Abstract LB048: ARC-401 - a triple payload first-in-class ADC against Nectin-4 designed to overcome cancer resistance and tumor heterogeneity shows broad anti-tumor activity and high tolerability in rats and non-human primates

Abstract ARC-401, a triple payload first-in-class ADC against Nectin-4 designed to overcome cancer resistance and tumor heterogeneity, shows broad anti-tumor activity and high tolerability in rats and non-human primates. The Araris’ site-specific and one-step linker conjugation technology AraLinQ™ generates stable, safe and highly potent ADCs without the need for antibody engineering prior to payload conjugation. ARC-401 is a proprietary first-in-class Nectin-4 targeting triple-warhead ADC (DAR2+2+2) using a combination of MMAE and two different topoisomerase-1 (TOP1) inhibitors designed to treat a broad range of Nectin-4 expressing solid tumors. ARC-401 is a highly homogenous and pure ADC with a DAR of 6 that and shows high stability under stressed conditions with no signs of aggregation. High stability was also confirmed in mouse, cyno, and human sera in vitro, as well as in rodent and cyno circulation, with no observed linker-payload deconjugation or linker cleavage. In vivo, ARC-401 showed a favorable pharmacokinetic profile with no signs of payload loss. Importantly, in a repeat dose toxicity study in rats, high tolerability was observed resulting in an HNSTD of 20 mg/kg (as comparison, the FDA-approved enfortumab vedotin (EV) reported a HNSTD of 5 mg/kg). This enhanced tolerability was similarly mirrored in a non-human primate repeat-dose toxicology study. High target-specific anti-tumor activity was confirmed in vitro and in vivo studies. Importantly, we could demonstrate the benefit of co-administering 3 different payloads on one ADC in a SUM-190PT breast cancer model, where ARC-401 was injected as a single dose of either 0. 5 or 1. 5 mg/kg. The 1. 5 mg/kg dose led to long-lasting and complete tumor regression and even the 0. 5 mg/kg dose induced strong anti-tumor efficacy. This effect was target specific, as control ADCs using non-target binding antibodies did not exhibit any effect using the same dose. Similarly, enfortumab-vedotin did not show any effect at 0. 5mg/kg. Further, the combination of the respective MMAE (DAR2) and TOP1i (DAR2+2) ADCs, each dosed at 0. 5 mg/kg, produced no observable anti-tumor response, demonstrating the benefit of our triple payload ADC. Further, ARC-401 showed high anti-tumor activity in several mouse and rat PDX models with complete anti-tumor responses at very low doses, where EV and Sacituzumab govitecan, the FDA-approved ADC for TNBC, showed only limited to transient anti-tumor activity. In conclusion, we present data on ARC-401, a proprietary, first-in-class Nectin-4 targeting triple-payload ADC demonstrating robust, target-specific anti-tumor efficacy in CDX and PDX models in mice and rats. Importantly, we confirm high tolerability in both rats and non-human primates suggesting a high therapeutic index. Further we show that combining multiple payloads within a single ADC can lead to improved anti-tumor activity compared to combination treatments. Citation Format: Isabella Attinger-Toller, Philipp Probst, Romain Bertrand, Rachael Fay, Lia Kallenberger, Ramona Stark, Patrick Maurhofer, Emma Renard, Roger Santimaria, Bernd Schlereth, Dragan Grabulovski, Philipp Rene Spycher. ARC-401 - a triple payload first-in-class ADC against Nectin-4 designed to overcome cancer resistance and tumor heterogeneity shows broad anti-tumor activity and high tolerability in rats and non-human primates abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB048.