An IgM-like inhalable ACE2 fusion protein broadly neutralizes SARS-CoV-2 variants

Juan Liu; Fengfeng Mao; Jianhe Chen; Shuaiyao Lu; Yonghe Qi; Yinyan Sun; Linqiang Fang; Man Lung Yeung; Chunmei Liu; Guimei Yu; Guangyu Li; Ximing Liu; Yuansheng Yao; Panpan Huang; Dongxia Hao; Zibing Liu; Yu Ding; Haimo Liu; Fang Yang; Pan Chen; Rigai Sa; Yao Sheng; Xinxin Tian; Ran Peng; Xue Li; Junmian Luo; Yurui Cheng; Yule Zheng; Yongqing Lin; Rui Song; Ronghua Jin; Baoying Huang; Hyeryun Choe; Michael Farzan; Kwok Yung Yuen; Wenjie Tan; Xiaozhong Peng; Jianhua Sui; Wenhui Li

doi:10.1038/s41467-023-40933-3

An IgM-like inhalable ACE2 fusion protein broadly neutralizes SARS-CoV-2 variants

Juan Liu, Fengfeng Mao, Jianhe Chen, Shuaiyao Lu, Yonghe Qi, Yinyan Sun, Linqiang Fang, Man Lung Yeung, Chunmei Liu, Guimei Yu, Guangyu Li, Ximing Liu, Yuansheng Yao, Panpan Huang, Dongxia Hao, Zibing Liu, Yu Ding, Haimo Liu, Fang Yang, Pan ChenRigai Sa, Yao Sheng, Xinxin Tian, Ran Peng, Xue Li, Junmian Luo, Yurui Cheng, Yule Zheng, Yongqing Lin, Rui Song, Ronghua Jin, Baoying Huang, Hyeryun Choe, Michael Farzan, Kwok Yung Yuen, Wenjie Tan, Xiaozhong Peng, Jianhua Sui, Wenhui Li

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

Abstract

Many of the currently available COVID-19 vaccines and therapeutics are not effective against newly emerged SARS-CoV-2 variants. Here, we developed the metallo-enzyme domain of angiotensin converting enzyme 2 (ACE2)—the cellular receptor of SARS-CoV-2—into an IgM-like inhalable molecule (HH-120). HH-120 binds to the SARS-CoV-2 Spike (S) protein with high avidity and confers potent and broad-spectrum neutralization activity against all known SARS-CoV-2 variants of concern. HH-120 was developed as an inhaled formulation that achieves appropriate aerodynamic properties for rodent and monkey respiratory system delivery, and we found that early administration of HH-120 by aerosol inhalation significantly reduced viral loads and lung pathology scores in male golden Syrian hamsters infected by the SARS-CoV-2 ancestral strain (GDPCC-nCoV27) and the Delta variant. Our study presents a meaningful advancement in the inhalation delivery of large biologics like HH-120 (molecular weight (MW) ~ 1000 kDa) and demonstrates that HH-120 can serve as an efficacious, safe, and convenient agent against SARS-CoV-2 variants. Finally, given the known role of ACE2 in viral reception, it is conceivable that HH-120 has the potential to be efficacious against additional emergent coronaviruses.

Original language	English
Article number	5191
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-40933-3
Publication status	Published - Dec 2023
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2023, Springer Nature Limited.

ASJC Scopus Subject Areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-023-40933-3

Cite this

Liu, J, Mao, F, Chen, J, Lu, S, Qi, Y, Sun, Y, Fang, L, Yeung, ML, Liu, C, Yu, G, Li, G, Liu, X, Yao, Y, Huang, P, Hao, D, Liu, Z, Ding, Y, Liu, H, Yang, F, Chen, P, Sa, R, Sheng, Y, Tian, X, Peng, R, Li, X, Luo, J, Cheng, Y, Zheng, Y, Lin, Y, Song, R, Jin, R, Huang, B, Choe, H, Farzan, M, Yuen, KY, Tan, W, Peng, X, Sui, J & Li, W 2023, 'An IgM-like inhalable ACE2 fusion protein broadly neutralizes SARS-CoV-2 variants', Nature Communications, vol. 14, no. 1, 5191. https://doi.org/10.1038/s41467-023-40933-3

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abstract = "Many of the currently available COVID-19 vaccines and therapeutics are not effective against newly emerged SARS-CoV-2 variants. Here, we developed the metallo-enzyme domain of angiotensin converting enzyme 2 (ACE2)—the cellular receptor of SARS-CoV-2—into an IgM-like inhalable molecule (HH-120). HH-120 binds to the SARS-CoV-2 Spike (S) protein with high avidity and confers potent and broad-spectrum neutralization activity against all known SARS-CoV-2 variants of concern. HH-120 was developed as an inhaled formulation that achieves appropriate aerodynamic properties for rodent and monkey respiratory system delivery, and we found that early administration of HH-120 by aerosol inhalation significantly reduced viral loads and lung pathology scores in male golden Syrian hamsters infected by the SARS-CoV-2 ancestral strain (GDPCC-nCoV27) and the Delta variant. Our study presents a meaningful advancement in the inhalation delivery of large biologics like HH-120 (molecular weight (MW) ~ 1000 kDa) and demonstrates that HH-120 can serve as an efficacious, safe, and convenient agent against SARS-CoV-2 variants. Finally, given the known role of ACE2 in viral reception, it is conceivable that HH-120 has the potential to be efficacious against additional emergent coronaviruses.",

author = "Juan Liu and Fengfeng Mao and Jianhe Chen and Shuaiyao Lu and Yonghe Qi and Yinyan Sun and Linqiang Fang and Yeung, {Man Lung} and Chunmei Liu and Guimei Yu and Guangyu Li and Ximing Liu and Yuansheng Yao and Panpan Huang and Dongxia Hao and Zibing Liu and Yu Ding and Haimo Liu and Fang Yang and Pan Chen and Rigai Sa and Yao Sheng and Xinxin Tian and Ran Peng and Xue Li and Junmian Luo and Yurui Cheng and Yule Zheng and Yongqing Lin and Rui Song and Ronghua Jin and Baoying Huang and Hyeryun Choe and Michael Farzan and Yuen, {Kwok Yung} and Wenjie Tan and Xiaozhong Peng and Jianhua Sui and Wenhui Li",

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AU - Qi, Yonghe

AU - Sun, Yinyan

AU - Fang, Linqiang

AU - Yeung, Man Lung

AU - Liu, Chunmei

AU - Yu, Guimei

AU - Li, Guangyu

AU - Liu, Ximing

AU - Yao, Yuansheng

AU - Huang, Panpan

AU - Hao, Dongxia

AU - Liu, Zibing

AU - Ding, Yu

AU - Liu, Haimo

AU - Yang, Fang

AU - Chen, Pan

AU - Sa, Rigai

AU - Sheng, Yao

AU - Tian, Xinxin

AU - Peng, Ran

AU - Li, Xue

AU - Luo, Junmian

AU - Cheng, Yurui

AU - Zheng, Yule

AU - Lin, Yongqing

AU - Song, Rui

AU - Jin, Ronghua

AU - Huang, Baoying

AU - Choe, Hyeryun

AU - Farzan, Michael

AU - Yuen, Kwok Yung

AU - Tan, Wenjie

AU - Peng, Xiaozhong

AU - Sui, Jianhua

AU - Li, Wenhui

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An IgM-like inhalable ACE2 fusion protein broadly neutralizes SARS-CoV-2 variants

Abstract

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0318_TWC Internal: Research Talent Hub for Technology Companies Conducting R&D Activities in Hong Kong (RTH-TC)

Cite this

An IgM-like inhalable ACE2 fusion protein broadly neutralizes SARS-CoV-2 variants

Abstract

Bibliographical note

ASJC Scopus Subject Areas

Access to Document

Other files and links

Projects

0318_TWC Internal: Research Talent Hub for Technology Companies Conducting R&D Activities in Hong Kong (RTH-TC)

Cite this