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理性工程改进了腺脱氨酶2酶,用于武器化T细胞疗法

J R Cox¹, M Jennings¹, C Lenahan¹

¹School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, USA.

Immuno-oncology technology

|July 31, 2023

概括

工程细胞可以分泌腺脱氨酶 (ADA) 来降低瘤中的免疫抑制腺. 这通过改善免疫细胞功能来增强仿真抗原受体 (CAR) T 细胞疗法.

科学领域:

免疫学免疫学免疫学
生物化学生物化学
生物技术是生物技术.

背景情况:

腺素是一种免疫抑制代谢物,在固体瘤中积累.
与瘤相关的腺抑制抗瘤免疫反应,包括CAR T细胞疗法.

研究的目的:

为了设计人类细胞分泌腺脱氨酶 (ADA) 以进行细胞外腺降解.
为了提高仿真抗原受体 (CAR) T细胞疗法的疗效.

主要方法:

研究了ADA1和ADA2异型的分泌.
利用了遗传学分析和突变调查来优化ADA2活动.
开发了一种高通量屏幕,用于增强ADA2介导的腺降解.
设计了Jurkat和CAR T细胞来表达优化的ADA2变异体.

主要成果:

高活性的ADA1异型是细胞内;标准分泌信号是无效的.
活性较低的ADA2异型是自然分泌的.
一种新型的,具有高度催化效率的ADA2变体被分离出来,表现出比野生类型的细胞外腺降解活性高30倍.
工程Jurkat和CAR T细胞在体外显示出显著的细胞外腺降解.

结论:

高活性 ADA2 变体的工程分泌提供了一个有希望的策略来抵消瘤免疫抑制.
这种方法有可能提高CAR T细胞免疫疗法对固体瘤的有效性.

关键词:

通过T细胞治疗治疗.检查点抑制抑制检查点的抑制免疫疗法免疫疗法蛋白质工程工程蛋白质工程

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