上海交通大学Jian-wei Zhu等研究人员合作开发出通过靶向间皮素治疗实体瘤的T细胞定向抗体。2024年6月10日，国际知名学术期刊《中国药理学报》在线发表了这一成果。

据了解，T 细胞参与性双特异性抗体（TCB）最近在癌症治疗中发挥了重要作用。研究人员开发了一种新型双特异性抗体MSLN490，它是针对间皮素（MSLN）设计的，间皮素是一种在各种癌症中高度表达的糖基磷脂酰肌醇（GPI）连接糖蛋白，研究人员还评估了它对实体瘤的疗效。为了提高亲代抗体M912的亲和力，研究人员采用了CDR walking和噬菌体展示技术，从而产生了对MSLN具有不同亲和力的抗体池。从这个抗体池中组合出了各种双特异性抗体（BsAb）。

值得注意的是，具有 gG-[L]-scFv结构的MSLN490对表达MSLN的肿瘤具有显著的抗肿瘤活性（在HT-29-hMSLN细胞中的EC₅₀：0.16pM）。此外，即使存在非膜支链 MSLN（可溶性 MSLN），MSLN490也能保持有效。

此外，MSLN490与Atezolizumab或TAA × CD28 BsAb联合使用时，其抗肿瘤活性也会增强。值得注意的是，MSLN490与紫杉醇之间产生了协同效应，紫杉醇破坏了实体瘤内的免疫抑制微环境，增强了免疫细胞浸润，进而提高了抗肿瘤疗效。总之，MSLN490表现出强大的抗肿瘤活性、抗可溶性MSLN干扰的能力以及与其他疗法联合使用时增强的抗肿瘤效果，为治疗各种实体瘤提供了广阔的前景。这项研究为进一步探索MSLN490的临床潜力奠定了坚实的基础。

附：英文原文

Title: T cell-redirecting antibody for treatment of solid tumors via targeting mesothelin

Author: Liu, Jun-jun, Pan, Zhi-di, Yue, Ya-li, Wang, Shu-sheng, Chen, Jie, Jiang, Hua, Zhang, Bao-hong, Wu, Ming-yuan, Yuan, Yun-sheng, Bian, Yan-lin, Yin, Hai-yang, Wang, Lei, Li, Jun-yan, Gilly, John, Xie, Yue-qing, Zhu, Jian-wei

Issue&Volume: 2024-06-10

Abstract: T cell engaging bispecific antibodies (TCBs) have recently become significant in cancer treatment. In this study we developed MSLN490, a novel TCB designed to target mesothelin (MSLN), a glycosylphosphatidylinositol (GPI)-linked glycoprotein highly expressed in various cancers, and evaluated its efficacy against solid tumors. CDR walking and phage display techniques were used to improve affinity of the parental antibody M912, resulting in a pool of antibodies with different affinities to MSLN. From this pool, various bispecific antibodies (BsAbs) were assembled. Notably, MSLN490 with its IgG-[L]-scFv structure displayed remarkable anti-tumor activity against MSLN-expressing tumors (EC50: 0.16 pM in HT-29-hMSLN cells). Furthermore, MSLN490 remained effective even in the presence of non-membrane-anchored MSLN (soluble MSLN). Moreover, the anti-tumor activity of MSLN490 was enhanced when combined with either Atezolizumab or TAA×CD28 BsAbs. Notably, a synergistic effect was observed between MSLN490 and paclitaxel, as paclitaxel disrupted the immunosuppressive microenvironment within solid tumors, enhancing immune cells infiltration and improved anti-tumor efficacy. Overall, MSLN490 exhibits robust anti-tumor activity, resilience to soluble MSLN interference, and enhanced anti-tumor effects when combined with other therapies, offering a promising future for the treatment of a variety of solid tumors. This study provides a strong foundation for further exploration of MSLN490’s clinical potential.

DOI: 10.1038/s41401-024-01316-6

Source: https://www.nature.com/articles/s41401-024-01316-6