Receptor mimicry by antibody F045-092 facilitates universal binding to the H3 subtype of influenza virus.
Influenza viruses present a significant health challenge each year, as in the H3N2 epidemic of 2012-2013. Here we describe an antibody, F045-092, that possesses broadly neutralizing activity against the entire H3 subtype and accommodates the natural variation and additional glycosylation in all strains tested from 1963 to 2011. Crystal structures of F045-092 in complex with HAs from 1975 and 2011 H3N2 viruses reveal the structural basis for its neutralization breadth through insertion of its 23-residue HCDR3 into the receptor-binding site that involves striking receptor mimicry. F045-092 extends its recognition to divergent subtypes, including H1, H2 and H13, using the enhanced avidity of its IgG to overcome lower-affinity Fab binding, as observed with other antibodies that target the receptor-binding site. This unprecedented level of antibody cross-reactivity against the H3 subtype can potentially inform on development of a pan-H3 vaccine or small-molecule therapeutics.
1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA [2] The Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Peter S
PS
Lee
Division of Antibody Project, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
Nobuko
N
Ohshima
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Robyn L
RL
Stanfield
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Wenli
W
Yu
Division of Antibody Project, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
Yoshitaka
Y
Iba
Kanonji Institute, The Research Foundation for Microbial Diseases, Osaka University, Kanonji, Kagawa 768-0061, Japan.
Yoshinobu
Y
Okuno
Division of Antibody Project, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
Yoshikazu
Y
Kurosawa
1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA [2] The Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Ian A
IA
Wilson
D057134:Antibodies, Neutralizing / Q000378:metabolism*; D000914:Antibodies, Viral / Q000378:metabolism*; D001665:Binding Sites; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism; D053122:Influenza A Virus, H3N2 Subtype / Q000378:metabolism*; D009980:Influenza A virus / Q000378:metabolism
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus