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CLDN18.2 in Gastric Cancer: Current Therapeutic Landscape and Future Perspectives
Fei Zhang1, Ukyo Okazaki2, Izuma Nakayama3
1Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Abstract:
Claudin 18.2 (CLDN18.2), a tight junction protein selectively expressed in normal gastric epithelium and widely retained during carcinogenesis, has emerged as a promising therapeutic target for advanced gastric cancer (AGC). SPOTLIGHT and GLOW trials evaluated the anti-CLDN18.2 monoclonal antibody (mAb) zolbetuximab in combination with first-line chemotherapy, and established CLDN18.2 as a therapeutic target, initiating a paradigm shift toward a biomarker-driven treatment approach in AGC. In addition, from zolbetuximab to a diverse pipeline of promising high-affinity mAbs, bispecific antibodies, antibody-drug conjugates and chimeric antigen receptor T cells, this target has established a new and highly effective therapeutic avenue for CLDN18.2-expressing AGC. Therefore, as research progresses, CLDN18.2-targeted therapy is poised to become a cornerstone of treatment across multiple disease stages and cancer types. This review describes the biological role of CLDN18.2 in normal gastric epithelium and gastric carcinogenesis and summarizes the current therapeutic landscape and future perspectives targeting CLDN18.2 in AGC.
Insights
Claudin 18.2 is a promising target for advanced gastric cancer. Therapies targeting this protein, like zolbetuximab, are shifting treatment towards a biomarker-driven approach for better outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Claudin 18.2 (CLDN18.2) is a tight junction protein found in normal gastric epithelium.
- It is frequently retained during gastric carcinogenesis, making it a potential target for cancer therapy.
Purpose of the Study:
- To review the biological role of CLDN18.2 in gastric epithelium and cancer.
- To summarize the current and future therapeutic strategies targeting CLDN18.2 in advanced gastric cancer (AGC).
Main Methods:
- Review of clinical trials (SPOTLIGHT, GLOW) evaluating zolbetuximab, an anti-CLDN18.2 monoclonal antibody.
- Analysis of the emerging pipeline of CLDN18.2-targeted therapies.
Main Results:
- Zolbetuximab in combination with chemotherapy established CLDN18.2 as a viable therapeutic target for AGC.
- A diverse range of CLDN18.2-targeted agents, including mAbs, bispecific antibodies, ADCs, and CAR T cells, are under development.
- These therapies offer a new, effective treatment avenue for CLDN18.2-expressing AGC.
Conclusions:
- CLDN18.2-targeted therapy represents a paradigm shift towards biomarker-driven treatment in AGC.
- CLDN18.2-targeted therapies are expected to become a cornerstone treatment for various stages and types of cancer.
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