Journal
CELL
Volume 166, Issue 3, Pages 596-608Publisher
CELL PRESS
DOI: 10.1016/j.cell.2016.05.073
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Funding
- European Research Council [670955 BROADimmune]
- Swiss National Science Foundation [160279]
- Helmut Horten Foundation
- Francis Crick Institute, London
- Marie Curie Actions Intra-European Fellowship [629829]
- Cancer Research UK
- The Francis Crick Institute [10015] Funding Source: researchfish
- Medical Research Council [MC_U117584222, G0600522] Funding Source: researchfish
- The Francis Crick Institute [10078, 10080] Funding Source: researchfish
- MRC [MC_U117584222, G0600522] Funding Source: UKRI
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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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