title: Structure and Function Analysis of an Antibody Recognizing All Influenza A Subtypes.
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.
authors.affiliation: Department of Infectious Disease and Vaccines, MedImmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Kallewaard
authors.affiliation: Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland.
authors.forename: Davide
authors.initials: D
authors.lastname: Corti
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, London NW7 1AA, UK.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Collins
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, London NW7 1AA, UK.
authors.forename: Ursula
authors.initials: U
authors.lastname: Neu
authors.affiliation: Department of Infectious Disease and Vaccines, MedImmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
authors.forename: Josephine M
authors.initials: JM
authors.lastname: McAuliffe
authors.affiliation: Department of Infectious Disease and Vaccines, MedImmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
authors.forename: Ebony
authors.initials: E
authors.lastname: Benjamin
authors.affiliation: Department of Infectious Disease and Vaccines, MedImmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Wachter-Rosati
authors.affiliation: Department of Infectious Disease and Vaccines, MedImmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
authors.forename: Frances J
authors.initials: FJ
authors.lastname: Palmer-Hill
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
authors.forename: Andy Q
authors.initials: AQ
authors.lastname: Yuan
authors.affiliation: Structural Biology Science Technology Platform, Mill Hill Laboratory, Francis Crick Institute, London NW7 1AA, UK.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Walker
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, London NW7 1AA, UK.
authors.forename: Matthias K
authors.initials: MK
authors.lastname: Vorlaender
authors.affiliation: Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland.
authors.forename: Siro
authors.initials: S
authors.lastname: Bianchi
authors.affiliation: Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Guarino
authors.affiliation: Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: De Marco
authors.affiliation: Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland.
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Vanzetta
authors.affiliation: Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland.
authors.forename: Gloria
authors.initials: G
authors.lastname: Agatic
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Foglierini
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland.
authors.forename: Debora
authors.initials: D
authors.lastname: Pinna
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland.
authors.forename: Blanca
authors.initials: B
authors.lastname: Fernandez-Rodriguez
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Fruehwirth
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland.
authors.forename: Chiara
authors.initials: C
authors.lastname: Silacci
authors.affiliation: Structural Biology Science Technology Platform, Mill Hill Laboratory, Francis Crick Institute, London NW7 1AA, UK.
authors.forename: Roksana W
authors.initials: RW
authors.lastname: Ogrodowicz
authors.affiliation: Structural Biology Science Technology Platform, Mill Hill Laboratory, Francis Crick Institute, London NW7 1AA, UK.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Martin
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland.
authors.forename: Federica
authors.initials: F
authors.lastname: Sallusto
authors.affiliation: Department of Infectious Disease and Vaccines, MedImmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
authors.forename: JoAnn A
authors.initials: JA
authors.lastname: Suzich
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland; Institute for Microbiology, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lanzavecchia
authors.affiliation: Department of Infectious Disease and Vaccines, MedImmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA. Electronic address: zhuq@medimmune.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, London NW7 1AA, UK.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Gamblin
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, London NW7 1AA, UK. Electronic address: john.skehel@crick.ac.uk.
authors.forename: John J
authors.initials: JJ
authors.lastname: Skehel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology / Q000302:isolation & purification; D000914:Antibodies, Viral / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D000918:Antibody Specificity; D001666:Binding Sites, Antibody; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000276:immunology; D005289:Ferrets; D006801:Humans; D007252:Influenza Vaccines; D029521:Alphainfluenzavirus / Q000276:immunology*; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000517:prevention & control; D011487:Protein Conformation
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D007252:Influenza Vaccines; C000612541:MED18852