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

Tingting Li, Hongmin Cai, Hebang Yao, Bingjie Zhou, Ning Zhang, Martje Fentener van 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 BaoCaixuan Liu, Yifan Wang, Audrey S. Richard, Hervé Raoul, Jiaming Lan, Markus A. Seeger, Yao Cong, Barry Rockx, Gary Wong*, Yuhai Bi*, Dimitri Lavillette*, Dianfan Li*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Scopus)

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.

Original languageEnglish
Article number4635
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 30 Jul 2021

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