Structure and function analysis of an antibody recognizing all influenza A subtypes
journal contributionposted on 2020-08-05, 17:13 authored by Nicole L Kallewaard, Davide Corti, Patrick J Collins, Ursula Neu, Josephine M McAuliffe, Ebony Benjamin, Leslie Wachter-Rosati, Frances J Palmer-Hill, Andy Q Yuan, Philip A Walker, Matthias K Vorlaender, Siro Bianchi, Barbara Guarino, Anna De Marco, Fabrizia Vanzetta, Gloria Agatic, Mathilde Foglierini, Debora Pinna, Blanca Fernandez-Rodriguez, Alexander Fruehwirth, Chiara Silacci, Roksana W Ogrodowicz, Stephen R Martin, Federica Sallusto, JoAnn A Suzich, Antonio Lanzavecchia, Qing Zhu, Steven J Gamblin, John J Skehel
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.
Amino Acid SequenceAnimalsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntibodies, NeutralizingAntibodies, ViralAntibody SpecificityBinding Sites, AntibodyCrystallography, X-RayEpitopesFerretsHumansInfluenza VaccinesInfluenzavirus AMiceOrthomyxoviridae InfectionsProtein ConformationGamblin FC001078SBDevelopmental Biology06 Biological Sciences11 Medical and Health Sciences