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Protein engineering of a stable and potent anti-inflammatory IL-37-Fc fusion with enhanced therapeutic potential
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2021-10-25 , DOI: 10.1016/j.chembiol.2021.10.004
Alexander Bujotzek 1 , Georg Tiefenthaler 1 , Laurent Lariviere 1 , Laura D'Andrea 2 , Elsa A Marquez 2 , Ina Rudloff 3 , Steven X Cho 3 , Nadia S Deen 3 , Wolfgang Richter 4 , Franziska Regenass-Lechner 4 , Alexander Poehler 1 , James C Whisstock 5 , Jasmin Sydow-Andersen 1 , Xaver Reiser 1 , Sabine Schuster 1 , Jeannette Neubauer 1 , Sebastian Hoepfl 1 , Kirsten Richter 4 , Marcel F Nold 6 , Claudia A Nold-Petry 7 , Felix Schumacher 4 , Andrew M Ellisdon 2
Affiliation  

Harnessing the immunomodulatory activity of cytokines is a focus of therapies targeting inflammatory disease. The interleukin (IL)-1 superfamily contains pro-inflammatory and anti-inflammatory members that help orchestrate the immune response in adaptive and innate immunity. Of these molecules, IL-37 has robust anti-inflammatory activity across a range of disease models through inhibition of pro-inflammatory signaling cascades downstream of tumor necrosis factor, IL-1, and toll-like receptor pathways. We find that IL-37 is unstable with a poor pharmacokinetic and manufacturing profile. Here, we present the engineering of IL-37 from an unstable cytokine into an anti-inflammatory molecule with an excellent therapeutic likeness. We overcame these shortcomings through site-directed mutagenesis, the addition of a non-native disulfide bond, and the engineering of IL-37 as an Fc-fusion protein. Our results provide a platform for preclinical testing of IL-37 Fc-fusion proteins. The engineering approaches undertaken herein will apply to the conversion of similar potent yet short-acting cytokines into therapeutics.



中文翻译:

具有增强治疗潜力的稳定有效的抗炎 IL-37-Fc 融合蛋白工程

利用细胞因子的免疫调节活性是针对炎症性疾病的治疗的重点。白细胞介素 (IL)-1 超家族包含促炎和抗炎成员,有助于协调适应性和先天免疫中的免疫反应。在这些分子中,IL-37 通过抑制肿瘤坏死因子、IL-1 和 toll 样受体通路下游的促炎信号级联反应,在一系列疾病模型中具有强大的抗炎活性。我们发现 IL-37 不稳定,药代动力学和制造特性较差。在这里,我们展示了将 IL-37 从不稳定的细胞因子工程改造为具有出色治疗相似性的抗炎分子。我们通过定点诱变、添加非天然二硫键、以及将 IL-37 工程化为 Fc 融合蛋白。我们的结果为 IL-37 Fc 融合蛋白的临床前测试提供了一个平台。本文采用的工程方法将适用于将类似有效但短效的细胞因子转化为治疗剂。

更新日期:2021-10-25
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