CMG901, a Claudin18.2-specific antibody-drug conjugate, for the treatment of solid tumors.

IF 11.7 1区 医学 Q1 CELL BIOLOGY Cell Reports Medicine Pub Date : 2024-09-17 Epub Date: 2024-09-03 DOI:10.1016/j.xcrm.2024.101710
Gang Xu, Wei Liu, Ying Wang, Xiaoli Wei, Furong Liu, Yanyun He, Libo Zhang, Qin Song, Zhiyao Li, Changyu Wang, Ruihua Xu, Bo Chen
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Abstract

Claudin18.2 has been recently recognized as a potential therapeutic target for gastric/gastroesophageal junction or pancreatic cancer. Here, we develop a Claudin18.2-directed antibody-drug conjugate (ADC), CMG901, with a potent microtubule-targeting agent MMAE (monomethyl auristatin E) and evaluate its preclinical profiles. In vitro studies show that CMG901 binds specifically to Claudin18.2 on the cell surface and kills tumor cells through direct cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and bystander killing activity. In vivo pharmacological studies show significant antitumor activity in patient-derived xenograft (PDX) models. Toxicity studies show that the major adverse effects related to CMG901 are reversible hematopoietic changes attributed to MMAE. The highest non-severely toxic dose (HNSTD) is 6 mg/kg in cynomolgus monkeys and 10 mg/kg in rats once every 3 weeks. CMG901's favorable preclinical profile supports its entry into the human clinical study. CMG901 is currently under phase 3 investigation in patients with advanced gastric/gastroesophageal junction adenocarcinoma expressing Claudin18.2 (NCT06346392).

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用于治疗实体瘤的 Claudin18.2 特异性抗体-药物共轭物 CMG901。
最近,Claudin18.2 被认为是胃癌/胃食管交界处癌或胰腺癌的潜在治疗靶点。在此,我们开发了一种以Claudin18.2为靶向的抗体-药物共轭物(ADC)CMG901,并将其与强效微管靶向药物MMAE(单甲基金丝桃素E)结合,对其临床前特征进行了评估。体外研究表明,CMG901 能与细胞表面的 Claudin18.2 特异性结合,并通过直接细胞毒性、抗体依赖性细胞毒性(ADCC)、补体依赖性细胞毒性(CDC)和旁观者杀伤活性杀死肿瘤细胞。体内药理学研究显示,在患者异种移植(PDX)模型中,该药物具有显著的抗肿瘤活性。毒性研究表明,CMG901 的主要不良反应是 MMAE 引起的可逆造血变化。对猴的最高非剧毒剂量(HNSTD)为 6 毫克/千克,对大鼠的最高非剧毒剂量(HNSTD)为 10 毫克/千克,每 3 周一次。CMG901良好的临床前特征为其进入人体临床研究提供了支持。CMG901目前正在对表达Claudin18.2的晚期胃/胃食管交界腺癌患者进行3期临床研究(NCT06346392)。
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来源期刊
Cell Reports Medicine
Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
15.00
自引率
1.40%
发文量
231
审稿时长
40 days
期刊介绍: Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.
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