Abstract C113: Discovery of a novel auristatin antibody drug conjugate drug linker with equal efficacy and reduced bone marrow toxicity compared to vedotin

Abstract There are four vedotin drug linker containing antibody drug conjugates currently approved for treating cancer patients, proving that this technology platform is an effective modality for the treatment of both hematologic and solid tumors. The primary mechanism of vedotin ADCs, direct cytotoxicity, is the result of intracellular release of monomethyl auristatin E (MMAE) after cleavage of the valine-citrulline (Val-Cit) dipeptide by lysosomal proteases. However, off-tumor delivery of MMAE can result in dose limiting bone marrow toxicity in preclinical models. Maintaining potency in cancer cells while reducing the bone marrow toxicity of vedotin ADCs could allow higher or more frequent clinical dosing and potentially improved response rates and patient outcomes. To decrease bone marrow toxicity of MMAE empowered ADCs, we developed a process to identify peptidic linker systems that provide selectivity for cancer cells over bone marrow cells. From this process we identified a tripeptide sequence (D-leucine-alanine-glutamate, dLAE) that is preferentially cleaved in cancer cells and used it to develop a drug linker that releases MMAE upon cleavage of this tripeptide. Here, we present in vitro and in vivo data comparing ADCs containing vedotin and dLAE tripeptide drug linkers. While ADCs with the dLAE drug linker had comparable in vitro cytotoxicity and antitumor activity to vedotin, the dLAE ADCs had a higher maximum tolerated dose in exploratory rat and cynomolgus macaque toxicity studies due to a reduction in bone marrow toxicity. Reduced bone marrow toxicity was correlated with decreased linker catabolism in bone marrow cells for conjugates bearing the dLAE tripeptide compared to Val-Cit, while similar catabolism was observed in cancer cells. Together, these preclinical data highlight that changing the peptide of the vedotin drug linker from Val-Cit to dLAE can yield ADCs with an improved preclinical therapeutic window. Given the preclinical characteristics of the dLAE drug linker, a clinical trial is being planned to evaluate an anti-CD30 ADC (SGN-35T). Citation Format: Noah A Bindman, Roma Yumul, Erica E McKinney, Scott Blackburn, Nicole Blesie, Xinqun Zhang, Brendan Drouhard, Sarah Anderson, Calvin Neace, David Ortiz, KC Crowder, Nancy Everds, Chris Carosino, Forgivemore Magunda, Django Sussman, Esther Trueblood, Nicole M. Okeley, Peter Senter. Discovery of a novel auristatin antibody drug conjugate drug linker with equal efficacy and reduced bone marrow toxicity compared to vedotin [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C113.