CTLA4-Ig-Based Bifunctional Costimulation Inhibitor Blocks CD28 and ICOS Signaling to Prevent T Cell Priming and Effector Function
CTLA4-Ig-Based Bifunctional Costimulation Inhibitor Blocks CD28 and ICOS Signaling to Prevent T Cell Priming and Effector Function
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DOI：
10.4049/jimmunol.2001100
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发表时间：
2021-03-01
影响因子：
4.4
通讯作者：
Akamatsu, Yoshiko
中科院分区：
文献类型：
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作者：
Goenka, Radhika;Xu, Zhenghai;Akamatsu, Yoshiko
CTLA4-Ig/abatacept通过阻断CD28的共刺激抑制初始T细胞的激活。它是一种被批准用于治疗类风湿性关节炎的药物，但在其他一些自身免疫性疾病中未能发挥疗效。一种解释是，激活的T细胞对CD28信号的依赖较少，并使用替代的辅助受体来发挥效应器功能。ICOS是激活T依赖的体液免疫反应的关键，T依赖的体液免疫反应推动了免疫球蛋白G介导的自身免疫性疾病的病理生理过程。在这项研究中，我们询问CD28和ICOS在维持小鼠模型的T依赖反应中是否发挥了非多余的作用。使用半抗原蛋白免疫模型，我们表明在正在进行的生发中心反应中，CTLA4-Ig和ICOS配体(ICOSL)联合治疗完全溶解正在进行的生发中心反应，而单独的试剂只显示部分活性。接下来，我们采取了两种方法来设计一种阻断这两条途径的治疗分子。首先，我们设计了CTLA4-Ig来增强与ICOSL的结合，同时保持与CD80/CD86的亲和力。使用文库方法，CTLA4-Ig与人ICOSL的结合亲和力从检测不到的显著增加到15-42 nM；然而，亲和力仍然不足以完全阻断ICOSL与ICOS的结合。其次，我们设计了一种高亲和力CTLA4胞外区与抗ICOSL抗体融合的双功能共刺激抑制物，称为双功能共刺激抑制物。通过这种双特异性方法，我们实现了CD80和CD86与CD28的结合以及ICOS与ICOSL的结合的完全抑制。与单独使用CTLA4-Ig相比，这种双特异性分子可能在免疫球蛋白介导的炎症性疾病中提供更大的治疗益处。
CTLA4-Ig/abatacept dampens activation of naive T cells by blocking costimulation via CD28. It is an approved drug for rheumatoid arthritis but failed to deliver efficacy in a number of other autoimmune diseases. One explanation is that activated T cells rely less on CD28 signaling and use alternate coreceptors for effector function. ICOS is critical for activation of T-dependent humoral immune responses, which drives pathophysiology of IgG-mediated autoimmune diseases. In this study, we asked whether CD28 and ICOS play nonredundant roles for maintenance of T-dependent responses in mouse models. Using a hapten-protein immunization model, we show that during an ongoing germinal center response, combination treatment with CTLA4-Ig and ICOS ligand (ICOSL) blocking Ab completely dissolves ongoing germinal center responses, whereas single agents show only partial activity. Next, we took two approaches to engineer a therapeutic molecule that blocks both pathways. First, we engineered CTLA4-Ig to enhance binding to ICOSL while retaining affinity to CD80/CD86. Using a library approach, binding affinity of CTLA4-Ig to human ICOSL was increased significantly from undetectable to 15-42 nM; however, the affinity was still insufficient to completely block binding of ICOSL to ICOS. Second, we designed a bispecific costimulation inhibitor with high-affinity CTLA4 extracellular domains fused to anti-ICOSL Ab termed bifunctional costimulation inhibitor. With this bispecific approach, we achieved complete inhibition of CD80 and CD86 binding to CD28 as well as ICOS binding to ICOSL. Such bispecific molecules may provide greater therapeutic benefit in IgG-mediated inflammatory diseases compared with CTLA4-Ig alone.