Multistate design of influenza antibodies improves affinity and breadth against seasonal viruses
Identifieur interne : 000C23 ( Pmc/Curation ); précédent : 000C22; suivant : 000C24Multistate design of influenza antibodies improves affinity and breadth against seasonal viruses
Auteurs : Alexander M. Sevy ; Nicholas C. Wu ; Iuliia M. Gilchuk ; Erica H. Parrish ; Sebastian Burger [Allemagne] ; Dina Yousif ; Marcus B. M. Nagel ; Kevin L. Schey ; Ian A. Wilson ; James E. Crowe ; Jens MeilerSource :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2019.
Abstract
Influenza is an annual threat to global public health, in part because of constant antigenic drift that facilitates evasion of the antibody response. Rapid changes in the influenza HA protein make it difficult for an antibody to achieve broad activity against different virus subtypes. We developed a computational method that can optimize an antibody sequence to be robust against seasonal variation. As a proof of concept, we tested this method by redesigning a known antibody against a set of diverse HA antigens and showed that the variant redesigned antibodies have improved activity against the virus panel, as predicted. This work shows that computational design can improve naturally occurring antibodies for recognition of different virus strains.
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DOI: 10.1073/pnas.1806004116
PubMed: 30642961
PubMed Central: 6358683
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Multistate design of influenza antibodies improves affinity and breadth against seasonal viruses</title><author><name sortKey="Sevy, Alexander M" sort="Sevy, Alexander M" uniqKey="Sevy A" first="Alexander M." last="Sevy">Alexander M. Sevy</name><affiliation><nlm:aff id="aff1">Chemical & Physical Biology Program,<institution>Vanderbilt University</institution>, Nashville,<addr-line>TN</addr-line> 37235;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Center for Structural Biology,<institution>Vanderbilt University</institution>, Nashville,<addr-line>TN</addr-line> 37235;</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Vanderbilt Vaccine Center,<institution>Vanderbilt University Medical Center</institution>, Nashville,<addr-line>TN</addr-line> 37232;</nlm:aff></affiliation></author><author><name sortKey="Wu, Nicholas C" sort="Wu, Nicholas C" uniqKey="Wu N" first="Nicholas C." last="Wu">Nicholas C. Wu</name><affiliation><nlm:aff id="aff4">Department of Integrative Structural and Computational Biology,<institution>The Scripps Research Institute</institution>, La Jolla,<addr-line>CA</addr-line> 92037;</nlm:aff></affiliation></author><author><name sortKey="Gilchuk, Iuliia M" sort="Gilchuk, Iuliia M" uniqKey="Gilchuk I" first="Iuliia M." last="Gilchuk">Iuliia M. Gilchuk</name><affiliation><nlm:aff id="aff3">Vanderbilt Vaccine Center,<institution>Vanderbilt University Medical Center</institution>, Nashville,<addr-line>TN</addr-line> 37232;</nlm:aff></affiliation></author><author><name sortKey="Parrish, Erica H" sort="Parrish, Erica H" uniqKey="Parrish E" first="Erica H." last="Parrish">Erica H. Parrish</name><affiliation><nlm:aff id="aff3">Vanderbilt Vaccine Center,<institution>Vanderbilt University Medical Center</institution>, Nashville,<addr-line>TN</addr-line> 37232;</nlm:aff></affiliation></author><author><name sortKey="Burger, Sebastian" sort="Burger, Sebastian" uniqKey="Burger S" first="Sebastian" last="Burger">Sebastian Burger</name><affiliation wicri:level="1"><nlm:aff id="aff5">Department of Mathematics,<institution>University of Leipzig</institution>, 04109 Leipzig,<country>Germany</country>;</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Yousif, Dina" sort="Yousif, Dina" uniqKey="Yousif D" first="Dina" last="Yousif">Dina Yousif</name><affiliation><nlm:aff id="aff3">Vanderbilt Vaccine Center,<institution>Vanderbilt University Medical Center</institution>, Nashville,<addr-line>TN</addr-line> 37232;</nlm:aff></affiliation></author><author><name sortKey="Nagel, Marcus B M" sort="Nagel, Marcus B M" uniqKey="Nagel M" first="Marcus B. M." last="Nagel">Marcus B. M. Nagel</name><affiliation><nlm:aff id="aff2">Center for Structural Biology,<institution>Vanderbilt University</institution>, Nashville,<addr-line>TN</addr-line> 37235;</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Vanderbilt Mass Spectrometry Research Center and Department of Biochemistry,<institution>Vanderbilt University School of Medicine</institution>, Nashville,<addr-line>TN</addr-line> 37232;</nlm:aff></affiliation></author><author><name sortKey="Schey, Kevin L" sort="Schey, Kevin L" uniqKey="Schey K" first="Kevin L." last="Schey">Kevin L. Schey</name><affiliation><nlm:aff id="aff6">Vanderbilt Mass Spectrometry Research Center and Department of Biochemistry,<institution>Vanderbilt University School of Medicine</institution>, Nashville,<addr-line>TN</addr-line> 37232;</nlm:aff></affiliation></author><author><name sortKey="Wilson, Ian A" sort="Wilson, Ian A" uniqKey="Wilson I" first="Ian A." last="Wilson">Ian A. Wilson</name><affiliation><nlm:aff id="aff4">Department of Integrative Structural and Computational Biology,<institution>The Scripps Research Institute</institution>, La Jolla,<addr-line>CA</addr-line> 92037;</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">The Skaggs Institute for Chemical Biology,<institution>The Scripps Research Institute</institution>, La Jolla,<addr-line>CA</addr-line> 92037;</nlm:aff></affiliation></author><author><name sortKey="Crowe, James E" sort="Crowe, James E" uniqKey="Crowe J" first="James E." last="Crowe">James E. Crowe</name><affiliation><nlm:aff id="aff1">Chemical & Physical Biology Program,<institution>Vanderbilt University</institution>, Nashville,<addr-line>TN</addr-line> 37235;</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Vanderbilt Vaccine Center,<institution>Vanderbilt University Medical Center</institution>, Nashville,<addr-line>TN</addr-line> 37232;</nlm:aff></affiliation><affiliation><nlm:aff id="aff8">Department of Pediatrics,<institution>Vanderbilt University Medical Center</institution>, Nashville,<addr-line>TN</addr-line> 37232;</nlm:aff></affiliation></author><author><name sortKey="Meiler, Jens" sort="Meiler, Jens" uniqKey="Meiler J" first="Jens" last="Meiler">Jens Meiler</name><affiliation><nlm:aff id="aff1">Chemical & Physical Biology Program,<institution>Vanderbilt University</institution>, Nashville,<addr-line>TN</addr-line> 37235;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Center for Structural Biology,<institution>Vanderbilt University</institution>, Nashville,<addr-line>TN</addr-line> 37235;</nlm:aff></affiliation><affiliation><nlm:aff id="aff9">Department of Chemistry,<institution>Vanderbilt University</institution>, Nashville,<addr-line>TN</addr-line> 37235</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30642961</idno><idno type="pmc">6358683</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358683</idno><idno type="RBID">PMC:6358683</idno><idno type="doi">10.1073/pnas.1806004116</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000C23</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000C23</idno><idno type="wicri:Area/Pmc/Curation">000C23</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000C23</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Multistate design of influenza antibodies improves affinity and breadth against seasonal viruses</title><author><name sortKey="Sevy, Alexander M" sort="Sevy, Alexander M" uniqKey="Sevy A" first="Alexander M." last="Sevy">Alexander M. Sevy</name><affiliation><nlm:aff id="aff1">Chemical & Physical Biology Program,<institution>Vanderbilt University</institution>, Nashville,<addr-line>TN</addr-line> 37235;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Center for Structural Biology,<institution>Vanderbilt University</institution>, Nashville,<addr-line>TN</addr-line> 37235;</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Vanderbilt Vaccine Center,<institution>Vanderbilt University Medical Center</institution>, Nashville,<addr-line>TN</addr-line> 37232;</nlm:aff></affiliation></author><author><name sortKey="Wu, Nicholas C" sort="Wu, Nicholas C" uniqKey="Wu N" first="Nicholas C." last="Wu">Nicholas C. Wu</name><affiliation><nlm:aff id="aff4">Department of Integrative Structural and Computational Biology,<institution>The Scripps Research Institute</institution>, La Jolla,<addr-line>CA</addr-line> 92037;</nlm:aff></affiliation></author><author><name sortKey="Gilchuk, Iuliia M" sort="Gilchuk, Iuliia M" uniqKey="Gilchuk I" first="Iuliia M." last="Gilchuk">Iuliia M. Gilchuk</name><affiliation><nlm:aff id="aff3">Vanderbilt Vaccine Center,<institution>Vanderbilt University Medical Center</institution>, Nashville,<addr-line>TN</addr-line> 37232;</nlm:aff></affiliation></author><author><name sortKey="Parrish, Erica H" sort="Parrish, Erica H" uniqKey="Parrish E" first="Erica H." last="Parrish">Erica H. Parrish</name><affiliation><nlm:aff id="aff3">Vanderbilt Vaccine Center,<institution>Vanderbilt University Medical Center</institution>, Nashville,<addr-line>TN</addr-line> 37232;</nlm:aff></affiliation></author><author><name sortKey="Burger, Sebastian" sort="Burger, Sebastian" uniqKey="Burger S" first="Sebastian" last="Burger">Sebastian Burger</name><affiliation wicri:level="1"><nlm:aff id="aff5">Department of Mathematics,<institution>University of Leipzig</institution>, 04109 Leipzig,<country>Germany</country>;</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Yousif, Dina" sort="Yousif, Dina" uniqKey="Yousif D" first="Dina" last="Yousif">Dina Yousif</name><affiliation><nlm:aff id="aff3">Vanderbilt Vaccine Center,<institution>Vanderbilt University Medical Center</institution>, Nashville,<addr-line>TN</addr-line> 37232;</nlm:aff></affiliation></author><author><name sortKey="Nagel, Marcus B M" sort="Nagel, Marcus B M" uniqKey="Nagel M" first="Marcus B. M." last="Nagel">Marcus B. M. Nagel</name><affiliation><nlm:aff id="aff2">Center for Structural Biology,<institution>Vanderbilt University</institution>, Nashville,<addr-line>TN</addr-line> 37235;</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Vanderbilt Mass Spectrometry Research Center and Department of Biochemistry,<institution>Vanderbilt University School of Medicine</institution>, Nashville,<addr-line>TN</addr-line> 37232;</nlm:aff></affiliation></author><author><name sortKey="Schey, Kevin L" sort="Schey, Kevin L" uniqKey="Schey K" first="Kevin L." last="Schey">Kevin L. Schey</name><affiliation><nlm:aff id="aff6">Vanderbilt Mass Spectrometry Research Center and Department of Biochemistry,<institution>Vanderbilt University School of Medicine</institution>, Nashville,<addr-line>TN</addr-line> 37232;</nlm:aff></affiliation></author><author><name sortKey="Wilson, Ian A" sort="Wilson, Ian A" uniqKey="Wilson I" first="Ian A." last="Wilson">Ian A. Wilson</name><affiliation><nlm:aff id="aff4">Department of Integrative Structural and Computational Biology,<institution>The Scripps Research Institute</institution>, La Jolla,<addr-line>CA</addr-line> 92037;</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">The Skaggs Institute for Chemical Biology,<institution>The Scripps Research Institute</institution>, La Jolla,<addr-line>CA</addr-line> 92037;</nlm:aff></affiliation></author><author><name sortKey="Crowe, James E" sort="Crowe, James E" uniqKey="Crowe J" first="James E." last="Crowe">James E. Crowe</name><affiliation><nlm:aff id="aff1">Chemical & Physical Biology Program,<institution>Vanderbilt University</institution>, Nashville,<addr-line>TN</addr-line> 37235;</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Vanderbilt Vaccine Center,<institution>Vanderbilt University Medical Center</institution>, Nashville,<addr-line>TN</addr-line> 37232;</nlm:aff></affiliation><affiliation><nlm:aff id="aff8">Department of Pediatrics,<institution>Vanderbilt University Medical Center</institution>, Nashville,<addr-line>TN</addr-line> 37232;</nlm:aff></affiliation></author><author><name sortKey="Meiler, Jens" sort="Meiler, Jens" uniqKey="Meiler J" first="Jens" last="Meiler">Jens Meiler</name><affiliation><nlm:aff id="aff1">Chemical & Physical Biology Program,<institution>Vanderbilt University</institution>, Nashville,<addr-line>TN</addr-line> 37235;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Center for Structural Biology,<institution>Vanderbilt University</institution>, Nashville,<addr-line>TN</addr-line> 37235;</nlm:aff></affiliation><affiliation><nlm:aff id="aff9">Department of Chemistry,<institution>Vanderbilt University</institution>, Nashville,<addr-line>TN</addr-line> 37235</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Significance</title><p>Influenza is an annual threat to global public health, in part because of constant antigenic drift that facilitates evasion of the antibody response. Rapid changes in the influenza HA protein make it difficult for an antibody to achieve broad activity against different virus subtypes. We developed a computational method that can optimize an antibody sequence to be robust against seasonal variation. As a proof of concept, we tested this method by redesigning a known antibody against a set of diverse HA antigens and showed that the variant redesigned antibodies have improved activity against the virus panel, as predicted. This work shows that computational design can improve naturally occurring antibodies for recognition of different virus strains.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Rolfes, Ma" uniqKey="Rolfes M">MA Rolfes</name></author><author><name sortKey="Foppa, Im" uniqKey="Foppa I">IM Foppa</name></author><author><name sortKey="Garg, S" uniqKey="Garg S">S Garg</name></author><author><name sortKey="Flannery, B" uniqKey="Flannery B">B Flannery</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Belongia, Ea" uniqKey="Belongia E">EA Belongia</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ekiert, Dc" uniqKey="Ekiert D">DC Ekiert</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Krause, Jc" uniqKey="Krause J">JC Krause</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Whittle, Jrr" uniqKey="Whittle 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="iso-abbrev">Proc. Natl. Acad. Sci. U.S.A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30642961</article-id><article-id pub-id-type="pmc">6358683</article-id><article-id pub-id-type="publisher-id">201806004</article-id><article-id pub-id-type="doi">10.1073/pnas.1806004116</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Biophysics and Computational Biology</subject></subj-group></subj-group></article-categories><title-group><article-title>Multistate design of influenza antibodies improves affinity and breadth against seasonal viruses</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0002-2380-2861</contrib-id><name><surname>Sevy</surname><given-names>Alexander M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wu</surname><given-names>Nicholas C.</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gilchuk</surname><given-names>Iuliia M.</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Parrish</surname><given-names>Erica H.</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Burger</surname><given-names>Sebastian</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yousif</surname><given-names>Dina</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nagel</surname><given-names>Marcus B. M.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="aff" rid="aff6"><sup>f</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schey</surname><given-names>Kevin L.</given-names></name><xref ref-type="aff" rid="aff6"><sup>f</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wilson</surname><given-names>Ian A.</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref><xref ref-type="aff" rid="aff7"><sup>g</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0002-0049-1079</contrib-id><name><surname>Crowe</surname><given-names>James E.</given-names><suffix>Jr.</suffix></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff3"><sup>c</sup></xref><xref ref-type="aff" rid="aff8"><sup>h</sup></xref><xref ref-type="corresp" rid="cor1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Meiler</surname><given-names>Jens</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="aff" rid="aff9"><sup>i</sup></xref><xref ref-type="corresp" rid="cor1"><sup>1</sup></xref></contrib><aff id="aff1"><sup>a</sup>Chemical & Physical Biology Program,<institution>Vanderbilt University</institution>, Nashville,<addr-line>TN</addr-line> 37235;</aff><aff id="aff2"><sup>b</sup>Center for Structural Biology,<institution>Vanderbilt University</institution>, Nashville,<addr-line>TN</addr-line> 37235;</aff><aff id="aff3"><sup>c</sup>Vanderbilt Vaccine Center,<institution>Vanderbilt University Medical Center</institution>, Nashville,<addr-line>TN</addr-line> 37232;</aff><aff id="aff4"><sup>d</sup>Department of Integrative Structural and Computational Biology,<institution>The Scripps Research Institute</institution>, La Jolla,<addr-line>CA</addr-line> 92037;</aff><aff id="aff5"><sup>e</sup>Department of Mathematics,<institution>University of Leipzig</institution>, 04109 Leipzig,<country>Germany</country>;</aff><aff id="aff6"><sup>f</sup>Vanderbilt Mass Spectrometry Research Center and Department of Biochemistry,<institution>Vanderbilt University School of Medicine</institution>, Nashville,<addr-line>TN</addr-line> 37232;</aff><aff id="aff7"><sup>g</sup>The Skaggs Institute for Chemical Biology,<institution>The Scripps Research Institute</institution>, La Jolla,<addr-line>CA</addr-line> 92037;</aff><aff id="aff8"><sup>h</sup>Department of Pediatrics,<institution>Vanderbilt University Medical Center</institution>, Nashville,<addr-line>TN</addr-line> 37232;</aff><aff id="aff9"><sup>i</sup>Department of Chemistry,<institution>Vanderbilt University</institution>, Nashville,<addr-line>TN</addr-line> 37235</aff></contrib-group><author-notes><corresp id="cor1"><sup>1</sup>To whom correspondence may be addressed. Email: <email>james.crowe@vanderbilt.edu</email> or <email>jens.meiler@vanderbilt.edu</email>.</corresp><fn fn-type="edited-by"><p>Edited by David Baker, University of Washington, Seattle, WA, and approved December 6, 2018 (received for review April 9, 2018)</p></fn><fn fn-type="con"><p>Author contributions: A.M.S., J.E.C., and J.M. designed research; A.M.S., N.C.W., I.M.G., E.H.P., S.B., D.Y., and M.B.M.N. performed research; A.M.S. contributed new reagents/analytic tools; A.M.S., N.C.W., I.M.G., S.B., M.B.M.N., K.L.S., I.A.W., J.E.C., and J.M. analyzed data; and A.M.S., J.E.C., and J.M. wrote the paper.</p></fn></author-notes><pub-date pub-type="ppub"><day>29</day><month>1</month><year>2019</year></pub-date><pub-date pub-type="epub"><day>14</day><month>1</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>14</day><month>1</month><year>2019</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>116</volume><issue>5</issue><fpage>1597</fpage><lpage>1602</lpage><permissions><copyright-statement>Copyright © 2019 the Author(s). Published by PNAS.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by-nc-nd/4.0/"><ali:license_ref specific-use="vor"></ali:license_ref><license-p>This open access article is distributed under <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by-nc-nd/4.0/">Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND)</ext-link>.</license-p></license></permissions><self-uri xlink:title="pdf" xlink:href="pnas.201806004.pdf"></self-uri><abstract abstract-type="executive-summary"><title>Significance</title><p>Influenza is an annual threat to global public health, in part because of constant antigenic drift that facilitates evasion of the antibody response. Rapid changes in the influenza HA protein make it difficult for an antibody to achieve broad activity against different virus subtypes. We developed a computational method that can optimize an antibody sequence to be robust against seasonal variation. As a proof of concept, we tested this method by redesigning a known antibody against a set of diverse HA antigens and showed that the variant redesigned antibodies have improved activity against the virus panel, as predicted. This work shows that computational design can improve naturally occurring antibodies for recognition of different virus strains.</p></abstract><abstract><p>Influenza is a yearly threat to global public health. Rapid changes in influenza surface proteins resulting from antigenic drift and shift events make it difficult to readily identify antibodies with broadly neutralizing activity against different influenza subtypes with high frequency, specifically antibodies targeting the receptor binding domain (RBD) on influenza HA protein. We developed an optimized computational design method that is able to optimize an antibody for recognition of large panels of antigens. To demonstrate the utility of this multistate design method, we used it to redesign an antiinfluenza antibody against a large panel of more than 500 seasonal HA antigens of the H1 subtype. As a proof of concept, we tested this method on a variety of known antiinfluenza antibodies and identified those that could be improved computationally. We generated redesigned variants of antibody C05 to the HA RBD and experimentally characterized variants that exhibited improved breadth and affinity against our panel. C05 mutants exhibited improved affinity for three of the subtypes used in design by stabilizing the CDRH3 loop and creating favorable electrostatic interactions with the antigen. These mutants possess increased breadth and affinity of binding while maintaining high-affinity binding to existing targets, surpassing a major limitation up to this point.</p></abstract><kwd-group><kwd>influenza</kwd><kwd>antibody design</kwd><kwd>multistate design</kwd><kwd>broadly neutralizing antibodies</kwd></kwd-group><funding-group><award-group id="gs1"><funding-source id="sp1">HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)<named-content content-type="funder-id">100000060</named-content></funding-source><award-id rid="sp1">U19 AI117905</award-id><principal-award-recipient>Alexander M. Sevy</principal-award-recipient><principal-award-recipient>Iuliia M Gilchuk</principal-award-recipient><principal-award-recipient>Erica H Parrish</principal-award-recipient><principal-award-recipient>Sebastian Burger</principal-award-recipient><principal-award-recipient>Dina Yousif</principal-award-recipient><principal-award-recipient>James E. Crowe, Jr.</principal-award-recipient><principal-award-recipient>Jens Meiler</principal-award-recipient></award-group><award-group id="gs2"><funding-source id="sp2">Vanderbilt University<named-content content-type="funder-id">100006537</named-content></funding-source><award-id rid="sp2">Trans-Institutional Program</award-id><principal-award-recipient>Marcus BM Nagel</principal-award-recipient><principal-award-recipient>Kevin L Schey</principal-award-recipient><principal-award-recipient>James E. Crowe, Jr.</principal-award-recipient><principal-award-recipient>Jens Meiler</principal-award-recipient></award-group></funding-group><counts><page-count count="6"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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