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基于米诺环素诱导的蛋白质与蛋白质相互作用的破坏的设计者小分子控制系统

Ram Jha^1,2, Alexander Kinna¹, Alastair Hotblack²

¹Autolus Therapeutics, London W12 7FP, U.K.

ACS chemical biology

|January 20, 2024

概括

一种新的两组系统使用抗生素米诺环林来控制细胞疗法. 这种多功能平台能够精确,可逆调节治疗干预措施,提高临床应用中的安全性和有效性.

科学领域:

生物技术是生物技术.
免疫学免疫学免疫学
药理学药理学是指药理学的学科.

背景情况:

临床细胞疗法需要精确,安全和有效的控制系统.
现有的控制系统往往缺乏多功能性或难以实施.
基于小分子的系统为远程和可调节的调节提供了潜力.

研究的目的:

开发一种多功能,安全和有效的两组小分子控制系统,用于临床细胞治疗.
为了利用米诺环素,FDA批准的抗生素,作为蛋白质-蛋白质相互作用中断的核心成分.
为了证明该系统在各种细胞疗法模式中的适用性.

主要方法:

开发了一个系统,包括一种抗米诺环素单域抗体 (sdAb) 和一种可取代米诺环素的循环.
设计的OFF开关分割CAR系统 (MinoCAR) 和通用CAR适配器 (MinoUniCAR).
将该系统应用于可调节的T细胞激活模块,可控制的细胞有效载荷分泌和可诱导的细胞-细胞连接.

主要成果:

已证明可逆,暂时和剂量依赖的CAR系统的抑制.
通过MyD88/CD40信号实现了可调节的T细胞激活.
启用可控制的IL12分泌和可诱导的细胞-细胞连接.
通过各种应用验证了系统的安全性和有效性.

结论:

开发的基于米诺环素的系统为精确控制细胞疗法提供了一个多功能平台.
这项技术推动了远程控制治疗干预的发展,提高了安全性和有效性.
该系统的适应性对未来的临床细胞疗法应用具有重大前景.

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相关概念视频

Protein-protein Interfaces

Protein-protein Interfaces

Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...