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通过亲和度调制来调整ImmTAC分子的效能和选择性

Ian B Robertson¹, Rachel Mulvaney¹, Nele Dieckmann¹

¹Immunocore Limited, Drug Discovery and Protein Engineering, Abingdon, Oxon, UK.

Clinical and experimental immunology

|November 6, 2023

概括

优化T细胞参与的双特异性包括平衡结合亲缘关系. 将高亲和度T细胞受体与中等亲和度抗CD3部分结合起来,可以增强T细胞激活和选择性,用于癌症治疗.

科学领域:

免疫学免疫学免疫学
在瘤学瘤学.
生物化学生物化学

背景情况:

参与T细胞的双特异性药物在治疗癌症和传染病方面表现有前途.
了解结合亲和力/动力学和双特异分子强度/特异性之间的关系至关重要,但不完整.

研究的目的:

调查如何改变目标和CD3结合亲和力影响重定向T细胞反应的效力和特异性.
使用免疫调动单克隆TCRs对抗癌症 (ImmTAC) 分子来建模这些关系.

主要方法:

使用ImmTAC分子,其特点是用于向结合的亲和增强的T细胞受体和抗CD3功效分子.
系统地改变了目标和CD3域的结合亲和力.
测量T细胞激活,细胞因子释放和选择性.

主要成果:

通过高亲和度T细胞受体和中级亲和度抗CD3域实现了最佳的T细胞激活.
在目标和效应器领域的高亲缘关系减少了最大的细胞因子释放.
优化对两个域的亲和力提高了分子的选择性.
实验观测是由有限信号的动态校对模型解释的.

结论:

向和CD3域的亲和力显著影响双特定分子的疗效和特异性.
过强的结合会导致T细胞受体通过信号"黑暗状态"被禁用.
研究结果为设计强效和选择性的基于抗CD3的双特异性疗法提供了关键的见解.

关键词:

激活T细胞的激活过程两种类型的两种类型的区分的集群 3 区分的集群细胞因子释放细胞因子释放细胞毒性细胞毒性

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