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Site-specific PEGylation of interleukin-2 enhances immunosuppression via the sustained activation of regulatory T cells
Nature Biomedical Engineering ( IF 26.8 ) Pub Date : 2021-09-27 , DOI: 10.1038/s41551-021-00797-8
Bo Zhang 1, 2 , Jiaqi Sun 2 , Yan Wang 2 , Dezhong Ji 2 , Yeshuang Yuan 3, 4 , Shengjie Li 1 , Yeting Sun 1, 5 , Yingqin Hou 6 , Pengchong Li 1, 5 , Lidan Zhao 1, 5 , Fei Yu 2 , Wenxiao Ma 2 , Boyang Cheng 2 , Ling Wu 2 , Jin Hu 1 , Min Wang 3, 4 , Wei Song 1 , Xiaogang Li 1 , Hao Li 7 , Yunyun Fei 1, 5 , Hua Chen 1, 5 , Lihe Zhang 2 , George C Tsokos 7 , Demin Zhou 2 , Xuan Zhang 4
Affiliation  

The preferential activation of regulatory T (Treg) cells by interleukin-2 (IL-2), which selectively binds to the trimeric IL-2 receptor (IL-2R) on Treg cells, makes this cytokine a promising therapeutic for the treatment of autoimmune diseases. However, IL-2 has a narrow therapeutic window and a short half-life. Here, we show that the pharmacokinetics and half-life of IL-2 can be substantially improved by orthogonally conjugating the cytokine to poly(ethylene glycol) (PEG) moieties via a copper-free click reaction through the incorporation of azide-bearing amino acids at defined sites. Subcutaneous injection of a PEGylated IL-2 that optimally induced sustained Treg-cell activation and expansion over a wide range of doses through highly selective binding to trimeric IL-2R led to enhanced therapeutic efficacy in mouse models of lupus, collagen-induced arthritis and graft-versus-host disease without compromising the immune defences of the host against viral infection. Site-specific PEGylation could be used more generally to engineer cytokines with improved therapeutic performance for the treatment of autoimmune diseases.



中文翻译:

白细胞介素 2 的位点特异性聚乙二醇化通过调节性 T 细胞的持续激活增强免疫抑制

白细胞介素 2 (IL-2)优先激活调节性 T (T reg ) 细胞,它选择性地结合 T reg细胞上的三聚体 IL-2 受体 (IL-2R),使这种细胞因子成为一种有前途的治疗药物自身免疫性疾病。然而,IL-2 的治疗窗窄且半衰期短。在这里,我们表明,通过掺入含叠氮氨基酸的无铜点击反应,将细胞因子与聚乙二醇 (PEG) 部分正交偶联,可以显着改善 IL-2 的药代动力学和半衰期在定义的站点。皮下注射聚乙二醇化 IL-2,可最佳诱导持续 T reg- 通过与三聚体 IL-2R 的高度选择性结合,在广泛的剂量范围内激活和扩增细胞,从而在不损害宿主免疫防御能力的情况下增强狼疮、胶原诱导的关节炎和移植物抗宿主病小鼠模型的治疗效果抗病毒感染。位点特异性聚乙二醇化可更广泛地用于改造细胞因子,以改善治疗自身免疫性疾病的治疗性能。

更新日期:2021-09-27
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