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Nature 子刊：白细胞介素2的位点特异性聚乙二醇化通过持续激活调节性T细胞增强免疫抑制

2021-10-03 MedSci原创 MedSci原创

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设计位点特异性的细胞因子聚乙二醇化能改善其治疗性能，用于治疗自身免疫性疾病。

      白介素2 (IL-2)选择性结合调节性T细胞(Treg)上的三聚体IL-2受体(IL-2R)，优先激活Treg细胞，使IL2成为有前景的治疗自身免疫性疾病的细胞因子。然而，IL-2的治疗窗口窄且半衰期短。

     在这篇研究中，协和医院张烜教授及合作团队通过无铜点击反应在指定位点掺入含叠氮化物的氨基酸，将细胞因子与聚乙二醇（PEG）部分正交结合而得到药代动力学和半衰期都大大提高的IL-2（如上图所示），尤其是在Tyr31和Thr51位点均被20 kDa PEG化的IL-2优先结合IL-2α亚基而不是β亚基，从而持续活化Treg细胞同时对CD8+ T细胞的活化程度低。皮下注射不同剂量的聚乙二醇化IL-2通过高度选择性地与三聚体IL-2R结合诱导Treg细胞持续活化并扩增，可增强狼疮、胶原诱导性关节炎和移植物抗宿主小鼠模型的疾病治疗效果而不损害宿主对病毒感染的免疫防御。以狼疮小鼠模型为例，如下图所示，图a验证人IL-2在给定剂量在小鼠模型上的交叉反应性以及对Treg细胞的活化；图b说明双-31/51-20K可以降低狼疮小鼠模型的疾病情况，具体表现为减少蛋白尿、血清抗双链DNA（dsDNA）抗体和抗核抗体降低。

结论：

  更普遍地设计位点特异性的细胞因子聚乙二醇化能改善其治疗性能，用于治疗自身免疫性疾病。

 

出处：

Zhang B, Sun J, Wang Y, Ji D, Yuan Y, Li S, Sun Y, Hou Y, Li P, Zhao L, Yu F, Ma W, Cheng B, Wu L, Hu J, Wang M, Song W, Li X, Li H, Fei Y, Chen H, Zhang L, Tsokos GC, Zhou D, Zhang X. Site-specific PEGylation of interleukin-2 enhances immunosuppression via the sustained activation of regulatory T cells. Nat Biomed Eng. 2021 Sep 27. doi: 10.1038/s41551-021-00797-8. Epub ahead of print. PMID: 34580438.

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    2021-10-18 weiz

    #乙二醇#

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    2021-10-30 jinweidong

    #特异性#

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    2021-10-04 liye789132251

    #Nat#

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    2021-10-06 yxch43

    #白细胞介素#

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