Nasal delivery of an IgM offers broad protection from SARS-CoV-2 variants

Zhiqiang Ku, Xuping Xie, Paul R. Hinton, Xinli Liu, Xiaohua Ye, Antonio E. Muruato, Dean C. Ng, Sujit Biswas, Jing Zou, Yang Liu, Deepal Pandya, Vineet D. Menachery, Sachi Rahman, Yu-An Cao, Hui Deng, Wei Xiong, Kevin B. Carlin, Junquan Liu, Hang Su, Elizabeth J. Haanes, Bruce A. Keyt (), Ningyan Zhang (), Stephen F. Carroll (), Pei-Yong Shi () and Zhiqiang An ()
Additional contact information
Zhiqiang Ku: The University of Texas Health Science Center at Houston
Xuping Xie: University of Texas Medical Branch
Paul R. Hinton: IGM Biosciences
Xinli Liu: University of Houston
Xiaohua Ye: The University of Texas Health Science Center at Houston
Antonio E. Muruato: University of Texas Medical Branch
Dean C. Ng: IGM Biosciences
Sujit Biswas: University of Houston
Jing Zou: University of Texas Medical Branch
Yang Liu: University of Texas Medical Branch
Deepal Pandya: IGM Biosciences
Vineet D. Menachery: University of Texas Medical Branch
Sachi Rahman: IGM Biosciences
Yu-An Cao: IGM Biosciences
Hui Deng: The University of Texas Health Science Center at Houston
Wei Xiong: The University of Texas Health Science Center at Houston
Kevin B. Carlin: IGM Biosciences
Junquan Liu: The University of Texas Health Science Center at Houston
Hang Su: The University of Texas Health Science Center at Houston
Elizabeth J. Haanes: IGM Biosciences
Bruce A. Keyt: IGM Biosciences
Ningyan Zhang: The University of Texas Health Science Center at Houston
Stephen F. Carroll: IGM Biosciences
Pei-Yong Shi: University of Texas Medical Branch
Zhiqiang An: The University of Texas Health Science Center at Houston

Nature, 2021, vol. 595, issue 7869, 718-723

Abstract: Abstract Resistance represents a major challenge for antibody-based therapy for COVID-191–4. Here we engineered an immunoglobulin M (IgM) neutralizing antibody (IgM-14) to overcome the resistance encountered by immunoglobulin G (IgG)-based therapeutics. IgM-14 is over 230-fold more potent than its parental IgG-14 in neutralizing SARS-CoV-2. IgM-14 potently neutralizes the resistant virus raised by its corresponding IgG-14, three variants of concern—B.1.1.7 (Alpha, which first emerged in the UK), P.1 (Gamma, which first emerged in Brazil) and B.1.351 (Beta, which first emerged in South Africa)—and 21 other receptor-binding domain mutants, many of which are resistant to the IgG antibodies that have been authorized for emergency use. Although engineering IgG into IgM enhances antibody potency in general, selection of an optimal epitope is critical for identifying the most effective IgM that can overcome resistance. In mice, a single intranasal dose of IgM-14 at 0.044 mg per kg body weight confers prophylactic efficacy and a single dose at 0.4 mg per kg confers therapeutic efficacy against SARS-CoV-2. IgM-14, but not IgG-14, also confers potent therapeutic protection against the P.1 and B.1.351 variants. IgM-14 exhibits desirable pharmacokinetics and safety profiles when administered intranasally in rodents. Our results show that intranasal administration of an engineered IgM can improve efficacy, reduce resistance and simplify the prophylactic and therapeutic treatment of COVID-19.

Date: 2021
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DOI: 10.1038/s41586-021-03673-2

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