Claudin 18.2 as a novel therapeutic target

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. The development and successful phase III testing of the anti-claudin 18.2 antibody zolbetuximab has provided a novel targeted therapy for the 30-40% of patients with strongly claudin 18.2-positive gastric cancers. Furthermore, the development of an effective targeted therapy for a target that does not have a driver role in cancer development provides a novel drug development paradigm. In this Review, the authors describe the development of claudin 18.2-targeted therapies, including zolbetuximab, as well as novel therapies, including chimeric antigen receptor (CAR) T cells, antibody-drug conjugates and bispecific antibodies, all of which have the potential to expand the number of patients who can derive benefit from claudin 18.2-targeted therapies in the near future. 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.