Cross-neutralization of influenza A viruses mediated by a single antibody loop

Damian C. Ekiert, Arun K. Kashyap, John Steel, Adam Rubrum, Gira Bhabha, Reza Khayat, Jeong Hyun Lee, Michael A. Dillon, Ryann E. O’Neil, Aleksandr M. Faynboym, Michael Horowitz, Lawrence Horowitz, Andrew B. Ward, Peter Palese, Richard Webby, Richard A. Lerner, Ramesh R. Bhatt () and Ian A. Wilson ()
Additional contact information
Damian C. Ekiert: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Arun K. Kashyap: Sea Lane Biotechnologies, 2450 Bayshore Parkway
John Steel: Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, New York 10029-6574, USA
Adam Rubrum: St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA
Gira Bhabha: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Reza Khayat: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Jeong Hyun Lee: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Michael A. Dillon: Sea Lane Biotechnologies, 2450 Bayshore Parkway
Ryann E. O’Neil: Sea Lane Biotechnologies, 2450 Bayshore Parkway
Aleksandr M. Faynboym: Sea Lane Biotechnologies, 2450 Bayshore Parkway
Michael Horowitz: Sea Lane Biotechnologies, 2450 Bayshore Parkway
Lawrence Horowitz: Sea Lane Biotechnologies, 2450 Bayshore Parkway
Andrew B. Ward: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Peter Palese: Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, New York 10029-6574, USA
Richard Webby: St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA
Richard A. Lerner: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Ramesh R. Bhatt: Sea Lane Biotechnologies, 2450 Bayshore Parkway
Ian A. Wilson: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA

Nature, 2012, vol. 489, issue 7417, 526-532

Abstract: Abstract Immune recognition of protein antigens relies on the combined interaction of multiple antibody loops, which provide a fairly large footprint and constrain the size and shape of protein surfaces that can be targeted. Single protein loops can mediate extremely high-affinity binding, but it is unclear whether such a mechanism is available to antibodies. Here we report the isolation and characterization of an antibody called C05, which neutralizes strains from multiple subtypes of influenza A virus, including H1, H2 and H3. X-ray and electron microscopy structures show that C05 recognizes conserved elements of the receptor-binding site on the haemagglutinin surface glycoprotein. Recognition of the haemagglutinin receptor-binding site is dominated by a single heavy-chain complementarity-determining region 3 loop, with minor contacts from heavy-chain complementarity-determining region 1, and is sufficient to achieve nanomolar binding with a minimal footprint. Thus, binding predominantly with a single loop can allow antibodies to target small, conserved functional sites on otherwise hypervariable antigens.

Date: 2012
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DOI: 10.1038/nature11414

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