ARC-401——一种旨在克服癌症耐药和肿瘤异质性的靶向Nectin-4的三载荷first-in-class ADC，在大鼠和非人灵长类动物中显示出广泛的抗肿瘤活性和高耐受性

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.