Structure and function analysis of an antibody recognizing all influenza A subtypes

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.

doi:10.1016/j.cell.2016.05.073

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Journal article

Structure and function analysis of an antibody recognizing all influenza A subtypes

Kallewaard, Nicole L. Department of Infectious Disease and Vaccines, MedImmune LLC, One MedImmune Way, Gaithersburg, USA
Corti, Davide Humabs BioMed SA, Bellinzona, Switzerland
Collins, Patrick J. Mill Hill Laboratory, The Francis Crick Institute, London, UK
Neu, Ursula Mill Hill Laboratory, The Francis Crick Institute, London, UK
McAuliffe, Josephine M. Department of Infectious Disease and Vaccines, MedImmune LLC, One MedImmune Way, Gaithersburg, USA
Benjamin, Ebony Department of Infectious Disease and Vaccines, MedImmune LLC, One MedImmune Way, Gaithersburg, USA
Wachter-Rosati, Leslie Department of Infectious Disease and Vaccines, MedImmune LLC, One MedImmune Way, Gaithersburg, USA
Palmer-Hill, Frances J. Department of Infectious Disease and Vaccines, MedImmune LLC, One MedImmune Way, Gaithersburg, USA
Yuan, Andy Q. Department of Antibody Discovery and Protein Engineering, MedImmune LLC, One MedImmune Way, Gaithersburg, USA
Walker, Philip A. Structural Biology Science Technology Platform, Mill Hill Laboratory, Francis Crick Institute, London, UK
Vorlaender, Matthias K. Mill Hill Laboratory, The Francis Crick Institute, London, UK
Bianchi, Siro Humabs BioMed SA, Bellinzona, Switzerland
Guarino, Barbara Humabs BioMed SA, Bellinzona, Switzerland
De Marco, Anna Humabs BioMed SA, Bellinzona, Switzerland
Vanzetta, Fabrizia Humabs BioMed SA, Bellinzona, Switzerland
Agatic, Gloria Humabs BioMed SA, Bellinzona, Switzerland
Foglierini, Mathilde Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Pinna, Debora Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Fernandez-Rodriguez, Blanca Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Fruehwirth, Alexander Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Silacci, Chiara Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Ogrodowicz, Roksana W. Structural Biology Science Technology Platform, Mill Hill Laboratory, Francis Crick Institute, London, UK
Martin, Stephen R. Structural Biology Science Technology Platform, Mill Hill Laboratory, Francis Crick Institute, London, UK
Sallusto, Federica Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Suzich, JoAnn A. Department of Infectious Disease and Vaccines, MedImmune LLC, One MedImmune Way, Gaithersburg, USA
Lanzavecchia, Antonio Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Institute for Microbiology, ETH Zurich, Switzerland
Zhu, Qing Department of Infectious Disease and Vaccines, MedImmune LLC, One MedImmune Way, Gaithersburg, USA
Gamblin, Steven J. Mill Hill Laboratory, The Francis Crick Institute, London, UK
Skehel, John J. Mill Hill Laboratory, The Francis Crick Institute, London, UK

21.07.2016

Published in:

Cell. - 2016, vol. 166, no. 3, p. 596-608

English 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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