An intranasally administered IgM protects against antigenically distinct subtypes of influenza A viruses

Engineering broadly neutralizing monoclonal antibodies (mAbs) targeting the hemagglutinin (HA) of Influenza A virus (IAV) is a promising approach for intervention of seasonal flu. However, HA plasticity often leads to resistant strains that compromise mAb potency as bivalent IgGs. Here we hypothesize that multimerization of anti-IAV antibodies as IgMs can enhance coverage and neutralization potency. Here, we construct 18 IgM antibodies from known broadly neutralizing IgGs targeting different IAV HA epitopes and evaluate their breadth and potency of neutralization against distinct H1N1 and H3N2 IAVs. The IgM version of receptor binding site-specific IgG F045-092 shows increased breadth and antiviral potency compared to its parental IgG. Engineered IgM molecules overcome IAV strain resistance by expanded avidity, providing potent neutralization in vitro at sub-nanomolar ranges while retaining parental IgG specificity. Intranasal delivery of engineered IgM-F045-092 in female mice demonstrates efficient bio-retention in nasal cavities and lungs, offering protection against lethal doses of H1N1 and H3N2 IAV when administered prophylactically. Optimal epitope selection, trans-crosslinking, decavalent avidity, and intranasal administration contribute to the broader protection and potency of engineered IgM antibodies against diverse IAV subtypes.

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Publication Details

Journal
Nature Communications
Published
2025-04-29
DOI
https://doi.org/10.1038/s41467-025-59294-0
Citations
1
Primary Topic
Influenza Virus Research Studies
Type
article
Field-Weighted Citation Impact
1.35

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article

An intranasally administered IgM protects against antigenically distinct subtypes of influenza A viruses

Tongqing Zhou, Jwala Priyadarsini Sivaccumar, John W. Shiver, Hailong Guo et al.
1 citations
Nature Communications
Influenza Virus Research Studies
1.35
article

An intranasally administered IgM protects against antigenically distinct subtypes of influenza A viruses

Tongqing Zhou, Jwala Priyadarsini Sivaccumar, John W. Shiver, Hailong Guo, Zhiqiang An, Ashwin Ramesh, Chen‐Ni Chin, Kai Xu, William R. Strohl, Sha Ha, Tong‐Ming Fu, Xiaohua Ye, Ningyan Zhang, Li Yang, Yan Xu, Xinli Liu, Haijuan Du
article en
1 citations

Abstract

Engineering broadly neutralizing monoclonal antibodies (mAbs) targeting the hemagglutinin (HA) of Influenza A virus (IAV) is a promising approach for intervention of seasonal flu. However, HA plasticity often leads to resistant strains that compromise mAb potency as bivalent IgGs. Here we hypothesize that multimerization of anti-IAV antibodies as IgMs can enhance coverage and neutralization potency. Here, we construct 18 IgM antibodies from known broadly neutralizing IgGs targeting different IAV HA epitopes and evaluate their breadth and potency of neutralization against distinct H1N1 and H3N2 IAVs. The IgM version of receptor binding site-specific IgG F045-092 shows increased breadth and antiviral potency compared to its parental IgG. Engineered IgM molecules overcome IAV strain resistance by expanded avidity, providing potent neutralization in vitro at sub-nanomolar ranges while retaining parental IgG specificity. Intranasal delivery of engineered IgM-F045-092 in female mice demonstrates efficient bio-retention in nasal cavities and lungs, offering protection against lethal doses of H1N1 and H3N2 IAV when administered prophylactically. Optimal epitope selection, trans-crosslinking, decavalent avidity, and intranasal administration contribute to the broader protection and potency of engineered IgM antibodies against diverse IAV subtypes.

Nature CommunicationsVol. 16(1)
National Institutes of Health (US), Westlake University (CN), IGM Biosciences (United States) (US), National Institute of Allergy and Infectious Diseases (US), Brown Foundation (US), University of Houston (US), The Ohio State University (US), The University of Texas Health Science Center at Houston (US)
Welch Foundation, Ohio State University, National Institutes of Health, University of California, San Francisco, National Institute of Allergy and Infectious Diseases
Good health and well-being
Openalex Percentile: Top 20%
Influenza Virus Research Studies
1.35
DOIOpen Access PDFOpenAlex
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