Cell · 2016
Structure and Function Analysis of an Antibody Recognizing All Influenza A Subtypes.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Kallewaard Nicole L, Corti Davide, Collins Patrick J, Neu Ursula, McAuliffe Josephine M, Benjamin Ebony, Wachter-Rosati Leslie, Palmer-Hill Frances J, Yuan Andy Q, Walker Philip A, Vorlaender Matthias K, Bianchi Siro, Guarino Barbara, De Marco Anna, Vanzetta Fabrizia, Agatic Gloria, Foglierini Mathilde, Pinna Debora, Fernandez-Rodriguez Blanca, Fruehwirth Alexander, Silacci Chiara, Ogrodowicz Roksana W, Martin Stephen R, Sallusto Federica, Suzich JoAnn A, Lanzavecchia Antonio, Zhu Qing, Gamblin Steven J, Skehel John J
Аннотация
Influenza virus remains a threat because of its ability to evade vaccine-induced immune responses due to antigenic drift. Here, we describe the isolation, evolution, and structure of a broad-spectrum human monoclonal antibody (mAb), MEDI8852, effectively reacting with all influenza A hemagglutinin (HA) subtypes. MEDI8852 uses the heavy-chain VH6-1 gene and has higher potency and breadth when compared to other anti-stem antibodies. MEDI8852 is effective in mice and ferrets with a therapeutic window superior to that of oseltamivir. Crystallographic analysis of Fab alone or in complex with H5 or H7 HA proteins reveals that MEDI8852 binds through a coordinated movement of CDRs to a highly conserved epitope encompassing a hydrophobic groove in the fusion domain and a large portion of the fusion peptide, distinguishing it from other structurally characterized cross-reactive antibodies. The unprecedented breadth and potency of neutralization by MEDI8852 support its development as immunotherapy for influenza virus-infected humans.