Document Type
Article
Publication Date
9-12-2025
Original Citation
Kim T,
Bimler L,
Ronzulli S,
Song A,
Johnson S,
Jones C,
Tompkins S,
Paust S.
Non-neutralizing antibodies to influenza A matrix-protein-2-ectodomain are broadly effective therapeutics and resistant to viral escape mutations. Sci Adv. 2025;11(37):eadx3505.
Keywords
JGM, Animals, Humans, Mice, Antibodies, Viral, Mutation, Viral Matrix Proteins, Influenza A virus, Antibodies, Monoclonal, Antibodies, Neutralizing, Orthomyxoviridae Infections, Epitopes, Influenza, Human, Viroporin Proteins
JAX Source
Sci Adv. 2025;11(37):eadx3505.
ISSN
2375-2548
PMID
40929256
DOI
https://doi.org/10.1126/sciadv.adx3505
Grant
this work was supported by the Albert and Margaret Alkek Foundation, houston tX, 2015 (to S.P.), national institutes of health grant R01Ai130065 (to S.P. and S.M.t.)
Abstract
Influenza A viruses remain a global health threat, yet no universal antibody therapy exists. Clinical programs have centered on neutralizing mAbs, only to be thwarted by strain specificity and rapid viral escape. We instead engineered three non-neutralizing IgG2a mAbs that target distinct, overlapping epitopes within the conserved N terminus of the M2 ectodomain (M2e). Combined at low dose, this "triple M2e-mAb" confers robust prophylactic and therapeutic protection in mice challenged with diverse human and zoonotic IAV strains, including highly pathogenic variants. Therapeutic efficacy depends on Fc-mediated effector activity via FcγRI, FcγRIII, and FcγRIV, rather than in vitro neutralization. Serial passaging in triple M2e-mAb-treated immunocompetent and immunodeficient hosts failed to generate viral escape mutants. Our findings redefine the influenza-specific antibody therapeutic design and support Fc-optimized, non-neutralizing M2e-mAbs as a broadly effective, mutation-resistant, off-the-shelve therapy with direct relevance to human pandemic preparedness.
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License