Long‐Circulating Nanobody Confers Durable Prophylaxis against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Infection

Long‐Circulating Nanobody Confers Durable Prophylaxis against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Infection

Breakthrough infections in vaccinated population and continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants make it imperative to develop more efficacious medical countermeasures. Previously, an anti‐SARS‐CoV‐2 nanobody, Nanosota‐3A, that neutralizes the infect...

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Main Authors: Geetha Jyothi Vaskuri, Gang Ye, Fan Bu, Dong Yang, Colleen B. Jonsson, Hailey Turner‐Hubbard, Sydney Winecke, Alise Mendoza, Fang Li, Chalet Tan
Format: Article
Language:English
Published: Wiley-VCH 2025-08-01
Series:Advanced NanoBiomed Research
Subjects:
Fc engineering
FcRn
half‐life extension
nanobody
pharmacokinetics
pre‐exposure prophylaxis
Online Access:https://doi.org/10.1002/anbr.202400214
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Summary:Breakthrough infections in vaccinated population and continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants make it imperative to develop more efficacious medical countermeasures. Previously, an anti‐SARS‐CoV‐2 nanobody, Nanosota‐3A, that neutralizes the infection of live Omicron BA.1 with picomolar potency, is identified. Herein, Nanosota‐3A is fused with the crystallizable fragment (Fc) domain of human IgG1 that contains M252Y/S254T/T256E (YTE) substitutions, named Nanosota‐3A‐Fc‐YTE. Compared to Nanosota‐3A‐Fc, Nanosota‐3A‐Fc‐YTE exhibits identical binding to the SARS‐CoV‐2 spike protein yet displays eightfold higher binding affinity for human neonatal Fc receptor (hFcRn) at pH 6.0. In hFcRn transgenic mice, the half‐life of Nanosota‐3A‐Fc and Nanosota‐3A‐Fc‐YTE is 5.1 days and 24.8 days, respectively. The mice are challenged with intranasal exposure of Omicron B.1.1.529 virus 55 days after a single dose of Nanosota‐3A fusions (20 mg kg−1) is administered. Compared to the untreated controls, the lung viral titers in mice receiving Nanosota‐3A‐Fc‐YTE are reduced by 104.7‐fold (p = 0.007) with 50% of the mice free of detectable virus. By contrast, Nanosota‐3A‐Fc‐treated mice show only 3.5‐fold reduction in the viral titers (p = 0.41). The durable protection conferred by a single dose of Nanosota‐3A‐Fc‐YTE administered nearly 2 months prior to the virus exposure demonstrates the promise of long‐circulating nanobodies as powerful prophylactics against SARS‐CoV‐2.
ISSN:2699-9307

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