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Abstract Nectin-4 is a well validated tumor target, which is highly expressed in several solid cancers, while expression in normal tissues is limited. A first-generation antibody-drug conjugate targeting Nectin-4, called enfortumab vedotin-ejfv (EV), was granted accelerated FDA approval in 2019 for urothelial cancers, and is currently approved for frontline therapy in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma, providing groundbreaking improvement in patient survival. However, clinical use of EV has also revealed safety-driven limitations, which result in reduced and/or interrupted drug exposures impacting efficacy. To overcome these limitations in therapeutic window, Adcentrx has developed ADRX-0706, a Nectin-4-targeting next-generation ADC with a drug-antibody ratio (DAR) of 8. ADRX-0706 utilizes a novel tubulin inhibitor payload AP052 with a proprietary cleavable linker utilizing Adcentrx’ proprietary i-ConjugationTM technology, which results in excellent biophysical features. Most noteworthy, ADRX-0706 displays a very stable PK profile with overlapping curves for total antibody and ADC as well as full DAR retention in circulation as determined by mass spectrometry. This translates to superior efficacy of ADRX-0706 over EV in multiple in vivo cancer cell line- and patient-derived xenograft mouse models across indications. Detailed PK/PD characterization of ADRX-0706 validates the mechanism of action as an anti-mitotic agent inducing cell cycle arrest and apoptosis. In addition, ADRX-0706 treatment leads to increased PD-L1 expression in mouse pharmacology models, which is a consequence of immunogenic cell death as described for this payload class. These findings are in line with emerging data on EV and provide rationale for combination regimens with checkpoint inhibitors. Besides the improvement in efficacy, ADRX-0706 was also designed for superior safety. A payload distribution study in tumor-bearing mice reveals a preferential and increased delivery of payload to tumors and lower payload delivery to normal tissues as well as lower free payload levels in plasma for ADRX-0706 compared to EV. Taken together, these data provide association of the improved drug-linker stability of ADRX-0706 to an improved Nectin-4 directed delivery of AP052 payload to the tumor and lower exposure in normal tissues, which may translate to an improved therapeutic window. In summary, the preclinical efficacy and safety properties of ADRX-0706 support clinical evaluation of this next generation anti-Nectin-4 ADC. ADRX-0706 is currently in a phase 1a/b study (NCT06036121). Citation Format: Maria Shahmoradgoli, Andrew Hau, Dong Jun Lee, Anna Wang, Peter P. Challita, Oscar Betancourt, Wes Sisson, Mario M. Kuo, Kris Zhang, Albert Goldson, Sam Janssen, Paul Datta, Felipe Acosta, Alexander Chu-Kung, Hui Li, Pia M. Challita-Eid, Sabine Rottmann. ADRX-0706 Nectin-4 antibody-drug conjugate PK/PD characterization elucidates its widened therapeutic window 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 1902.
Shahmoradgoli et al. (Fri,) studied this question.