linked conjugates showed excellent on-target cytotoxicity against cancer cells and induction of immunogenic cell death. Tolerability of Auristatin S was improved relative to historical controls, and in vivo activity and bystander activity were confirmed in a Karpas/KarpasBVR model.