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  • Review Article
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Claudin 18.2 as a novel therapeutic target

Nature Reviews Clinical Oncology volume 21, pages 354–369 (2024)Cite this article

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Abstract

Claudin 18.2, a tight-junction molecule predominantly found in the nonmalignant gastric epithelium, becomes accessible on the tumour cell surface during malignant transformation, thereby providing an appealing target for cancer therapy. Data from two phase III trials testing the anti-claudin 18.2 antibody zolbetuximab have established claudin 18.2-positive advanced-stage gastric cancers as an independent therapeutic subset that derives benefit from the addition of this agent to chemotherapy. This development has substantially increased the percentage of patients eligible for targeted therapy. Furthermore, newer treatments, such as high-affinity monoclonal antibodies, bispecific antibodies, chimeric antigen receptor T cells and antibody–drug conjugates capable of bystander killing effects, have shown considerable promise in patients with claudin 18.2-expressing gastric cancers. This new development has resulted from drug developers moving beyond traditional targets, such as driver gene alterations or growth factors. In this Review, we highlight the biological rationale and explore the clinical activity of therapies that target claudin 18.2 in patients with advanced-stage gastric cancer and explore the potential for expansion of claudin 18.2-targeted therapies to patients with other claudin 18.2-positive solid tumours.

Key points

  • Claudin 18.2 is expressed almost exclusively in the gastric mucosa, and no clear evidence exists of a role of this tight-junction protein in the carcinogenesis and/or proliferation of gastric cancer.

  • Two pivotal phase III trials to test zolbetuximab, a monoclonal antibody that targets claudin 18.2, have demonstrated statistically significant improvements in both the progression-free and overall survival of patients with unresectable gastric cancer and have established claudin 18.2 as a validated therapeutic target.

  • Determination of the optimal treatment sequence, especially for patients who are potentially eligible for several targeted therapies or immunotherapies, as well as the feasibility of biomarker tests for multiple proteins, will be the subject of much debate following the clinical implementation of zolbetuximab.

  • Claudin 18.2 can potentially be targeted using a wide range of therapeutic modalities beyond monoclonal antibodies including bispecific antibodies, antibody–drug conjugates, chimeric antigen receptor T cells and mRNA-based approaches.

  • The development of claudin 18.2-targeted therapies is expanding and will probably encompass other claudin 18.2-positive cancer types.

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Fig. 1: Claudin 18.2 structure, function and expression patterns.
Fig. 2: Claudin 18.2 expression during malignant transformation.
Fig. 3: CLDN18–ARHGAP fusions.
Fig. 4: Mechanisms of action of the various classes of developmental claudin 18.2-targeted therapies.
Fig. 5: Suggested utilization of the diverse range of claudin 18.2-targeted therapy approaches.

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Acknowledgements

The authors gratefully acknowledge T. Kuwata of National Cancer Center Hospital East, Kashiwa, Japan for providing images used in this publication.

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  1. These authors contributed equally: Izuma Nakayama, Changsong Qi.

Authors and Affiliations

  1. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan

    Izuma Nakayama, Yoshiaki Nakamura & Kohei Shitara

  2. Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China

    Changsong Qi, Yang Chen & Lin Shen

  3. Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan

    Yoshiaki Nakamura

  4. International Research Promotion Office, National Cancer Center Hospital East, Kashiwa, Japan

    Yoshiaki Nakamura

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Y.N. has acted as consultant and/or adviser of Daiichi Sankyo, Exact Sciences Corporation, Gilead Sciences, Guardant Health, Natera, Premo Partners, Roche, Seagen, Takeda Pharmaceutical and has acted as a speaker for Becton Dickinson and Company, CareNet, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Guardant Health, Genomedia, Hisamitsu, Merck, Miyarisan, MSD, Roche Diagnostics, Seagen, Taiho Pharmaceutical, Tempus Labs, Zeria Pharmaceutical. K.S. has acted as a consultant and/or adviser of ALX Oncology, Inc., Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Guardant Health Japan, Janssen, Merck Pharmaceutical, Novartis, Ono Pharmaceutical, Takeda, Zymeworks Biopharmaceuticals and has received (institutional) research funding from Astellas, Amgen, Chugai, Daiichi Sankyo, Eisai, Merck Pharmaceutical, Ono Pharmaceutical, PRA Health Sciences, Syneos Health and Taiho Pharmaceutical. The other authors declare no competing interests.

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Nakayama, I., Qi, C., Chen, Y. et al. Claudin 18.2 as a novel therapeutic target. Nat Rev Clin Oncol 21, 354–369 (2024). https://doi.org/10.1038/s41571-024-00874-2

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