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Cell. 2016 Jul 28;166(3):596-608. doi: 10.1016/j.cell.2016.05.073. Epub 2016 Jul 21.

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

Author information

1
Department of Infectious Disease and Vaccines, MedImmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
2
Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland.
3
Mill Hill Laboratory, The Francis Crick Institute, London NW7 1AA, UK.
4
Department of Antibody Discovery and Protein Engineering, MedImmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
5
Structural Biology Science Technology Platform, Mill Hill Laboratory, Francis Crick Institute, London NW7 1AA, UK.
6
Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland.
7
Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland; Institute for Microbiology, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland.
8
Department of Infectious Disease and Vaccines, MedImmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA. Electronic address: zhuq@medimmune.com.
9
Mill Hill Laboratory, The Francis Crick Institute, London NW7 1AA, UK. Electronic address: john.skehel@crick.ac.uk.

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.

PMID:
27453466
PMCID:
PMC4967455
DOI:
10.1016/j.cell.2016.05.073
[Indexed for MEDLINE]
Free PMC Article

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