靶向Claudin18.2的新型抗肿瘤药物——佐妥昔单抗

doi:10.12092/j.issn.1009-2501.2026.05.013

摘要/Abstract

摘要：

紧密连接蛋白18.2（Claudin18.2，CLDN18.2）是一种属于Claudin蛋白家族的跨膜蛋白，主要参与构成细胞间的紧密连接结构，维持上皮细胞极性和屏障功能。其在正常健康组织中表达量较低，因紧密连接破坏而异常高表达于肿瘤细胞表面，与肿瘤增殖、侵袭、转移及不良预后密切相关。2024年12月，佐妥昔单抗获得国家药品监督管理局（National Medical Products Administration，NMPA）批准上市，用于联合含氟尿嘧啶类和铂类药物化疗，治疗CLDN18.2阳性、人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）阴性的局部晚期不可切除或转移性胃或胃食管交界处（gastric or gastric esophageal junction，G/GEJ）腺癌患者的一线治疗。该药是全球首款获批的CLDN18.2靶向单克隆抗体，也是我国首个针对该靶点的创新药物。本文对佐妥昔单抗的分子结构及理化特性、药理作用机制与临床研究进展进行综述，并对其在肿瘤治疗领域的未来应用潜力及发展方向进行深入探讨。

关键词: 佐妥昔单抗, Claudin18.2, 胃或胃食管交界处腺癌

Abstract:

Claudin 18.2 (CLDN18.2), a transmembrane protein belonging to the Claudin family, primarily participates in forming tight junction structures between cells to maintain epithelial cell polarity and barrier function. While exhibiting low expression in normal healthy tissues, it is aberrantly overexpressed on the surface of tumor cells due to disrupted tight junctions and is closely associated with tumor proliferation, invasion, metastasis, and poor prognosis. In december 2024, zolbetuximab received approval from the National Medical Products Administration (NMPA) for use in combination with fluorouracil-based and platinum-containing chemotherapy regimens as first-line treatment for patients with CLDN18.2-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. This drug represents the world's first approved monoclonal antibody targeting CLDN18.2 and marks China's inaugural innovative therapy for this target. This article reviews the molecular structure and physicochemical properties, pharmacological mechanism and clinical research progress of zolbetuximab, and discusses its future application potential and development direction in the field of tumor therapy.

Key words: zolbetuximab, Claudin18.2, gastric or gastroesophageal junction adenocarcinoma

中图分类号:

何一帆, 于泽芳, 马银玲, 吴惠珍. 靶向Claudin18.2的新型抗肿瘤药物——佐妥昔单抗[J]. 中国临床药理学与治疗学, 2026, 31(5): 683-690.

Yifan HE, Zefang YU, Yinling MA, Huizhen WU. A novel anti-tumor drug targeting Claudin18.2: zolbetuximab[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(5): 683-690.

图/表 4

参考文献 33

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研究名称（阶段）	患者特征与设计	治疗方案	主要疗效结果
MONO （Ⅱ期）	?样本量：54例； ?人群：CLDN18.2≥50%中-强阳性晚期G/GEJ/食管腺癌； ?终点：单药活性与耐受性	佐妥昔单抗单药	?ORR：14%（CLDN18.2≥70%亚组）； ?临床受益率：23%
日本Ⅰ期	?样本量：17例（可评估）； ?人群：CLDN18.2阳性日本患者； ?终点：安全性及初步有效性	佐妥昔单抗单药（600～1 000 mg/m2）	?DCR：64.7%（95% CI: 38.3%～85.8%）； ?中位PFS：2.6个月； ?中位OS：4.4个月
FAST （Ⅱ期）	?样本量：246例； ?人群：CLDN18.2≥40%中-强阳性晚期G/GEJ腺癌； ?设计：随机、多中心	第2组：EOX+佐妥昔单抗（800→600 mg/m2）第1组：EOX单药	?中位PFS： 7.5 vs. 5.3个月（HR=0.44, P<0.05）； ?中位OS： 13.0 vs. 8.3个月（HR=0.55, P<0.05）； ?ORR：39% vs. 25%
SPOTLIGHT （Ⅲ期）	?样本量：565例； ?人群：CLDN18.2≥75%、HER2阴性晚期G/GEJ腺癌； ?设计：全球双盲、安慰剂对照	试验组：佐妥昔单抗+mFOLFOX6 对照组：安慰剂+mFOLFOX6	?中位PFS： 11.04 vs. 8.94个月（HR=0.734, P<0.05）； ?中位OS： 18.23 vs. 15.57个月（HR=0.784, P<0.05）； ?ORR：48.1% vs. 47.5%
GLOW （Ⅲ期）	?样本量：507例； ?人群：CLDN18.2≥75%、HER2阴性晚期G/GEJ腺癌； ?设计：全球双盲、安慰剂对照	试验组：佐妥昔单抗+CAPOX 对照组：安慰剂+CAPOX	?中位PFS： 8.21 vs. 6.80个月（HR=0.687, P<0.05）； ?中位OS： 14.39 vs. 12.16个月（HR=0.771, P<0.05）； ?ORR：42.5% vs. 40.3%

研究名称（阶段）	患者特征与设计	治疗方案	主要疗效结果
MONO （Ⅱ期）	?样本量：54例； ?人群：CLDN18.2≥50%中-强阳性晚期G/GEJ/食管腺癌； ?终点：单药活性与耐受性	佐妥昔单抗单药	?ORR：14%（CLDN18.2≥70%亚组）； ?临床受益率：23%
日本Ⅰ期	?样本量：17例（可评估）； ?人群：CLDN18.2阳性日本患者； ?终点：安全性及初步有效性	佐妥昔单抗单药（600～1 000 mg/m2）	?DCR：64.7%（95% CI: 38.3%～85.8%）； ?中位PFS：2.6个月； ?中位OS：4.4个月
FAST （Ⅱ期）	?样本量：246例； ?人群：CLDN18.2≥40%中-强阳性晚期G/GEJ腺癌； ?设计：随机、多中心	第2组：EOX+佐妥昔单抗（800→600 mg/m2）第1组：EOX单药	?中位PFS： 7.5 vs. 5.3个月（HR=0.44, P<0.05）； ?中位OS： 13.0 vs. 8.3个月（HR=0.55, P<0.05）； ?ORR：39% vs. 25%
SPOTLIGHT （Ⅲ期）	?样本量：565例； ?人群：CLDN18.2≥75%、HER2阴性晚期G/GEJ腺癌； ?设计：全球双盲、安慰剂对照	试验组：佐妥昔单抗+mFOLFOX6 对照组：安慰剂+mFOLFOX6	?中位PFS： 11.04 vs. 8.94个月（HR=0.734, P<0.05）； ?中位OS： 18.23 vs. 15.57个月（HR=0.784, P<0.05）； ?ORR：48.1% vs. 47.5%
GLOW （Ⅲ期）	?样本量：507例； ?人群：CLDN18.2≥75%、HER2阴性晚期G/GEJ腺癌； ?设计：全球双盲、安慰剂对照	试验组：佐妥昔单抗+CAPOX 对照组：安慰剂+CAPOX	?中位PFS： 8.21 vs. 6.80个月（HR=0.687, P<0.05）； ?中位OS： 14.39 vs. 12.16个月（HR=0.771, P<0.05）； ?ORR：42.5% vs. 40.3%

药品名称	研发单位	NCT	靶点	药品分类	适应症	研发阶段
LM-302	礼新医药	05001516	CLDN 18.2	抗体偶联药物	胃癌或胃食管交界处腺癌	Ⅲ期
IBI-343	信达生物	06238843	CLDN 18.2	抗体偶联药物、人源/ 全人源化抗体	胆道癌、胰腺导管癌	Ⅲ期
PT-886	Phanes Thera	05482893	CLDN 18.2/CD47	双特异性抗体	胰腺导管癌	Ⅲ期
LB-4330	健信生物	05707676	CLDN 18.2/CD8	融合蛋白/多肽	晚期/转移性实体瘤	Ⅲ期
QLS-31905	齐鲁制药	05278832	CLDN 18.2/CD3	人源化抗体、双特异性抗体	肿瘤、晚期恶性实体瘤	Ⅱ期
CT-048	科济药业	05393986	CLDN 18.2/CCL21/IL7	CAR-T、表达CCL21、表达IL-7、T细胞、嵌合抗原受体	食管胃腺癌	Ⅰ期
AMG910	Amgen; BeiGene	04260191	CLDN 18.2/CD3	双特异性抗体	胃癌或胃食管交界处腺癌	Ⅰ期
ASP2138	阿斯利康	05365581	CLDN 18.2/CD3	双特异性抗体	胃癌或胃食管交界处腺癌、胰腺癌	Ⅰ期
DR30318	华东医药	/	CLDN 18.2/CD3E/ALB	单链抗体、sdAb-sdAb-scFv、双特异性抗体、单域抗体	肿瘤	临床前

药品名称	研发单位	NCT	靶点	药品分类	适应症	研发阶段
LM-302	礼新医药	05001516	CLDN 18.2	抗体偶联药物	胃癌或胃食管交界处腺癌	Ⅲ期
IBI-343	信达生物	06238843	CLDN 18.2	抗体偶联药物、人源/ 全人源化抗体	胆道癌、胰腺导管癌	Ⅲ期
PT-886	Phanes Thera	05482893	CLDN 18.2/CD47	双特异性抗体	胰腺导管癌	Ⅲ期
LB-4330	健信生物	05707676	CLDN 18.2/CD8	融合蛋白/多肽	晚期/转移性实体瘤	Ⅲ期
QLS-31905	齐鲁制药	05278832	CLDN 18.2/CD3	人源化抗体、双特异性抗体	肿瘤、晚期恶性实体瘤	Ⅱ期
CT-048	科济药业	05393986	CLDN 18.2/CCL21/IL7	CAR-T、表达CCL21、表达IL-7、T细胞、嵌合抗原受体	食管胃腺癌	Ⅰ期
AMG910	Amgen; BeiGene	04260191	CLDN 18.2/CD3	双特异性抗体	胃癌或胃食管交界处腺癌	Ⅰ期
ASP2138	阿斯利康	05365581	CLDN 18.2/CD3	双特异性抗体	胃癌或胃食管交界处腺癌、胰腺癌	Ⅰ期
DR30318	华东医药	/	CLDN 18.2/CD3E/ALB	单链抗体、sdAb-sdAb-scFv、双特异性抗体、单域抗体	肿瘤	临床前