Engineering mesenchymal stromal cells with neutralizing and anti-inflammatory capability against SARS-CoV-2 infection

Xiaoqing Zhang; Ping Han; Haiyong Wang; Yanqin Xu; Fanlin Li; Min Li; Lilv Fan; Huihui Zhang; Qiang Dai; Hao Lin; Xinyue Qi; Jie Liang; Xin Wang; Xuanming Yang

doi:10.1016/j.omtm.2021.05.004

Engineering mesenchymal stromal cells with neutralizing and anti-inflammatory capability against SARS-CoV-2 infection

Mol Ther Methods Clin Dev. 2021 Jun 11:21:754-764. doi: 10.1016/j.omtm.2021.05.004. Epub 2021 May 14.

Authors

Xiaoqing Zhang^{1

2}, Ping Han^{1

2}, Haiyong Wang^{1

2}, Yanqin Xu^{1

2}, Fanlin Li^{1

2}, Min Li^{1

2}, Lilv Fan^{1

2}, Huihui Zhang^{1

2}, Qiang Dai^{1

2}, Hao Lin^{1

2}, Xinyue Qi^{1

2}, Jie Liang^{1

2}, Xin Wang³, Xuanming Yang^{1

2}

Affiliations

¹ Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
² Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
³ Shanghai Longyao Biotechnology Limited, Shanghai 201203, China.

Abstract

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)_1-740-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_1-740-Fc and scFv-IL6R-Fc delivery system, which could serve as a potential therapy strategy for urgent clinical needs of patients with COVID-19.

Keywords: ACE2; COVID-19; IL-6 blockade; SARS-CoV-2; cell therapy; mesenchymal stromal cell.