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影响逻辑门控 CAR T 细胞行为的几何参数。

Geometric parameters that affect the behavior of logic-gated CAR T cells.

机构信息

A2 Biotherapeutics, Inc., Agoura Hills, CA, United States.

出版信息

Front Immunol. 2024 Jan 26;15:1304765. doi: 10.3389/fimmu.2024.1304765. eCollection 2024.

Abstract

Clinical applications of CAR-T cells are limited by the scarcity of tumor-specific targets and are often afflicted with the same on-target/off-tumor toxicities that plague other cancer treatments. A new promising strategy to enforce tumor selectivity is the use of logic-gated, two-receptor systems. One well-described application is termed Tmod™, which originally utilized a blocking inhibitory receptor directed towards HLA-I target antigens to create a protective NOT gate. Here we show that the function of Tmod blockers targeting non-HLA-I antigens is dependent on the height of the blocker antigen and is generally compatible with small, membrane-proximal targets. We compensate for this apparent limitation by incorporating modular hinge units to artificially extend or retract the ligand-binding domains relative to the effector cell surface, thereby modulating Tmod activator and blocker function. By accounting for structural differences between activator and blocker targets, we developed a set of simple geometric parameters for Tmod receptor design that enables targeting of blocker antigens beyond HLA-I, thereby broadening the applications of logic-gated cell therapies.

摘要

嵌合抗原受体 T 细胞(CAR-T 细胞)的临床应用受到肿瘤特异性靶标的稀缺性限制,并且经常受到困扰其他癌症治疗的相同靶标/非肿瘤毒性的影响。一种新的有前途的增强肿瘤选择性的策略是使用逻辑门控、双受体系统。一种描述得很好的应用称为 Tmod™,它最初利用一种针对 HLA-I 靶抗原的阻断抑制性受体来创建保护性 NOT 门。在这里,我们表明针对非 HLA-I 抗原的 Tmod 阻断剂的功能取决于阻断剂抗原的高度,并且通常与小的、靠近膜的靶标兼容。我们通过引入模块化铰链单元来补偿这种明显的限制,这些铰链单元相对于效应细胞表面人为地延长或缩短配体结合域,从而调节 Tmod 激活剂和阻断剂的功能。通过考虑激活剂和阻断剂靶标之间的结构差异,我们为 Tmod 受体设计开发了一组简单的几何参数,能够靶向 HLA-I 以外的阻断剂抗原,从而拓宽逻辑门控细胞治疗的应用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/906a/10853413/502664b8ac48/fimmu-15-1304765-g001.jpg

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