Zhang Xiaoqing, Han Ping, Wang Haiyong, Xu Yanqin, Li Fanlin, Li Min, Fan Lilv, Zhang Huihui, Dai Qiang, Lin Hao, Qi Xinyue, Liang Jie, Wang Xin, Yang Xuanming
Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
Mol Ther Methods Clin Dev. 2021 Jun 11;21:754-764. doi: 10.1016/j.omtm.2021.05.004. Epub 2021 May 14.
The emergence of the novel human severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to the pandemic of coronavirus disease 2019 (COVID-19), which has markedly affected global health and the economy. Both uncontrolled viral replication and a proinflammatory cytokine storm can cause severe tissue damage in patients with COVID-19. SARS-CoV-2 utilizes angiotensin-converting enzyme 2 (ACE2) as its entry receptor. In this study, we generated ACE2 extracellular domain-Fc and single-chain variable fragment-interleukin 6 (IL-6) single-chain variable fragment against IL-6 receptor (scFv-IL6R)-Fc fusion proteins to differentially neutralize viruses and ameliorate the cytokine storm. The human ACE2 (hACE2)-Fc fusion protein showed a potent inhibitory effect on pseudo-typed SARS-CoV-2 entry and a good safety profile in mice. In addition, scFv-IL6R-Fc strongly blocked IL-6 signal activation. We also established a mesenchymal stromal cell (MSC)-based hACE2-Fc and scFv-IL6R-Fc delivery system, which could serve as a potential therapy strategy for urgent clinical needs of patients with COVID-19.
新型人类严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的出现导致了2019冠状病毒病（COVID-19）的大流行，这对全球健康和经济产生了显著影响。在COVID-19患者中，不受控制的病毒复制和促炎细胞因子风暴均可导致严重的组织损伤。SARS-CoV-2利用血管紧张素转换酶2（ACE2）作为其进入受体。在本研究中，我们制备了ACE2细胞外结构域-Fc和抗白细胞介素6（IL-6）受体的单链可变片段-白细胞介素6（IL-6）单链可变片段（scFv-IL6R）-Fc融合蛋白，以分别中和病毒并减轻细胞因子风暴。人ACE2（hACE2）-Fc融合蛋白对假型SARS-CoV-2进入具有强大的抑制作用，并且在小鼠中具有良好的安全性。此外，scFv-IL6R-Fc强烈阻断IL-6信号激活。我们还建立了基于间充质基质细胞（MSC）的hACE2-Fc和scFv-IL6R-Fc递送系统，这可以作为满足COVID-19患者紧急临床需求的潜在治疗策略。
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