Abstract 1909: Advancing a novel tubulin-inhibitor ADC technology: The Adcentrx auristatin platform offers enhanced efficacy and safety profiles compared to vedotin technology

Abstract Auristatins represent an important class of anti-mitotic antibody-drug conjugate (ADC) payloads with potent cytotoxic effects on rapidly dividing cancer cells. Most notably, monomethyl auristatin E (MMAE) stands as the most extensively validated compound, laying the foundation for the vcMMAE (vedotin) linker-payload technology that has contributed to the approval of several ADCs, including brentuximab vedotin, polatuzumab vedotin-piiq, tisotumab vedotin-tftv, and enfortumab vedotin-ejfv. However, while these first-generation ADCs have paved the way for a paradigm shift in cancer treatment away from traditional chemotherapy, there remains a discernible opportunity for improvement in both efficacy and safety. In this context, we introduce the Adcentrx auristatin platform, which substantially expands the therapeutic window of auristatin-ADCs beyond the vedotin technology. Through systematic exploration, we have synthesized 100 proprietary auristatin analogues with a range of distinctive properties. We identified optimized linker-payloads by strategically pairing lead payload candidates with our proprietary i-ConjugationTM, an irreversible, stable cysteine conjugation technology, and fine-tuned linkers. The resulting ADCs with a drug-to-antibody ratio (DAR) of 8 were extremely hydrophilic with excellent in vivo pharmacokinetics, and sustained DAR retention for a period of 21-days. Comparative assessments against vedotin-ADCs revealed that Adcentrx-ADCs demonstrated superior efficacy across multiple targets and indications in various mouse xenograft models. In Sprague-Dawley rats, Adcentrx-ADCs exhibited remarkable tolerability, albeit their high drug loading of 8. In summary, our preclinical studies underscore the significant enhancement in the therapeutic index achieved by the Adcentrx auristatin platform. Furthermore, this technology presents a promising alternative mode of action to camptothecins, exhibiting tolerance to targets expressed in non-proliferative normal tissues but without the burden of severe dose-limiting toxicities such as interstitial lung disease. Citation Format: Dong Jun Lee, Sabine Rottmann, Anna Wang, Peter P. Challita, Andrew M. Hau, Wes Sisson, Mario M. Kuo, Kris Zhang, Monica Leung, Alexis Mahloch, Erin Nye, Paul Datta, Sam Janssen, Felipe Acosta, Oscar Betancourt, Maria Shahmoradgoli, Alexander Chu-Kung, MaoJun Guo, Pia M. Challita-Eid, Hui Li. Advancing a novel tubulin-inhibitor ADC technology: The Adcentrx auristatin platform offers enhanced efficacy and safety profiles compared to vedotin technology 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 1909.