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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 (MedImmune LLC) , Davide Corti (Humabs BioMed SA) , Patrick J. Collins (The Francis Crick Institute) , Ursula Neu (The Francis Crick Institute) , Josephine M. Mcauliffe (MedImmune LLC) , Ebony Benjamin (MedImmune LLC) , Leslie Wachter-Rosati (MedImmune LLC) , Frances J. Palmer-Hill (MedImmune LLC) , Andy Q. Yuan (MedImmune LLC) , Philip A. Walker (Francis Crick Institute) , Matthias Vorleander (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 (Università della Svizzera italiana) , Debora Pinna (Università della Svizzera italiana) , Blanca Fernandez-Rodriguez (Università della Svizzera italiana) , Alexander Fruehwirth (Università della Svizzera italiana) , Chiara Silacci (Università della Svizzera italiana) , Roksana W. Ogrodowicz (Francis Crick Institute) , Stephen R. Martin (Francis Crick Institute) , Federica Sallusto (Università della Svizzera italiana) , Joann A. Suzich (MedImmune LLC) , Antonio Lanzavecchia (Università della Svizzera italiana; Institute for Microbiology, ETH Zurich) , Qing Zhu (MedImmune LLC) , Steven J. Gamblin (The Francis Crick Institute) , John J. Skehel (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.

Diamond Keywords: Influenza; Viruses; Immunotherapy

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 12/10/2016 10:03

Documents:
1-s2.0-S0092867416307206-main.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)