A Fc engineering approach to define functional humoral correlates of immunity against Ebola virus
Protective Ebola virus (EBOV) antibodies have neutralizing activity and induction of antibody constant domain (Fc)-mediated innate immune effector functions. Efforts to enhance Fc effector functionality often focus on maximizing antibody-dependent cellular cytotoxicity, yet distinct combinations of...
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| Veröffentlicht in: | Immunity (Cambridge, Mass.) Mass.), 2021-04, Vol.54 (4), p.815-828.e5 |
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| creator | Gunn, Bronwyn M. Lu, Richard Slein, Matthew D. Ilinykh, Philipp A. Huang, Kai Atyeo, Caroline Schendel, Sharon L. Kim, Jiyoung Cain, Caitlin Roy, Vicky Suscovich, Todd J. Takada, Ayato Halfmann, Peter J. Kawaoka, Yoshihiro Pauthner, Matthias G. Momoh, Mambu Goba, Augustine Kanneh, Lansana Andersen, Kristian G. Schieffelin, John S. Grant, Donald Garry, Robert F. Saphire, Erica Ollmann Bukreyev, Alexander Alter, Galit |
| description | Protective Ebola virus (EBOV) antibodies have neutralizing activity and induction of antibody constant domain (Fc)-mediated innate immune effector functions. Efforts to enhance Fc effector functionality often focus on maximizing antibody-dependent cellular cytotoxicity, yet distinct combinations of functions could be critical for antibody-mediated protection. As neutralizing antibodies have been cloned from EBOV disease survivors, we sought to identify survivor Fc effector profiles to help guide Fc optimization strategies. Survivors developed a range of functional antibody responses, and we therefore applied a rapid, high-throughput Fc engineering platform to define the most protective profiles. We generated a library of Fc variants with identical antigen-binding fragments (Fabs) from an EBOV neutralizing antibody. Fc variants with antibody-mediated complement deposition and moderate natural killer (NK) cell activity demonstrated complete protective activity in a stringent in vivo mouse model. Our findings highlight the importance of specific effector functions in antibody-mediated protection, and the experimental platform presents a generalizable resource for identifying correlates of immunity to guide therapeutic antibody design.
[Display omitted]
•Ebola virus disease survivors develop diverse profiles of antibody responses•Fc engineering of monoclonal antibodies can replicate human functional profiles•A Fc variant panel was generated using an anti-Ebola virus neutralizing Fab domain•Fc variants with high complement yet moderate ADCC activity were protective in vivo
Gunn et al. profile Ebola virus disease survivors and apply a platform for engineering antibody Fc domains to define protective profiles. Fc variants with complement deposition yet moderate NK cell activity completely protected infected mice from disease. This experimental platform can be used for identifying correlates of immunity to other pathogens and to guide therapeutic antibody design. |
| doi_str_mv | 10.1016/j.immuni.2021.03.009 |
| format | Article |
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[Display omitted]
•Ebola virus disease survivors develop diverse profiles of antibody responses•Fc engineering of monoclonal antibodies can replicate human functional profiles•A Fc variant panel was generated using an anti-Ebola virus neutralizing Fab domain•Fc variants with high complement yet moderate ADCC activity were protective in vivo
Gunn et al. profile Ebola virus disease survivors and apply a platform for engineering antibody Fc domains to define protective profiles. Fc variants with complement deposition yet moderate NK cell activity completely protected infected mice from disease. This experimental platform can be used for identifying correlates of immunity to other pathogens and to guide therapeutic antibody design.</description><identifier>ISSN: 1074-7613</identifier><identifier>EISSN: 1097-4180</identifier><identifier>DOI: 10.1016/j.immuni.2021.03.009</identifier><identifier>PMID: 33852832</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>ADCC ; Animals ; Antibodies ; Antibodies, Neutralizing - immunology ; Antibodies, Viral - immunology ; antibody engineering ; Antibody Formation - immunology ; Antibody-Dependent Cell Cytotoxicity - immunology ; Antigens ; Biocompatibility ; complement ; Cytotoxicity ; Ebola virus ; Ebolavirus ; Ebolavirus - immunology ; Engineering ; Fc effector function ; Female ; HEK293 Cells ; Hemorrhagic Fever, Ebola - immunology ; Hemorrhagic Fever, Ebola - virology ; Humans ; Humoral immunity ; Immunity ; Immunoglobulin Fab Fragments - immunology ; Immunoglobulin Fc Fragments - immunology ; Immunoglobulin G - immunology ; Infections ; Infectious diseases ; Mice ; Mice, Inbred BALB C ; monoclonal antibody therapeutics ; Mutation ; Natural killer cells ; Neutralizing ; Optimization ; Pathogens ; phagocytosis ; Receptors, Fc - immunology ; Survival ; Toxicity ; Viral diseases ; Viruses</subject><ispartof>Immunity (Cambridge, Mass.), 2021-04, Vol.54 (4), p.815-828.e5</ispartof><rights>2021 Elsevier Inc.</rights><rights>Copyright © 2021 Elsevier Inc. All rights reserved.</rights><rights>2021. Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c491t-e92f41594b0b54f7d22bf3e4e35fe3cad8497f43816a342aad08ea3a821d9e9f3</citedby><cites>FETCH-LOGICAL-c491t-e92f41594b0b54f7d22bf3e4e35fe3cad8497f43816a342aad08ea3a821d9e9f3</cites><orcidid>0000-0002-5062-7261 ; 0000-0001-9212-4307 ; 0000-0001-8288-787X ; 0000-0002-1206-7451 ; 0000-0002-0342-4824 ; 0000-0003-4141-275X ; 0000-0002-3373-5594 ; 0000-0002-7489-0232 ; 0000-0002-9811-9792</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.immuni.2021.03.009$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,777,781,882,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33852832$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gunn, Bronwyn M.</creatorcontrib><creatorcontrib>Lu, Richard</creatorcontrib><creatorcontrib>Slein, Matthew D.</creatorcontrib><creatorcontrib>Ilinykh, Philipp A.</creatorcontrib><creatorcontrib>Huang, Kai</creatorcontrib><creatorcontrib>Atyeo, Caroline</creatorcontrib><creatorcontrib>Schendel, Sharon L.</creatorcontrib><creatorcontrib>Kim, Jiyoung</creatorcontrib><creatorcontrib>Cain, Caitlin</creatorcontrib><creatorcontrib>Roy, Vicky</creatorcontrib><creatorcontrib>Suscovich, Todd J.</creatorcontrib><creatorcontrib>Takada, Ayato</creatorcontrib><creatorcontrib>Halfmann, Peter J.</creatorcontrib><creatorcontrib>Kawaoka, Yoshihiro</creatorcontrib><creatorcontrib>Pauthner, Matthias G.</creatorcontrib><creatorcontrib>Momoh, Mambu</creatorcontrib><creatorcontrib>Goba, Augustine</creatorcontrib><creatorcontrib>Kanneh, Lansana</creatorcontrib><creatorcontrib>Andersen, Kristian G.</creatorcontrib><creatorcontrib>Schieffelin, John S.</creatorcontrib><creatorcontrib>Grant, Donald</creatorcontrib><creatorcontrib>Garry, Robert F.</creatorcontrib><creatorcontrib>Saphire, Erica Ollmann</creatorcontrib><creatorcontrib>Bukreyev, Alexander</creatorcontrib><creatorcontrib>Alter, Galit</creatorcontrib><title>A Fc engineering approach to define functional humoral correlates of immunity against Ebola virus</title><title>Immunity (Cambridge, Mass.)</title><addtitle>Immunity</addtitle><description>Protective Ebola virus (EBOV) antibodies have neutralizing activity and induction of antibody constant domain (Fc)-mediated innate immune effector functions. Efforts to enhance Fc effector functionality often focus on maximizing antibody-dependent cellular cytotoxicity, yet distinct combinations of functions could be critical for antibody-mediated protection. As neutralizing antibodies have been cloned from EBOV disease survivors, we sought to identify survivor Fc effector profiles to help guide Fc optimization strategies. Survivors developed a range of functional antibody responses, and we therefore applied a rapid, high-throughput Fc engineering platform to define the most protective profiles. We generated a library of Fc variants with identical antigen-binding fragments (Fabs) from an EBOV neutralizing antibody. Fc variants with antibody-mediated complement deposition and moderate natural killer (NK) cell activity demonstrated complete protective activity in a stringent in vivo mouse model. Our findings highlight the importance of specific effector functions in antibody-mediated protection, and the experimental platform presents a generalizable resource for identifying correlates of immunity to guide therapeutic antibody design.
[Display omitted]
•Ebola virus disease survivors develop diverse profiles of antibody responses•Fc engineering of monoclonal antibodies can replicate human functional profiles•A Fc variant panel was generated using an anti-Ebola virus neutralizing Fab domain•Fc variants with high complement yet moderate ADCC activity were protective in vivo
Gunn et al. profile Ebola virus disease survivors and apply a platform for engineering antibody Fc domains to define protective profiles. Fc variants with complement deposition yet moderate NK cell activity completely protected infected mice from disease. This experimental platform can be used for identifying correlates of immunity to other pathogens and to guide therapeutic antibody design.</description><subject>ADCC</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antibodies, Neutralizing - immunology</subject><subject>Antibodies, Viral - immunology</subject><subject>antibody engineering</subject><subject>Antibody Formation - immunology</subject><subject>Antibody-Dependent Cell Cytotoxicity - immunology</subject><subject>Antigens</subject><subject>Biocompatibility</subject><subject>complement</subject><subject>Cytotoxicity</subject><subject>Ebola virus</subject><subject>Ebolavirus</subject><subject>Ebolavirus - immunology</subject><subject>Engineering</subject><subject>Fc effector function</subject><subject>Female</subject><subject>HEK293 Cells</subject><subject>Hemorrhagic Fever, Ebola - immunology</subject><subject>Hemorrhagic Fever, Ebola - virology</subject><subject>Humans</subject><subject>Humoral immunity</subject><subject>Immunity</subject><subject>Immunoglobulin Fab Fragments - immunology</subject><subject>Immunoglobulin Fc Fragments - immunology</subject><subject>Immunoglobulin G - immunology</subject><subject>Infections</subject><subject>Infectious diseases</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>monoclonal antibody therapeutics</subject><subject>Mutation</subject><subject>Natural killer cells</subject><subject>Neutralizing</subject><subject>Optimization</subject><subject>Pathogens</subject><subject>phagocytosis</subject><subject>Receptors, Fc - immunology</subject><subject>Survival</subject><subject>Toxicity</subject><subject>Viral diseases</subject><subject>Viruses</subject><issn>1074-7613</issn><issn>1097-4180</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UctqHDEQFCEhfuUPQhDkkstM9Jod6RIwxnYChlzis9BoWrtaZqSNpFnw30frtZ3HIaduWtWl6iqE3lPSUkJXn7etn-cl-JYRRlvCW0LUK3RKieobQSV5feh70fQryk_QWc5bQqjoFHmLTjiXHZOcnSJziW8shrD2ASD5sMZmt0vR2A0uEY_g6hy7JdjiYzAT3ixzTLXamBJMpkDG0eGjkvKAzdr4kAu-HuJk8N6nJV-gN85MGd491XN0f3P94-prc_f99tvV5V1jhaKlAcWcoJ0SAxk64fqRscFxEMA7B9yaUQrVO8ElXRkumDEjkWC4kYyOCpTj5-jLkXe3DDOMFkKpQvUu-dmkBx2N13-_BL_R67jXklLar2Ql-PREkOLPBXLRs88WpskEiEvWrKOcCcbkAfrxH-g2Lqn684hinBOmaEWJI8qmmHMC9yKGEn3IUG_10Tl9yFATrmuGde3Dn4e8LD2H9vtSqHbuPSSdrYdgYfQJbNFj9P__4RfdIbEq</recordid><startdate>20210413</startdate><enddate>20210413</enddate><creator>Gunn, Bronwyn M.</creator><creator>Lu, Richard</creator><creator>Slein, Matthew D.</creator><creator>Ilinykh, Philipp A.</creator><creator>Huang, Kai</creator><creator>Atyeo, Caroline</creator><creator>Schendel, Sharon L.</creator><creator>Kim, Jiyoung</creator><creator>Cain, Caitlin</creator><creator>Roy, Vicky</creator><creator>Suscovich, Todd J.</creator><creator>Takada, Ayato</creator><creator>Halfmann, Peter J.</creator><creator>Kawaoka, Yoshihiro</creator><creator>Pauthner, Matthias G.</creator><creator>Momoh, Mambu</creator><creator>Goba, Augustine</creator><creator>Kanneh, Lansana</creator><creator>Andersen, Kristian G.</creator><creator>Schieffelin, John S.</creator><creator>Grant, Donald</creator><creator>Garry, Robert F.</creator><creator>Saphire, Erica Ollmann</creator><creator>Bukreyev, Alexander</creator><creator>Alter, Galit</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5062-7261</orcidid><orcidid>https://orcid.org/0000-0001-9212-4307</orcidid><orcidid>https://orcid.org/0000-0001-8288-787X</orcidid><orcidid>https://orcid.org/0000-0002-1206-7451</orcidid><orcidid>https://orcid.org/0000-0002-0342-4824</orcidid><orcidid>https://orcid.org/0000-0003-4141-275X</orcidid><orcidid>https://orcid.org/0000-0002-3373-5594</orcidid><orcidid>https://orcid.org/0000-0002-7489-0232</orcidid><orcidid>https://orcid.org/0000-0002-9811-9792</orcidid></search><sort><creationdate>20210413</creationdate><title>A Fc engineering approach to define functional humoral correlates of immunity against Ebola virus</title><author>Gunn, Bronwyn M. ; Lu, Richard ; Slein, Matthew D. ; Ilinykh, Philipp A. ; Huang, Kai ; Atyeo, Caroline ; Schendel, Sharon L. ; Kim, Jiyoung ; Cain, Caitlin ; Roy, Vicky ; Suscovich, Todd J. ; Takada, Ayato ; Halfmann, Peter J. ; Kawaoka, Yoshihiro ; Pauthner, Matthias G. ; Momoh, Mambu ; Goba, Augustine ; Kanneh, Lansana ; Andersen, Kristian G. ; Schieffelin, John S. ; Grant, Donald ; Garry, Robert F. ; Saphire, Erica Ollmann ; Bukreyev, Alexander ; Alter, Galit</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c491t-e92f41594b0b54f7d22bf3e4e35fe3cad8497f43816a342aad08ea3a821d9e9f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>ADCC</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antibodies, Neutralizing - 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Efforts to enhance Fc effector functionality often focus on maximizing antibody-dependent cellular cytotoxicity, yet distinct combinations of functions could be critical for antibody-mediated protection. As neutralizing antibodies have been cloned from EBOV disease survivors, we sought to identify survivor Fc effector profiles to help guide Fc optimization strategies. Survivors developed a range of functional antibody responses, and we therefore applied a rapid, high-throughput Fc engineering platform to define the most protective profiles. We generated a library of Fc variants with identical antigen-binding fragments (Fabs) from an EBOV neutralizing antibody. Fc variants with antibody-mediated complement deposition and moderate natural killer (NK) cell activity demonstrated complete protective activity in a stringent in vivo mouse model. Our findings highlight the importance of specific effector functions in antibody-mediated protection, and the experimental platform presents a generalizable resource for identifying correlates of immunity to guide therapeutic antibody design.
[Display omitted]
•Ebola virus disease survivors develop diverse profiles of antibody responses•Fc engineering of monoclonal antibodies can replicate human functional profiles•A Fc variant panel was generated using an anti-Ebola virus neutralizing Fab domain•Fc variants with high complement yet moderate ADCC activity were protective in vivo
Gunn et al. profile Ebola virus disease survivors and apply a platform for engineering antibody Fc domains to define protective profiles. Fc variants with complement deposition yet moderate NK cell activity completely protected infected mice from disease. This experimental platform can be used for identifying correlates of immunity to other pathogens and to guide therapeutic antibody design.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>33852832</pmid><doi>10.1016/j.immuni.2021.03.009</doi><orcidid>https://orcid.org/0000-0002-5062-7261</orcidid><orcidid>https://orcid.org/0000-0001-9212-4307</orcidid><orcidid>https://orcid.org/0000-0001-8288-787X</orcidid><orcidid>https://orcid.org/0000-0002-1206-7451</orcidid><orcidid>https://orcid.org/0000-0002-0342-4824</orcidid><orcidid>https://orcid.org/0000-0003-4141-275X</orcidid><orcidid>https://orcid.org/0000-0002-3373-5594</orcidid><orcidid>https://orcid.org/0000-0002-7489-0232</orcidid><orcidid>https://orcid.org/0000-0002-9811-9792</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1074-7613 |
| ispartof | Immunity (Cambridge, Mass.), 2021-04, Vol.54 (4), p.815-828.e5 |
| issn | 1074-7613 1097-4180 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8111768 |
| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | ADCC Animals Antibodies Antibodies, Neutralizing - immunology Antibodies, Viral - immunology antibody engineering Antibody Formation - immunology Antibody-Dependent Cell Cytotoxicity - immunology Antigens Biocompatibility complement Cytotoxicity Ebola virus Ebolavirus Ebolavirus - immunology Engineering Fc effector function Female HEK293 Cells Hemorrhagic Fever, Ebola - immunology Hemorrhagic Fever, Ebola - virology Humans Humoral immunity Immunity Immunoglobulin Fab Fragments - immunology Immunoglobulin Fc Fragments - immunology Immunoglobulin G - immunology Infections Infectious diseases Mice Mice, Inbred BALB C monoclonal antibody therapeutics Mutation Natural killer cells Neutralizing Optimization Pathogens phagocytosis Receptors, Fc - immunology Survival Toxicity Viral diseases Viruses |
| title | A Fc engineering approach to define functional humoral correlates of immunity against Ebola virus |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-18T13%3A31%3A44IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20Fc%20engineering%20approach%20to%20define%20functional%20humoral%20correlates%20of%20immunity%20against%20Ebola%20virus&rft.jtitle=Immunity%20(Cambridge,%20Mass.)&rft.au=Gunn,%20Bronwyn%20M.&rft.date=2021-04-13&rft.volume=54&rft.issue=4&rft.spage=815&rft.epage=828.e5&rft.pages=815-828.e5&rft.issn=1074-7613&rft.eissn=1097-4180&rft_id=info:doi/10.1016/j.immuni.2021.03.009&rft_dat=%3Cproquest_pubme%3E2512330291%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2512330291&rft_id=info:pmid/33852832&rft_els_id=S1074761321001217&rfr_iscdi=true |