Xu, Liu, and Wang et al. summarized preclinical data supporting the ongoing phase 3 clinical investigation of CMG901 in patients with advanced gastric/gastroesophageal junction tumors. CMG901, a Claudin 18.2-targeted Ab (CM311) conjugated to the microtubule-targeting agent MMAE, was shown to specifically bind to and be internalized by Claudin 18.2+ tumor cells. Mechanisms of killing included direct cytotoxicity, ADCC, and CDC, as well as bystander killing of Claudin 18.2-negative tumor cells. In patient-derived xenograft (PDX) models, CMG901 had significant antitumor efficacy, while toxicity studies in primates and rats revealed reversible hematological changes.
Contributed by Katherine Turner
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).
Author Info: (1) Research and Development Department, Keymed Biosciences (Chengdu) Limited, Chengdu, Sichuan 610219, China.(2) Department of Medical Oncology, Sun Yat-Sen University Cancer Cent
Author Info: (1) Research and Development Department, Keymed Biosciences (Chengdu) Limited, Chengdu, Sichuan 610219, China.(2) Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong 510060, China. (3) Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510060, China. (4) School of Biological Sciences, Nanyang Technological University 60 Nanyang Drive, Singapore 637551, Singapore. (5) Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong 510060, China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, Guangdong 510060, China. Electronic address: xurh@sysucc.org.cn. (6) Research and Development Department, Keymed Biosciences (Chengdu) Limited, Chengdu, Sichuan 610219, China. Electronic address: knybochen@keymedbio.com.
