@article{APS11377,
author = {Ya-li Yue and Jun-jun Liu and Hang Ma and Zhi-di Pan and Lei Wang and Jia-wei Zhang and Shu-sheng Wang and Yue-qing Xie and Hua Jiang and Yan-lin Bian and Ming-yuan Wu and Yun-sheng Yuan and Bao-hong Zhang and Xiao-dong Xiao and Jian-wei Zhu},
title = {Generating potent and persistent antitumor immunity via affinity-tuned CAR-T cells targeting mesothelin},
journal = {Acta Pharmacologica Sinica},
volume = {46},
number = {10},
year = {2025},
keywords = {},
abstract = {Chimeric antigen receptor (CAR)-T cell therapy for solid tumors faces challenges of insufficient efficacy and a high recurrence rate. Mesothelin (MSLN) is a membrane glycoprotein highly expressed in various solid tumors that has restricted low expression in normal tissues such as the pleura, peritoneum, and pericardium. We previously performed affinity maturation based on the parental antibody M912, and constructed the phage display library. In this study we identified four novel human anti-MSLN antibodies (LP12, HP4-11, HP4-41/LP6, and HP4-44/LP2) with varying degrees of enhanced affinity. These third-generation CARs targeting MSLN were packaged into lentiviral vectors to generate stable CAR-T cells. The CAR-T variants induced robust cytolytic activity, significant cytokine production, and activation-induced clonal proliferation against various MSLN-positive tumors in vitro, and effectively cleared disseminated tumors in mice. A single administration of the CAR-T variant LP12 potently eradicated various types of MSLN-positive solid tumors, achieved long-term persistence in vivo, effectively prevented tumor recurrence, and exhibited no non-specific toxicity. Therefore, optimizing the affinity of antigen-binding domain in CAR represents a promising strategy for advancing the development of safe and effective CAR-T cell therapies. The LP12 CAR-T cells developed in this study have potential applications in patients with MSLN-positive solid tumors.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/11377}
}