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

被引：319

作者：

Kallewaard, Nicole L. ^{[1
]}

Corti, Davide ^{[2
]}

Collins, Patrick J. ^{[3
]}

Neu, Ursula ^{[3
]}

McAuliffe, Josephine M. ^{[1
]}

Benjamin, Ebony ^{[1
]}

Wachter-Rosati, Leslie ^{[1
]}

Palmer-Hill, Frances J. ^{[1
]}

Yuan, Andy Q. ^{[4
]}

Walker, Philip A. ^{[5
]}

Vorlaender, Matthias K. ^{[3
]}

Bianchi, Siro ^{[2
]}

Guarino, Barbara ^{[2
]}

De Marco, Anna ^{[2
]}

Vanzetta, Fabrizia ^{[2
]}

Agatic, Gloria ^{[2
]}

Foglierini, Mathilde ^{[6
]}

Pinna, Debora ^{[6
]}

Fernandez-Rodriguez, Blanca ^{[6
]}

Fruehwirth, Alexander ^{[6
]}

Silacci, Chiara ^{[6
]}

Ogrodowicz, Roksana W. ^{[5
]}

Martin, Stephen R. ^{[5
]}

Sallusto, Federica ^{[6
]}

Suzich, JoAnn A. ^{[1
]}

Lanzavecchia, Antonio ^{[6
,7
]}

Zhu, Qing ^{[1
]}

Gamblin, Steven J. ^{[3
]}

Skehel, John J. ^{[3
]}

机构：

[1] MedImmune LLC, Dept Infect Dis & Vaccines, One MedImmune Way, Gaithersburg, MD 20878 USA

[2] Humabs BioMed SA, Via Mirasole 1, CH-6500 Bellinzona, Switzerland

[3] Francis Crick Inst, Mill Hill Lab, London NW7 1AA, England

[4] MedImmune LLC, Dept Antibody Discovery & Prot Engn, One MedImmune Way, Gaithersburg, MD 20878 USA

[5] Francis Crick Inst, Mill Hill Lab, Struct Biol Sci Technol Platform, London NW7 1AA, England

[6] Univ Svizzera Italiana, Inst Res Biomed, CH-6500 Bellinzona, Switzerland

[7] Swiss Fed Inst Technol, Inst Microbiol, Wolfgang Pauli Str 10, CH-8093 Zurich, Switzerland

来源：

CELL | 2016年 / 166卷 / 03期

基金：

欧洲研究理事会; 瑞士国家科学基金会;

关键词：

MONOCLONAL-ANTIBODY; VIRUS; HEMAGGLUTININ; NEUTRALIZATION; EPITOPE;

D O I：

10.1016/j.cell.2016.05.073

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：596 / 608

页数：13

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