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bioRxiv · 10.64898/2026.11.09.765403

Binding mechanisms of therapeutic antibodies to human claudin-18.2

Wang, X.·Fu, C.·Ma, H.·Yang, P.·Yu, H.·Sun, Z.·Jin, L.·Su, Z.·Zhou, X.
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Abstract

Claudin-18.2 (CLDN18.2) is a tight junction component with highly restricted expression in the paracellular space of nonmalignant gastric epithelial cells. It becomes accessible on tumor cell surface during malignant transformation, making CLDN18.2 an attractive target for targeted therapies against gastric cancer. Recently, zolbetuximab has become the first FDA-approved monoclonal antibody that targets CLDN18.2 in advanced gastric cancer, and others like osemitamab have entered phase 3 clinical trials. However, the high-resolution structure of CLDN18.2 is lacking, and how CLDN18.2 is recognized by therapeutic antibodies remains undefined. Here, we report cryo-EM structures of human claudin-18.2 (hCLDN18.2) in complex with the Fab fragments of zolbetuximab and osemitamab, revealing the structure of hCLDN18.2 and its binding mechanism to the therapeutic antibodies. Further analyses reveal that three residues in the first extracellular loop of hCLDN18.2 that are different from human claudin-18.1 (hCLDN18.1) play a critical role in antibody binding. Our data elucidate the structural basis for selective binding of therapeutic antibodies to hCLDN18.2, which should aid rational design of next-generation immunotherapies targeting hCLDN18.2.

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Wang, X., Fu, C., Ma, H., Yang, P., Yu, H., Sun, Z., Jin, L., Su, Z., Zhou, X.. 2026-11-11. Binding mechanisms of therapeutic antibodies to human claudin-18.2. https://doi.org/10.64898/2026.11.09.765403

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