Structure and Function Analysis of an Antibody Recognizing All Influenza A Subtypes

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 (...

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Bibliographic Details
Published in:Cell Vol. 166; no. 3; pp. 596 - 608
Main Authors: 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
Format: Journal Article
Language:English
Published: United States 28.07.2016
Subjects:
Alphainfluenzavirus - immunology
Amino Acid Sequence
Animals
Antibodies, Monoclonal - chemistry
Antibodies, Monoclonal - immunology
Antibodies, Monoclonal - isolation & purification
Antibodies, Monoclonal, Humanized
Antibodies, Neutralizing - chemistry
Antibodies, Neutralizing - immunology
Antibodies, Neutralizing - isolation & purification
Antibodies, Viral - chemistry
Antibodies, Viral - immunology
Antibodies, Viral - isolation & purification
Antibody Specificity
Binding Sites, Antibody
Crystallography, X-Ray
Epitopes - immunology
Ferrets
Humans
Influenza Vaccines
Mice
Orthomyxoviridae Infections - prevention & control
Protein Conformation
ISSN:1097-4172
Online Access:Get more information
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Summary: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.
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ISSN:1097-4172
DOI:10.1016/j.cell.2016.05.073