Development of a trispecific fusion protein based on angiotensin-converting enzyme 2, glycoprotein 130, and tumor necrosis factor receptor 2 as a promising therapeutic for COVID-19
Yongfeng Qiao, Yanjun Han, Lu Zhao, Wenjing Gao, Hong Hu, Chao Su, Anqi Zheng, Junqing Sun, Mingxiong Tian, Yarong Wu, Lianmei Bai, Yuping Lei, Jiahao Wu, Weibing Zhang, Pu Han, Xiaoyu Li, Chunbo Dong, Haidong Wang, Zhida Liu, Pengcheng Han
Molecular Biomedicine, doi:10.1186/s43556-025-00320-4
Despite a substantial reduction in the incidence of coronavirus disease 2019 (COVID-19) infections, severe cases continue to pose a significant clinical burden, particularly among elderly individuals and patients with underlying medical conditions, due to high viral loads and cytokine storm syndrome. Elevated levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF), signaling through their respective receptors, glycoprotein 130 (GP130)/interleukin-6 receptor (IL-6R) and tumor necrosis factor receptor 2 (TNFR2), are independent predictors of disease severity and mortality. To address this challenge, a series of bifunctional and trifunctional decoy receptor fusion proteins were developed by fusing the extracellular domains of TNFR2 and/or GP130 to an engineered angiotensin-converting enzyme 2 (ACE2) protein, the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Five mutations (T27F, K31Y, L79W, R273Q, and N330Y) were introduced into the ACE2 domain to enhance its binding affinity and neutralizing activity against a broad range of SARS-CoV-2 variants, including the currently circulating JN.1 variant. The TNFR2 and GP130 domain confer strong binding to TNF and IL-6R-IL-6 complex, respectively, thereby effectively blocking pro-inflammatory signaling pathways. In a mouse model of acute lung inflammation induced by R848, treatment with the bifunctional and trifunctional fusion proteins markedly attenuated pulmonary pathology by dampening IL-6-and TNF-mediated inflammation. These findings demonstrate a promising therapeutic strategy for severe COVID-19 and offer a framework for designing multifunctional biologics against emerging viral infections.
Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s43556-025-00320-4 . Supplementary Material 1.
Authors' contributions
Declarations Ethics approval and consent to participate Animal studies were conducted following approval from the Research Ethics Committee of the Institute of Microbiology, Chinese Academy of Sciences (APIMCAS2022124) and Institutional Animal Care and Use Committee of Shanxi Agricultural University (SXAU-EAW-2023M.DF.001017216). The studies were conducted in accordance with the local legislation and institutional requirements.
Consent for publication Not applicable.
Competing interests Competing interests Z.L., P.H., C.D., Y.Q., Y.H., H.H. and L.Z. have filed a patent for protecting a bifunctional therapeutic protein ACE2 (M)-Fc-GP130-TNFR2 for the treatment of patients with SARS-CoV-2 infection. Author Hong Hu is an employee in Ankerui (Shanxi) Biological Cell Co, but has no potential relevant financial or non-financial interests to disclose. The other authors have no conflicts of interest to declare.
Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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