Abstract 7338: Evaluation of a novel target Claudin1 in preclinical models of nasopharyngeal carcinoma

Abstract Introduction: Epstein-Barr virus (EBV)+ve nasopharyngeal carcinoma (NPC) is prevalent in Southern China where patients with recurrent/ metastatic disease can be treated with chemotherapy and/or immune-checkpoint inhibitors. Claudin 1 (CLDN1) is a member of the tight junction (TJ) family of proteins that is overexpressed in some cancers with their non-junctional (NJ) epitopes exposed at the epithelium. This study investigated CLDN1 as a novel therapeutic target in NPC and evaluated the preclinical activity of ALE.C04 - a first-in-class, highly specific monoclonal antibody targeting NJ-CLDN1, in NPC models. Method: Expression of NJ-CLDN1 was assessed in three EBV+ve NPC cell lines (C666-1, NPC43 and C17C), four patient-derived- xenografts (PDXs) and NPC biopsies (n=44). The anti-proliferative effect of ALE.C04 was evaluated in NJ-CLDN1+ve NPC cell lines by clonogenic and invasion assay, co-cultured with or without human-derived natural killer (NK) cells. Results are validated in PDX models (C15, C17). ALE.C04 was administrated either as a single agent or in combination with chemotherapy or bevacizumab. Results: NJ-CLDN1 were overexpressed in two NPC cell line (NPC43 and C17C), three PDXs (C15, C17 and X2117) and biopsies (80%). Interestingly, NJ-CLDN1 was not detected in PDX Xeno-666 and its derived cell line, C666-1. A non-significant correlation trend was found between h-score with overall survival. Treatment with ALE.C04 suppressed colony formation of NJ-CLDN1+ve cell lines, with more significant effect observed in C17C. Effect of ALE.C04 as a single agent is modest on the growth of NJ-CLDN1+ve positive cell lines and C17 PDX model. Whilst in combinatorial approach, ALE.C04 showed synergism with gemcitabine as tumor growth was suppressed in C17 PDX. In contrast, ALE.C04 monotherapy significantly suppressed growth in C15 PDX, resulting in substantial changes in gene expression profile (via RNA-Sequencing) compared to the control group. The results of the in vitro coculture assay and in vivo combination with gemcitabine and bevacizumab will be presented. Conclusion: The results generated to date provide a proof-of-concept of targeting NJ-CLDN1 signaling in NPC using ALE.C04, especially in combination with chemotherapy or anti-vascular agent. ALE.C04 is now being evaluated in patients with NPC and other head and neck cancers in a phase 1 clinical trial (NCT06054477). Citation Format: Kar Wei Chin, Connie Wun Chun Hui, Chi-Hang Wong, Grace T. Y. Chung, Winky Lai, Alberto Toso, Luigi Manenti, Li Lili, Chi Man Tsang, Qian Tao, Edwin Pun Hui, Anthony T. C Chan, Kwok Wai Lo, Brigette B. Y. Ma. Evaluation of a novel target Claudin1 in preclinical models of nasopharyngeal carcinoma [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 7338.