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Combined at low dose, this \u201ctriple M2e-mAb\u201d 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 Fc\u03b3RI, Fc\u03b3RIII, and Fc\u03b3RIV, rather than in vitro neutralization. Serial passaging in triple M2e-mAb\u2013treated 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.<\/jats:p>","DOI":"10.1126\/sciadv.adx3505","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T18:01:02Z","timestamp":1757527262000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":9,"title":["Non-neutralizing antibodies to influenza A matrix-protein-2-ectodomain are broadly effective therapeutics and resistant to viral escape mutations"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4421-4620","authenticated-orcid":true,"given":"Teha","family":"Kim","sequence":"first","affiliation":[{"name":"The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA."},{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7473-9698","authenticated-orcid":true,"given":"Lynn","family":"Bimler","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"name":"Center for Human Immunobiology, Department of Pediatrics, Texas Children\u2019s Hospital, Houston, TX 77030, USA."},{"name":"Developing Investigative Scholar\u2019s Program (DISP), Rice University, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7481-1207","authenticated-orcid":true,"given":"Sydney L.","family":"Ronzulli","sequence":"additional","affiliation":[{"name":"Center for Vaccines and Immunology, University of Georgia, Athens, GA 30605, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2954-651X","authenticated-orcid":true,"given":"Amber Y.","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"name":"Center for Human Immunobiology, Department of Pediatrics, Texas Children\u2019s Hospital, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6861-8243","authenticated-orcid":true,"given":"Scott K.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Center for Vaccines and Immunology, University of Georgia, Athens, GA 30605, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7983-3205","authenticated-orcid":true,"given":"Cheryl A.","family":"Jones","sequence":"additional","affiliation":[{"name":"Center for Vaccines and Immunology, University of Georgia, Athens, GA 30605, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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