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单链Fab链交换 (scFab-PACE) 将向的前药物转化为功能性T细胞对瘤细胞的参与者

Vedran Vasic¹, Steffen Dickopf¹, Klaus Mayer¹

¹Roche Pharma Research and Early Development (pRED), Large Molecule Research (LMR), Roche Innovation Center Munich, Penzberg, Germany.

The Journal of biological chemistry

|July 18, 2025

概括

这项研究引入了一种精细的前药激活链交换 (PACE) 方法,用于T细胞激活抗体 (TCB). 这种新方法提高了安全性和疗效,使TCB前药物能够在瘤部位进行向激活.

科学领域:

免疫学免疫学免疫学
在瘤学瘤学.
生物技术是生物技术.

背景情况:

T细胞参与抗体 (TCB) 具有治疗潜力,但由于治疗窗口狭窄,因此面临限制.
在瘤上优先激活的前药物 (proTCBs) 可以减轻与TCBs相关的安全问题.

研究的目的:

为TCBs提出第二代前药物激活链交换 (PACE) 方法.
为了改善TCB前药物的药理动力学特性和条件激活.
为了证明同时参与T细胞的双前药功能.

主要方法:

开发了第二代PACE前药物,具有Fc域和单链Fab (scFab) 臂.
在Fd/光链接口上设计了具有排斥性电荷的scFab臂,在瘤细胞积累时触发激活.
利用 HER2 向的 scFab-PACE 前体来产生 CD3 结合剂前药物,并证明了双重 CD3/CD28 参与.

主要成果:

精制的PACE前药物表现出改善的药理动力学和最小化的溶液链交换,减少目标外激活.
向HER2的scFab-PACE预药以依赖HER2密度的方式获得CD3结合功能.
已证明具有双重前药能力,可使CD3和CD28在T细胞激活过程中被条件和同时激活.

结论:

第二代scFab-PACE方法为开发更安全,更有效的TCB前药提供了一个强大的平台.
这项技术允许精确的,瘤特异性的T细胞介导免疫的激活.
能够同时激活CD3和CD28的能力为增强癌症治疗中T细胞反应提供了一种新的策略.

关键词:

一个T细胞参与者.两种特异性的抗体.癌症免疫疗法免疫疗法链式交易所链式交易所链式交易所作为一种前药物,它是一种前药物.

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