美托洛尔
翻译(生物学)
药理学
医学
细胞因子
受体
药品
嵌合抗原受体
信使核糖核酸
免疫学
免疫系统
免疫疗法
内科学
生物
基因
生物化学
作者
Yan Yang,Y Zhang,Xiaoyan Xing,Gang Xu,Xin Lin,Yao Wang,M. Chen,Chunmeng Wang,Bin Zhang,Weidong Han,Xiaoyu Hu
摘要
Chimeric antigen receptor (CAR) T therapies have achieved remarkable success for treating hematologic malignancies, yet are often accompanied by severe cytokine release syndrome (CRS). Here, an accidental clinical observation raised the possibility that metoprolol, an FDA-approved β1 adrenergic receptor blocker widely used for cardiovascular conditions, may alleviate CAR T–induced CRS. Metoprolol effectively blocked IL-6 production in human monocytes through unexpected mechanisms of action of targeting IL-6 protein translation but not IL6 mRNA expression. Mechanistically, metoprolol diminished IL-6 protein synthesis via attenuating eEF2K–eEF2 axis–regulated translation elongation. Furthermore, an investigator-initiated phase I/II clinical trial demonstrated a favorable safety profile of metoprolol in CRS management and showed that metoprolol significantly alleviated CAR T–induced CRS without compromising CAR T efficacy. These results repurposed metoprolol, a WHO essential drug, as a potential therapeutic for CRS and implicated IL-6 translation as a mechanistic target of metoprolol, opening venues for protein translation–oriented drug developments for human inflammatory diseases.
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