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 () and Wenhui Li ()
Additional contact information
Juan Liu: National Institute of Biological Sciences
Fengfeng Mao: Huahui Health Ltd
Jianhe Chen: Huahui Health Ltd
Shuaiyao Lu: Chinese Academy of Medical Sciences and Peking Union Medical College
Yonghe Qi: Huahui Health Ltd
Yinyan Sun: National Institute of Biological Sciences
Linqiang Fang: National Institute of Biological Sciences
Man Lung Yeung: The University of Hong Kong
Chunmei Liu: Huahui Health Ltd
Guimei Yu: Huahui Health Ltd
Guangyu Li: Huahui Health Ltd
Ximing Liu: National Institute of Biological Sciences
Yuansheng Yao: Huahui Health Ltd
Panpan Huang: Huahui Health Ltd
Dongxia Hao: Huahui Health Ltd
Zibing Liu: Huahui Health Ltd
Yu Ding: Huahui Health Ltd
Haimo Liu: Huahui Health Ltd
Fang Yang: Huahui Health Ltd
Pan Chen: Huahui Health Ltd
Rigai Sa: Huahui Health Ltd
Yao Sheng: National Institute of Biological Sciences
Xinxin Tian: National Institute of Biological Sciences
Ran Peng: Huahui Health Ltd
Xue Li: Huahui Health Ltd
Junmian Luo: Huahui Health Ltd
Yurui Cheng: Huahui Health Ltd
Yule Zheng: Huahui Health Ltd
Yongqing Lin: Huahui Health Ltd
Rui Song: Beijing Ditan Hospital, Capital Medical University
Ronghua Jin: Beijing Ditan Hospital, Capital Medical University
Baoying Huang: National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC)
Hyeryun Choe: Scripps Research
Michael Farzan: Scripps Research
Kwok-Yung Yuen: The University of Hong Kong
Wenjie Tan: National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC)
Xiaozhong Peng: Chinese Academy of Medical Sciences and Peking Union Medical College
Jianhua Sui: National Institute of Biological Sciences
Wenhui Li: National Institute of Biological Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40933-3

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