Journal Article

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

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

2025

Overview

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. Influenza A HA plasticity often leads to resistant strains that compromise mAb potency as bivalent IgGs. Here, the authors show that engineered IgM molecules overcome this resistance by expanded avidity but still provide potent neutralization and in vivo protection while retaining parental IgG specificity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/109 / 14/28 / 14/34 / 14/63 / 38/22 / 38/23 / 38/77 / 631/1647/334/1874/345 / 631/250/2152/2153/1291 / 631/326/596/1578 / 64 / 64/60 / 692/420/254 / 82/16 / 82/29 / 82/80 / 82/81 / 82/83 / 96/106 / Administration, Intranasal / Animals / Antibodies / Antibodies, Monoclonal - administration & dosage / Antibodies, Monoclonal - immunology / Antibodies, Neutralizing - administration & dosage / Antibodies, Neutralizing - immunology / Antibodies, Viral - administration & dosage / Antibodies, Viral - immunology / Avidity / Binding sites / Crosslinking / Deformation resistance / Dogs / Epitopes / Epitopes - immunology / Female / Hemagglutinin Glycoproteins, Influenza Virus - immunology / Hemagglutinins / Humanities and Social Sciences / Humans / Immunoglobulin G / Immunoglobulin G - immunology / Immunoglobulin M / Immunoglobulin M - administration & dosage / Immunoglobulin M - genetics / Immunoglobulin M - immunology / Influenza / Influenza A / Influenza A virus - immunology / Influenza A Virus, H1N1 Subtype - immunology / Influenza A Virus, H3N2 Subtype - immunology / Influenza Vaccines - administration & dosage / Influenza Vaccines - immunology / Intranasal administration / Madin Darby Canine Kidney Cells / Mice / Mice, Inbred BALB C / Monoclonal antibodies / multidisciplinary / Neutralization / Neutralizing / Orthomyxoviridae Infections - immunology / Orthomyxoviridae Infections - prevention & control / Orthomyxoviridae Infections - virology / Plastic properties / Plasticity / Science / Science (multidisciplinary) / Strains (organisms)