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

DOI: 10.1016/j.cell.2016.05.073 DOI Help

Authors: Nicole l. Kallewaard (Department of Infectious Disease and Vaccines, MedImmune LLC) , Davide Corti (Humabs BioMed SA) , Patrick J. Collins (Mill Hill Laboratory, The Francis Crick Institute) , Ursula Neu (Mill Hill Laboratory, The Francis Crick Institute) , Josephine m. Mcauliffe (Department of Infectious Disease and Vaccines, MedImmune LLC) , Ebony Benjamin (Department of Infectious Disease and Vaccines, MedImmune LLC) , Leslie Wachter-rosati (Department of Infectious Disease and Vaccines, MedImmune LLC) , Frances j. Palmer-hill (Department of Infectious Disease and Vaccines, MedImmune LLC) , Andy q. Yuan (Department of Antibody Discovery and Protein Engineering, MedImmune LLC) , Philip A. Walker (Structural Biology Science Technology Platform, Mill Hill Laboratory, Francis Crick Institute) , Matthias Vorleander (Mill Hill Laboratory, The Francis Crick Institute) , Siro Bianchi (Humabs BioMed SA) , Barbara Guarino (Humabs BioMed SA) , Anna De marco (Humabs BioMed SA) , Fabrizia Vanzetta (Humabs BioMed SA) , Gloria Agatic (Humabs BioMed SA) , Mathilde Foglierini (Institute for Research in Biomedicine, Università della Svizzera italiana) , Debora Pinna (Institute for Research in Biomedicine, Università della Svizzera italiana) , Blanca Fernandez-rodriguez (Institute for Research in Biomedicine, Università della Svizzera italiana) , Alexander Fruehwirth (Institute for Research in Biomedicine, Università della Svizzera italiana) , Chiara Silacci (Institute for Research in Biomedicine, Università della Svizzera italiana) , Roksana W. Ogrodowicz (Structural Biology Science Technology Platform, Mill Hill Laboratory, Francis Crick Institute) , Stephen r. Martin (Structural Biology Science Technology Platform, Mill Hill Laboratory, Francis Crick Institute) , Federica Sallusto (Institute for Research in Biomedicine, Università della Svizzera italiana) , Joann A. Suzich (Department of Infectious Disease and Vaccines, MedImmune LLC) , Antonio Lanzavecchia (Institute for Research in Biomedicine, Università della Svizzera italiana; Institute for Microbiology, ETH Zurich) , Qing Zhu (Department of Infectious Disease and Vaccines, MedImmune LLC) , Steven J. Gamblin (Mill Hill Laboratory, The Francis Crick Institute) , John j. Skehel (Mill Hill Laboratory, The Francis Crick Institute)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Cell , VOL 166 , PAGES 596 - 608

State: Published (Approved)
Published: July 2016
Diamond Proposal Number(s): 9826

Open Access Open Access

Abstract: 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.

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 12/10/2016 10:03

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