靶向癌胚抗原相关细胞黏附分子5的抗体偶联药物——tusamitamab ravtansine

The antibody-drug conjugate carcinoembryonic antigen-related cell adhesion molecule 5-targeting:tusamitamab ravtansine

癌胚抗原相关细胞黏附分子5(CEACAM5)是通过糖基磷脂酰肌醇(GPI)与细胞膜连接的细胞表面糖蛋白,在正常组织中低表达而在多种肿瘤组织中高表达,尤其常见于非小细胞肺癌、胃肠道癌、结直肠癌、胰腺癌和乳腺癌。tusamitamab ravtansine(研发代号:SAR408701)是目前靶向CEACAM5的药物中研究进展最快的同类首创抗体偶联药物(ADC),目前正处于Ⅲ期临床试验阶段。临床前研究和多项临床研究证实,tusamitamab ravtansine单药治疗或与其他药物联用均对CEACAM5高表达的非小细胞肺癌、胃肠道癌、结直肠癌、胰腺癌和乳腺癌患者具有良好的抗肿瘤活性和安全性。虽然tusamitamab ravtansine的Ⅲ期临床试验中期分析结果显示,其未能达到无进展生存期主要终点,但总生存期趋势有所改善,而且其联合标准一线治疗方案展现出良好的抗肿瘤活性和安全性,因此其在CEACAM5高表达肿瘤患者中的应用潜力仍值得期待。本文对tusamitamab ravtansine的基本信息、作用机制、临床前研究、临床研究等信息作一概述。

Carcinoembryonic antigen-related cell adhesion molecule 5(CEACAM5),a cell surface glycoprotein linked to membranes by glycosylphosphatidylinositol(GPI),is lowly expressed in normal tissues but highly expressed in a variety of tumor tissues,especially in non-small-cell lung,gastrointestinal cancers,colorectal cancers,pancreatic cancer,and breast cancer.Tusamitamab ravtansine(research code:SAR408701),the fastest progressing first-in-class antibody-drug conjugate(ADC)targeting CEACAM5 is currently in Phase Ⅲ clinical trials.Preclinical studies and multiple clinical trials have confirmed the promising antitumor activity and safety profile of tusamitamab ravtansine,either as monotherapy or in combination with other agents,in patients with CEACAM5-expressing non-small cell lung cancer,gastrointestinal cancers,colorectal cancers,pancreatic cancers and breast cancers.Although the interim analysis of the phase Ⅲ clinical trial of tusamitamab ravtansine did not meet the primary endpoint of progression-free survival,there was an improvement trend in overall survival.Moreover,its combination with standard first-line treatment regimens showed promising antitumor activity and safety,indicating the poten⁃tial application of tusamitamab ravtansine in patients with CEACAM5-high expressing tumors.This article provides an over⁃view of the basic information,mechanism of action,preclinical studies,and clinical studies of tusamitamab ravtansine.