Cell Rep . A potent bispecific nanobody protects hACE2 mice against SARS-CoV-2 infection via intranasal administration

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Cell Rep


. 2021 Oct 6;109869.
doi: 10.1016/j.celrep.2021.109869. Online ahead of print.
A potent bispecific nanobody protects hACE2 mice against SARS-CoV-2 infection via intranasal administration


Xilin Wu ¹ , Lin Cheng ² , Ming Fu ³ , Bilian Huang ⁴ , Linjing Zhu ⁵ , Shijie Xu ¹ , Haixia Shi ⁶ , Doudou Zhang ⁵ , Huanyun Yuan ⁵ , Waqas Nawaz ⁴ , Ping Yang ⁷ , Qinxue Hu ⁸ , Yalan Liu ⁹ , Zhiwei Wu ¹⁰



Affiliations

• PMID: 34644535
• DOI: 10.1016/j.celrep.2021.109869

Abstract

The dramatically expanding coronavirus disease 2019 (COVID-19) needs multiple effective countermeasures. Neutralizing nanobodies (Nbs) are a potential therapeutic strategy for treating COVID-19. Here, we characterize several receptor binding domain (RBD)-specific Nbs isolated from an Nb library derived from an alpaca immunized with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (S); among them, three Nbs exhibit picomolar potency against SARS-CoV-2 live virus, pseudotyped viruses, and circulating SARS-CoV-2 variants. To improve their efficacy, various configurations of Nbs are engineered. Nb₁₅-Nb_H-Nb₁₅, a trimer constituted of three Nbs, is constructed to be bispecific for human serum albumin (HSA) and RBD of SARS-CoV-2. Nb₁₅-Nb_H-Nb₁₅ exhibits single-digit ng/ml neutralization potency against the wild-type and Delta variants of SARS-CoV-2 with a long half-life in vivo. In addition, we show that intranasal administration of Nb₁₅-Nb_H-Nb₁₅ provides effective protection for both prophylactic and therapeutic purposes against SARS-CoV-2 infection in transgenic hACE2 mice. Nb₁₅-Nb_H-Nb₁₅ is a potential candidate for both the prevention and treatment of SARS-CoV-2 through respiratory administration.

Keywords: Delta; Nb15; Nb15-NbH-Nb15; SARS-CoV-2; VHH; bispecific; hACE2 mice; intranasal; nanobody; potent neutralizing.