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.

Claudin 18.2 是一种主要存在于非恶性胃上皮中的紧密连接分子，在恶性转化过程中可进入肿瘤细胞表面，从而为癌症治疗提供了一个有吸引力的靶点。两项测试抗紧密蛋白 18.2 抗体 zolbetuximab 的 III 期试验数据已确定紧密蛋白 18.2 阳性晚期胃癌作为一个独立的治疗亚组，该亚组可从在化疗中添加该药物中获益。这一进展大大增加了有资格接受靶向治疗的患者比例。此外，新的治疗方法，如高亲和力单克隆抗体、双特异性抗体、嵌合抗原受体 T 细胞和具有旁观者杀伤作用的抗体药物偶联物，在表达密蛋白 18.2 的胃癌患者中显示出相当大的前景。这一新的进展是药物开发商超越传统目标（例如驱动基因改变或生长因子）的结果。在这篇综述中，我们强调了生物学原理，探讨了针对晚期胃癌患者的紧密蛋白 18.2 靶向疗法的临床活性，并探讨了将紧密蛋白 18.2 靶向疗法扩展到其他紧密蛋白 18.2 阳性实体瘤患者的潜力。