近日，上海交通大学教授朱建伟及其课题组提出了通过靶向间皮素的亲和力调节CAR-T细胞产生有效和持久的抗肿瘤免疫。相关论文于2025年5月8日发表在《中国药理学报》杂志上。

该课题组之前基于亲本抗体M912进行了亲和成熟，并构建了噬菌体展示文库。在这项研究中，该研究团队鉴定了具有不同程度增强亲和力的新型人抗MSLN抗体（LP12, HP4-11， HP4-41/LP6和HP4-44/LP2）。这些靶向MSLN的第三代CAR被包装成慢病毒载体，以产生稳定的CAR-T细胞。在体外，CAR-T变体诱导小鼠的细胞溶解活性、显著的细胞因子产生和激活诱导的针对各种MSLN阳性肿瘤的克隆增殖，并有效清除小鼠体内的播散性肿瘤。单次给药CAR-T变体LP12可有效根除多种类型的MSLN阳性实体瘤，实现体内长期存在，有效预防肿瘤复发，且无非特异性毒性。因此，优化CAR中抗原结合域的亲和力是促进安全有效的CAR-T细胞疗法发展的一个有希望的策略。本研究开发的LP12 CAR-T细胞在MSLN阳性实体瘤患者中具有潜在的应用前景。

据悉，嵌合抗原受体(CAR)-T细胞治疗实体瘤面临疗效不足和复发率高的挑战。间皮素（MSLN）是一种在多种实体瘤中高表达的膜糖蛋白，在胸膜、腹膜和心包膜等正常组织中低表达。

附：英文原文

Title: Generating potent and persistent antitumor immunity via affinity-tuned CAR-T cells targeting mesothelin

Author: Yue, Ya-li, Liu, Jun-jun, Ma, Hang, Pan, Zhi-di, Wang, Lei, Zhang, Jia-wei, Wang, Shu-sheng, Xie, Yue-qing, Jiang, Hua, Bian, Yan-lin, Wu, Ming-yuan, Yuan, Yun-sheng, Zhang, Bao-hong, Xiao, Xiao-dong, Zhu, Jian-wei

Issue&Volume: 2025-05-08

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.

DOI: 10.1038/s41401-025-01572-0

Source: https://www.nature.com/articles/s41401-025-01572-0