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

• 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 Elsevier Inc 28.07.2016; Cell Press
• 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; antigenic variation; Binding Sites, Antibody; Crystallography, X-Ray; epitopes; Epitopes - immunology; evolution; Ferrets; genes; hemagglutinins; Humans; hydrophobicity; immune response; immunotherapy; influenza; Influenza A virus; Influenza Vaccines; Mice; monoclonal antibodies; neutralization; Orthomyxoviridae Infections - prevention & control; oseltamivir; Protein Conformation
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2016.05.073

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. [Display omitted] •Binding to all influenza A subtypes neutralizing seasonal and pandemic strains•Utilizes a rare VH (VH6-1) and carries a low level of somatic mutations•Highly conserved epitope encompassing fusion peptide and hydrophobic groove•Superior therapeutic window compared to oseltamivir in animals Identification of a human monoclonal antibody that reacts effectively with all influenza A hemagglutinin subtypes paves the way for developing immunotherapy for people infected with the flu virus.