Samanta Ananya, Ghosh Arindam, Sarma Monalisa
School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, IND.
Biochemistry, Dr. B.C. Roy Multispeciality Medical Research Centre, Indian Institute of Technology, Kharagpur, IND.
Cureus. 2024 Dec 6;16(12):e75206. doi: 10.7759/cureus.75206. eCollection 2024 Dec.
This article comprehensively reviews the working, efficacy, and safety profile of zolbetuximab. Zolbetuximab is a pioneering chimeric monoclonal antibody designed to target Claudin 18.2 (CLDN18.2), a tight junction protein frequently overexpressed in various gastrointestinal cancers, including gastric (G) and gastroesophageal junction (GEJ) adenocarcinomas. This drug has captured attention in the treatment of unresectable and metastatic G/GEJ cancer, especially in HER2-negative patients whose tumours express CLDN18.2. Zolbetuximab is a drug that binds to CLDN18.2, and its binding initiates an immune response that attacks and kills the cancer cells. It is typically co-prescribed with fluoropyrimidine and platinum-containing chemotherapy. The drug (formerly IMAB362), brand name Vyloy, was developed by Astellas Pharma, Tokyo, Japan. After multiple rounds of clinical trials, it was approved by the U.S. Food and Drug Administration (FDA) as a first-line treatment for locally advanced, unresectable cancer, establishing itself as a promising option for advanced G/GEJ cancers. Studies reveal that it targets CLDN18.2 for the selective killing of cancer cells while sparing most healthy tissues. Zolbetuximab has demonstrated a significant improvement in progression-free survival (PFS) when combined with chemotherapy (like mFOLFOX6 or CAPOX). Also, it showed prolonged PFS compared to chemotherapy alone in previously untreated, CLDN18.2-positive, HER2-negative patients. Zolbetuximab has also shown improvements in overall survival (OS), regardless of whether the cancer progresses. This is a crucial benefit for patients with advanced G/GEJ adenocarcinomas. Additionally, zolbetuximab's dual action triggers antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). This enhances the immune system's ability to destroy cancerous cells and results in highly potent tumour destruction compared with chemotherapy alone. Zolbetuximab is a relatively safe drug with a few adverse effects. The most frequently reported side effects were gastrointestinal, namely nausea, fatigue, vomiting, decreased appetite, diarrhea, neutropenia, anemia, and thrombocytopenia, potentially due to specific CLDN18.2 expression in the gastric mucosa. Its side effects are generally manageable, with no unexpected toxicity beyond those typically seen in patients receiving chemotherapy.
本文全面综述了zolbetuximab的作用机制、疗效和安全性。Zolbetuximab是一种开创性的嵌合单克隆抗体，旨在靶向Claudin 18.2（CLDN18.2），这是一种紧密连接蛋白，在包括胃癌（G）和胃食管交界（GEJ）腺癌在内的各种胃肠道癌症中经常过度表达。这种药物在不可切除和转移性G/GEJ癌症的治疗中引起了关注，特别是在肿瘤表达CLDN18.2的HER2阴性患者中。Zolbetuximab是一种与CLDN18.2结合的药物，其结合引发免疫反应，攻击并杀死癌细胞。它通常与氟嘧啶和含铂化疗联合使用。该药物（原IMAB362），商品名Vyloy，由日本东京的安斯泰来制药公司研发。经过多轮临床试验，它被美国食品药品监督管理局（FDA）批准作为局部晚期、不可切除癌症的一线治疗药物，成为晚期G/GEJ癌症的一个有前景的选择。研究表明，它靶向CLDN18.2以选择性杀死癌细胞，同时使大多数健康组织免受影响。Zolbetuximab与化疗（如mFOLFOX6或CAPOX）联合使用时，无进展生存期（PFS）有显著改善。此外，在先前未治疗的CLDN18.2阳性、HER2阴性患者中，与单独化疗相比，它显示出更长的PFS。无论癌症是否进展，Zolbetuximab在总生存期（OS）方面也有改善。这对晚期G/GEJ腺癌患者来说是一项关键益处。此外，zolbetuximab的双重作用触发抗体依赖性细胞毒性（ADCC）和补体依赖性细胞毒性（CDC）。与单独化疗相比，这增强了免疫系统破坏癌细胞的能力，并导致高效的肿瘤破坏。Zolbetuximab是一种相对安全的药物，副作用较少。最常报告的副作用是胃肠道反应，即恶心、疲劳、呕吐、食欲下降、腹泻、中性粒细胞减少、贫血和血小板减少，这可能是由于胃黏膜中特定的CLDN18.2表达所致。其副作用通常是可控的，除了接受化疗的患者通常出现的那些副作用外，没有意外的毒性。
