MOG特异性CAR Tregs：治疗多发性硬化的新途径

MOG-specific CAR Tregs: a novel approach to treat multiple sclerosis

Journal of Neuroinflammation

影响因子:10.1

分区:医学1区 Top / 免疫学1区神经科学1区

发表日期:2024 Oct 20

作者: Jihane Frikeche, Marion David, Xavier Mouska, Damien Treguer, Yue Cui, Sandrine Rouquier, Enora Lecorgne, Emma Proics, Papa Babacar Fall, Audrey Lafon, Gregory Lara, Alexandra Menardi, David Fenard, Tobias Abel, Julie Gertner-Dardenne, Maurus de la Rosa, Celine Dumont

DOI: 10.1186/s12974-024-03262-w

摘要

多发性硬化（MS）是一种影响中枢神经系统（CNS）的自身免疫疾病，免疫系统攻击髓鞘，导致神经元死亡。虽然目前有多种疾病修饰疗法用于治疗MS，但这些疗法并非对所有患者都有效，且不能阻止疾病进展。亟需更个性化的长期治疗方案，目标是减少复发频率、延缓残疾积累以及改善日常功能的症状，同时促进神经保护和修复。嵌合抗原受体（CAR）T细胞疗法通过静脉注射（IV）方式给予高特异性T细胞，革新了癌症治疗。采用自体CAR T细胞结合抑制性调节性T细胞（Tregs）以诱导持久耐受，是理想的MS治疗策略。因此，我们将CAR技术应用于Tregs，开发针对MS的MOG（髓鞘少突胶质细胞糖蛋白）特异性CAR Treg细胞疗法。MOG表达于髓鞘外膜，是绝佳的CAR靶点。我们的主要候选产品为第二代CAR，由从大量人类文库筛选的抗MOG单链可变片段（scFv）组成。在体外实验中，验证了CAR依赖的功能性，并在被动型EAE小鼠模型中显示出疗效。MOG-CAR Tregs表现出极低的本底信号，具有理想的信噪比，显示出高度的CAR效能。综上所述，MOG-CAR Tregs有望成为一种具有潜力的MS长效耐受治疗方案。

Abstract

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS) with the immune system attacking myelin sheaths leading to neuronal death. While several disease-modifying therapies are available to treat MS, these therapies are not universally effective and do not stop disease progression. More personalized long-term treatment options that target specific aspects of the disease, such as reducing relapse frequency, delaying disability accumulation, and addressing symptoms that impact daily functioning, as well as therapies that can promote neuroprotection and repair are needed. Chimeric Antigen Receptor (CAR) Tcell therapies have revolutionized cancer treatment by intravenously (IV) administering a defined dose of T cells with high specificity provided by the CAR. An autologous CAR T cell therapy using suppressive regulatory T cells (Tregs) inducing long-lasting tolerance would be the ideal treatment for patients. Hence, we expanded the application of CAR-T cells by introducing a CAR into Tregs to treat MS patients. We developed a myelin oligodendrocyte glycoprotein (MOG)-specific CAR Treg cell therapy for patients with MS. MOG is expressed on the outer membrane of the myelin sheath, the insulating layer the forms around nerves, making it an ideal target for CAR Treg therapy. Our lead candidate is a 2nd generation CAR, composed of an anti-MOG scFv screened from a large human library. In vitro, we demonstrated CAR-dependent functionality and showed efficacy in vivo using a passive EAE mouse model. Additionally, the MOG-CAR Tregs have very low tonic signaling with a desirable signal-to-noise ratio resulting in a highly potent CAR. In summary our data suggest that MOG-CAR Tregs are a promising MS treatment option with the potential to induce long-lasting tolerance in patients.