A synthetic nanobody targeting RBD protects hamsters from SARS-CoV-2 infection

Tingting Li, Hongmin Cai, Hebang Yao, Bingjie Zhou, Ning Zhang, Martje Fentener Vlissingen, Thijs Kuiken, Wenyu Han, Corine H. GeurtsvanKessel, Yuhuan Gong, Yapei Zhao, Quan Shen, Wenming Qin, Xiao-Xu Tian, Chao Peng, Yanling Lai, Yanxing Wang, Cedric A. J. Hutter, Shu-Ming Kuo, Juan Bao, Caixuan Liu, Yifan Wang, Audrey S. Richard, Hervé Raoul, Jiaming Lan, Markus A. Seeger, Yao Cong, Barry Rockx, Gary Wong (), Yuhai Bi (), Dimitri Lavillette () and Dianfan Li ()
Additional contact information
Tingting Li: Chinese Academy of Sciences (CAS)
Hongmin Cai: Chinese Academy of Sciences (CAS)
Hebang Yao: Chinese Academy of Sciences (CAS)
Bingjie Zhou: University of CAS
Ning Zhang: CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID), CAS
Martje Fentener Vlissingen: Erasmus University Medical Center
Thijs Kuiken: European Research Infrastructure on Highly Pathogenic Agents (ERINHA-AISBL)
Wenyu Han: Chinese Academy of Sciences (CAS)
Corine H. GeurtsvanKessel: European Research Infrastructure on Highly Pathogenic Agents (ERINHA-AISBL)
Yuhuan Gong: University of CAS
Yapei Zhao: University of CAS
Quan Shen: CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID), CAS
Wenming Qin: Shanghai Advanced Research Institute (Zhangjiang Laboratory), CAS
Xiao-Xu Tian: Shanghai Advanced Research Institute (Zhangjiang Laboratory), CAS
Chao Peng: Shanghai Advanced Research Institute (Zhangjiang Laboratory), CAS
Yanling Lai: Chinese Academy of Sciences (CAS)
Yanxing Wang: Chinese Academy of Sciences (CAS)
Cedric A. J. Hutter: University of Zurich
Shu-Ming Kuo: Institut Pasteur of Shanghai CAS
Juan Bao: Chinese Academy of Sciences (CAS)
Caixuan Liu: Chinese Academy of Sciences (CAS)
Yifan Wang: Chinese Academy of Sciences (CAS)
Audrey S. Richard: European Research Infrastructure on Highly Pathogenic Agents (ERINHA-AISBL)
Hervé Raoul: European Research Infrastructure on Highly Pathogenic Agents (ERINHA-AISBL)
Jiaming Lan: Institut Pasteur of Shanghai CAS
Markus A. Seeger: University of Zurich
Yao Cong: Chinese Academy of Sciences (CAS)
Barry Rockx: European Research Infrastructure on Highly Pathogenic Agents (ERINHA-AISBL)
Gary Wong: Institut Pasteur of Shanghai CAS
Yuhai Bi: University of CAS
Dimitri Lavillette: Institut Pasteur of Shanghai CAS
Dianfan Li: Chinese Academy of Sciences (CAS)

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract SARS-CoV-2, the causative agent of COVID-191, features a receptor-binding domain (RBD) for binding to the host cell ACE2 protein1–6. Neutralizing antibodies that block RBD-ACE2 interaction are candidates for the development of targeted therapeutics7–17. Llama-derived single-domain antibodies (nanobodies, ~15 kDa) offer advantages in bioavailability, amenability, and production and storage owing to their small sizes and high stability. Here, we report the rapid selection of 99 synthetic nanobodies (sybodies) against RBD by in vitro selection using three libraries. The best sybody, MR3 binds to RBD with high affinity (KD = 1.0 nM) and displays high neutralization activity against SARS-CoV-2 pseudoviruses (IC50 = 0.42 μg mL−1). Structural, biochemical, and biological characterization suggests a common neutralizing mechanism, in which the RBD-ACE2 interaction is competitively inhibited by sybodies. Various forms of sybodies with improved potency have been generated by structure-based design, biparatopic construction, and divalent engineering. Two divalent forms of MR3 protect hamsters from clinical signs after live virus challenge and a single dose of the Fc-fusion construct of MR3 reduces viral RNA load by 6 Log10. Our results pave the way for the development of therapeutic nanobodies against COVID-19 and present a strategy for rapid development of targeted medical interventions during an outbreak.

Date: 2021
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DOI: 10.1038/s41467-021-24905-z

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