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 beta-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 beta-sheet, whereas a few other comparator antibodies target the side face of the beta-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.