A broadly neutralizing human monoclonal antibody directed against a novel conserved epitope on the influenza virus H3 hemagglutinin globular head.
Most neutralizing antibodies elicited during influenza virus infection or vaccination target immunodominant, variable epitopes on the globular head region of hemagglutinin (HA), which leads to narrow strain protection. In this report, we describe the properties of a unique anti-HA monoclonal antibody (MAb), D1-8, that was derived from human B cells and exhibits potent, broad neutralizing activity across antigenically diverse influenza H3 subtype viruses. Based on selection of escape variants, we show that D1-8 targets a novel epitope on the globular head region of the influenza virus HA protein. The HA residues implicated in D1-8 binding are highly conserved among H3N2 viruses and are located proximal to antigenic site D. We demonstrate that the potent in vitro antiviral activity of D1-8 translates into protective activity in mouse models of influenza virus infection. Furthermore, D1-8 exhibits superior therapeutic survival benefit in influenza virus-infected mice compared to the neuraminidase inhibitor oseltamivir when treatment is started late in infection. The present study suggests the potential application of this monoclonal antibody for the therapeutic treatment of H3N2 influenza virus infection.


OBJECTIVE
Recently, a few globular head-targeting MAbs have been discovered that exhibit activity against different subtypes of influenza subtypes, such as H1; however, none of the previously described MAbs showed broadly neutralizing activity against diverse H3 viruses. In this report, we describe a human MAb, D1-8, that exhibits potent, broadly neutralizing activity against antigenically diverse H3 subtype viruses. The genotypic analysis of escape mutants revealed a unique putative epitope region in the globular head of H3 HA that is comprised of highly conserved residues and is distinct from the receptor binding site. Furthermore, we demonstrate that D1-8 exhibits superior therapeutic efficacy in influenza virus-infected mice compared to the neuraminidase inhibitor oseltamivir when treatment is started late in infection. In addition to describing a novel anti-globular head of H3 HA MAb with potent broadly neutralizing activity, our report suggests the potential of D1-8 for therapeutic treatment of seasonal influenza virus H3 infection.
Department of Infectious Diseases and Vaccines, MedImmune LLC, Gaithersburg, Maryland, USA.
Ebony
E
Benjamin
Department of Infectious Diseases and Vaccines, MedImmune LLC, Gaithersburg, Maryland, USA.
Weijia
W
Wang
Department of Infectious Diseases and Vaccines, MedImmune LLC, Gaithersburg, Maryland, USA.
Josephine M
JM
McAuliffe
Department of Infectious Diseases and Vaccines, MedImmune LLC, Gaithersburg, Maryland, USA.
Frances J
FJ
Palmer-Hill
Department of Infectious Diseases and Vaccines, MedImmune LLC, Gaithersburg, Maryland, USA.
Nicole L
NL
Kallewaard
Department of Infectious Diseases and Vaccines, MedImmune LLC, Gaithersburg, Maryland, USA.
Zhongying
Z
Chen
Department of Infectious Diseases and Vaccines, MedImmune LLC, Gaithersburg, Maryland, USA.
JoAnn A
JA
Suzich
Department of Infectious Diseases and Vaccines, MedImmune LLC, Gaithersburg, Maryland, USA.
Wade S
WS
Blair
Department of Infectious Diseases and Vaccines, MedImmune LLC, Gaithersburg, Maryland, USA.
Hong
H
Jin
Department of Infectious Diseases and Vaccines, MedImmune LLC, Gaithersburg, Maryland, USA ZhuQ@MedImmune.com.
Qing
Q
Zhu
D020816:Amino Acid Motifs; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000276:immunology*; D000914:Antibodies, Viral / Q000008:administration & dosage / Q000276:immunology*; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D009980:Influenza A virus / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007251:Influenza, Human / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D019267:Hemagglutinin Glycoproteins, Influenza Virus