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

Author:

Li TingtingORCID,Cai HongminORCID,Yao HebangORCID,Zhou BingjieORCID,Zhang Ning,van Vlissingen Martje FentenerORCID,Kuiken ThijsORCID,Han Wenyu,GeurtsvanKessel Corine H.ORCID,Gong Yuhuan,Zhao YapeiORCID,Shen Quan,Qin Wenming,Tian Xiao-Xu,Peng ChaoORCID,Lai Yanling,Wang Yanxing,Hutter Cedric A. J.ORCID,Kuo Shu-MingORCID,Bao Juan,Liu Caixuan,Wang Yifan,Richard Audrey S.ORCID,Raoul HervéORCID,Lan Jiaming,Seeger Markus A.ORCID,Cong YaoORCID,Rockx BarryORCID,Wong GaryORCID,Bi YuhaiORCID,Lavillette DimitriORCID,Li DianfanORCID

Abstract

AbstractSARS-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.

Funder

National Natural Science Foundation of China

Publisher

Springer Science and Business Media LLC

Subject

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

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