Abstract 1573: MW-C1, a novel CLDN1-targeting ADC demonstrates compelling anti-tumor efficacy and favorable safety profile in preclinical studies

Abstract Background: Claudins are a family of tight junction proteins characterized by four transmembrane domains, with critical roles in epithelial cell junction formation. While claudins localize to tight junctions in healthy tissues, their overexpression in solid tumors leads to aberrant exposure outside of these junctions, making them attractive targets for ADC therapies. CLDN1, in particular, is overexpressed in several solid tumors, including head and neck squamous cell carcinoma (HNSCC), lung squamous cell carcinoma (LUSC), and hepatocellular carcinoma (HCC), where its expression correlates with tumor proliferation, invasion, metastasis, and poor prognosis. Here, we developed a novel CLDN1-targeting ADC, MW-C1, that has shown potent anti-tumor activity across various preclinical models, along with an encouraging safety profile in non-human primates (NHPs). Methods: MW-C1 was engineered by conjugating monomethyl auristatin E (MMAE) to a CLDN1-targeting monoclonal antibody using site-specific interchain-disulfide conjugation technology and a cleavable linker, resulting in a drug-to-antibody ratio (DAR) of 4. In vitro, the internalization and cytotoxicity of MW-C1 were assessed in SCC4, Cal27, Huh7, and OVCAR3 cell lines, which express varying levels of CLDN1. In vivo efficacy was evaluated in multiple cell-line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Toxicology and pharmacokinetic studies were conducted in cynomolgus monkeys. Results: CLDN1 was found to be overexpressed in 85.7% of HNSCC, 91.7% of HCC, 58% of LUSC, and 77% of cervical cancer samples. MW-C1 demonstrated robust binding, rapid internalization, and potent cytotoxicity in CLDN1-positive cancer cell lines. In in vivo studies, MW-C1 induced significant and durable tumor regression in both CDX and PDX models, with varying CLDN1 expression levels. Pharmacokinetic studies revealed favorable properties for MW-C1 in both mice and cynomolgus monkeys, which were attributed to its optimized biophysical characteristics and site-specific conjugation. In a non-GLP NHP toxicology study, MW-C1 was well tolerated, with no significant off-target toxicity or adverse events observed. Conclusions: MW-C1 demonstrated potent anti-tumor efficacy and a favorable safety profile, highlighting its potential as a transformative therapeutic candidate for the treatment of CLDN1-overexpressing malignancies. Citation Format: Zhongfei Li, Jun Yang, Peng Fang, Rongrong Hu, Cuicui Guo, Xiaoding Tan, Hai Wu, Xun Gui. MW-C1, a novel CLDN1-targeting ADC demonstrates compelling anti-tumor efficacy and favorable safety profile in preclinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1573.