What question did this study set out to answer?

This research aims to characterize the binding patterns and therapeutic potential of RC118, an anti-CLDN18.2 ADC, compared to other antibodies.

April 5, 2026

Abstract 5643: Preclinical characterization of RC118 ADC and identification of its differential binding pattern relative to other anti-CLDN18.2 antibodies.

Key Points

This research aims to characterize the binding patterns and therapeutic potential of RC118, an anti-CLDN18.2 ADC, compared to other antibodies.
Preclinical studies utilized cell lines expressing CLDN18.2 for binding analysis.
Structural modeling compared RC118 and zolbetuximab epitope recognition.
In vivo efficacy was assessed in patient-derived xenograft models of gastric and pancreatic cancers.
Targeted mutations were introduced in extracellular loops to evaluate their role in antibody recognition.
RC118 showed strong selective binding and potent cytotoxicity in vitro against CLDN18.2-positive cells.
In vivo models indicated robust antitumor efficacy for RC118 in gastric and pancreatic cancer.
Structural analyses demonstrated RC118 shares binding patterns with zolbetuximab but differs from other investigational antibodies.
RC118 remains a compelling candidate for clinical development due to promising findings and ongoing trials.

Abstract

Abstract CLDN18.2 is a tight junction transmembrane protein normally buried in the gastric epithelium, rendering it largely inaccessible under physiological conditions. However, it is frequently overexpressed in malignancies such as gastric, gastroesophageal junction (GEJ), and pancreatic adenocarcinomas, where it becomes exposed and functions as a tumor-associated antigen suitable for targeted therapy. Structurally, CLDN18.2 has four transmembrane domains anchoring two extracellular loops (ECL1 and ECL2) that extend into the extracellular space. These loops form β-sheet-rich structures with conserved charged and polar residues critical for paracellular ion selectivity and tight junction integrity. Many therapeutic antibodies and ADCs exploit these extracellular regions to selectively target CLDN18.2-positive cancer cells through diverse mechanisms. RC118 is an anti-CLDN18.2 antibody-drug conjugate (ADC) developed by RemeGen. It consists of a humanized anti-CLDN18.2 monoclonal antibody conjugated to the monomethyl auristatin E (MMAE) via a cleavable linker. RC118 exhibits strong and selective binding to CLDN18.2-positive cells, inducing rapid internalization and potent cytotoxicity in vitro. In multiple in vivo models, including patient-derived xenograft (PDX) models of gastric and pancreatic cancers, RC118 showed robust antitumor efficacy. Collectively, these findings support RC118 as a promising ADC candidate for gastric cancer therapy. Structural modeling indicated that RC118 and zolbetuximab, a FDA-approved CLDN18.2 antibody drug, recognize a similar epitope within ECL1 around a loop structure at the end of the β-sheet, whereas a few other comparator antibodies target the side face of the β-sheet region. To further delineate epitope specificity among CLDN18.2-targeting antibodies, we engineered chimeric CLDN18.2/CLDN3-expressing cell lines exposing different extracellular loop configurations for comparative binding analysis. Targeted mutations of the Cys52-Cys62 disulfide motif within ECL1 were introduced to evaluate its contribution to antibody recognition. These studies revealed that RC118 shares a similar binding pattern with zolbetuximab, while differing from other investigational CLDN18.2 antibodies. Structural analyses further suggest that variations in ECL1 engagement may underlie differences in therapeutic activity among these antibodies. RC118 is currently under evaluation in multiple clinical trials. At the 2025 ESMO meeting, combination data with immunotherapy showed encouraging results, supporting its potential in personalized treatment strategies for CLDN18.2-positive cancers. The emerging clinical outcomes, together with the structural insights into RC118-CLDN18.2 interactions, indicate that RC118 remains a strong and competitive candidate for continued clinical development. Citation Format: Lili Wang, Xiaoping Zhang, Mingyang Li, Xiao Wang, Yidan Xu, Xiaoli He, Shengle Ji, Shuya Ji, Shifu Wang, Yinghao Xin, Fanxue Bu, Yuelei Shen, Jianmin Fang, Yuanhao Li. Preclinical characterization of RC118 ADC and identification of its differential binding pattern relative to other anti-CLDN18.2 antibodies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5643.

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