瑞士洛桑联邦理工学院Bruno E. Correia、洛桑大学George Coukos和Melita Irving小组合作利用计算设计的嵌合抗原受体（CAR）为T细胞疗法提供了小分子安全开关。相关论文2020年2月3日在线发表在《自然—生物技术》杂志上。

为了提高CAR-T细胞疗法的安全性，研究人员基于两种人类蛋白质的结合，通过计算设计了一种化学可破坏的异二聚体（CDH）。CDH的自组装可被小分子药物破坏，并可与人类自身氨基酸数目相差无几的蛋白质形成高亲和力的蛋白质界面。研究人员将CDH与合成异二聚体CAR融合，命名为STOP-CAR；该CAR具有抗原识别链以及包含CD3ζ和CD28的内结构域信号链。研究人员在体外和体内测试了对两种抗原具有特异性的STOP-CAR-T细胞，发现与第二代（2G）CAR-T细胞相比，这两种细胞具有相似的抗肿瘤活性。定时给予小分子药物可动态调控STOP-CAR-T细胞的失活。该工作揭示了利用基于结构的设计为可控细胞疗法提供小分子开关的潜力。

据悉，增加嵌合抗原受体（CAR）-T细胞对实体瘤活性的方法也可能提高了增加细胞毒性和其他副作用的风险。

附：英文原文

Title: A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy

Author: Greta Giordano-Attianese, Pablo Gainza, Elise Gray-Gaillard, Elisabetta Cribioli, Sailan Shui, Seonghoon Kim, Mi-Jeong Kwak, Sabrina Vollers, Angel De Jesus Corria Osorio, Patrick Reichenbach, Jaume Bonet, Byung-Ha Oh, Melita Irving, George Coukos, Bruno E. Correia

Issue&Volume: 2020-02-03

Abstract: Approaches to increase the activity of chimeric antigen receptor (CAR)-T cells against solid tumors may also increase the risk of toxicity and other side effects. To improve the safety of CAR-T-cell therapy, we computationally designed a chemically disruptable heterodimer (CDH) based on the binding of two human proteins. The CDH self-assembles, can be disrupted by a small-molecule drug and has a high-affinity protein interface with minimal amino acid deviation from wild-type human proteins. We incorporated the CDH into a synthetic heterodimeric CAR, called STOP-CAR, that has an antigen-recognition chain and a CD3ζ- and CD28-containing endodomain signaling chain. We tested STOP-CAR-T cells specific for two antigens in vitro and in vivo and found similar antitumor activity compared to second-generation (2G) CAR-T cells. Timed administration of the small-molecule drug dynamically inactivated the activity of STOP-CAR-T cells. Our work highlights the potential for structure-based design to add controllable elements to synthetic cellular therapies.

DOI: 10.1038/s41587-019-0403-9

Source: https://www.nature.com/articles/s41587-019-0403-9