Development and Characterization of a Severe Acute Respiratory Syndrome—Associated Coronavirus—Neutralizing Human Monoclonal Antibody That Provides Effective Immunoprophylaxis in Mice
Identifieur interne : 000116 ( Istex/Curation ); précédent : 000115; suivant : 000117Development and Characterization of a Severe Acute Respiratory Syndrome—Associated Coronavirus—Neutralizing Human Monoclonal Antibody That Provides Effective Immunoprophylaxis in Mice
Auteurs : Thomas C. Greenough ; Gregory J. Babcock ; Anjeanette Roberts [États-Unis] ; Hector J. Hernandez ; William D. Thomas ; Jennifer A. Coccia ; Robert F. Graziano [États-Unis] ; Mohan Srinivasan [États-Unis] ; Israel Lowy [États-Unis] ; Robert W. Finberg ; Kanta Subbarao [États-Unis] ; Leatrice Vogel [États-Unis] ; Mohan Somasundaran ; Katherine Luzuriaga ; John L. Sullivan ; Donna M. Ambrosino [États-Unis]Source :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2005.
Abstract
Background. Severe acute respiratory syndrome (SARS) remains a significant public health concern after the epidemic in 2003. Human monoclonal antibodies (MAbs) that neutralize SARS-associated coronavirus (SARSCoV) could provide protection for exposed individuals. Methods. Transgenic mice with human immunoglobulin genes were immunized with the recombinant major surface (S) glycoprotein ectodomain of SARS-CoV. Epitopes of 2 neutralizing MAbs derived from these mice were mapped and evaluated in a murine model of SARS-CoV infection. Results. Both MAbs bound to S glycoprotein expressed on transfected cells but differed in their ability to block binding of S glycoprotein to Vero E6 cells. Immunoprecipitation analysis revealed 2 antibody-binding epitopes: one MAb (201) bound within the receptor-binding domain at aa 490–510, and the other MAb (68) bound externally to the domain at aa 130–150. Mice that received 40 mg/kg of either MAb prior to challenge with SARS-CoV were completely protected from virus replication in the lungs, and doses as low as 1.6 mg/kg offered significant protection. Conclusions. Two neutralizing epitopes were defined for MAbs to SARS-CoV S glycoprotein. Antibodies to both epitopes protected mice against SARS-CoV challenge. Clinical trials are planned to test MAb 201, a fully human MAb specific for the epitope within the receptor-binding region.
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DOI: 10.1086/427242
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Thomas C. Greenough<affiliation><mods:affiliation>Departments of Pediatrics and Medicine, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester</mods:affiliation><wicri:noCountry code="subField">Worcester</wicri:noCountry></affiliation><affiliation><mods:affiliation>Massachusetts Biologic Laboratories, University of Massachusetts Medical School, Jamaica Plain</mods:affiliation><wicri:noCountry code="subField">Plain</wicri:noCountry></affiliation><affiliation><mods:affiliation>Massachusetts Biologic Laboratories, University of Massachusetts Medical School, Jamaica Plain</mods:affiliation><wicri:noCountry code="subField">Plain</wicri:noCountry></affiliation><affiliation><mods:affiliation>Massachusetts Biologic Laboratories, University of Massachusetts Medical School, Jamaica Plain</mods:affiliation><wicri:noCountry code="subField">Plain</wicri:noCountry></affiliation><affiliation><mods:affiliation>Massachusetts Biologic Laboratories, University of Massachusetts Medical School, Jamaica Plain</mods:affiliation><wicri:noCountry code="subField">Plain</wicri:noCountry></affiliation><affiliation><mods:affiliation>Departments of Pediatrics and Medicine, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester</mods:affiliation><wicri:noCountry code="subField">Worcester</wicri:noCountry></affiliation><affiliation><mods:affiliation>Departments of Pediatrics and Medicine, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester</mods:affiliation><wicri:noCountry code="subField">Worcester</wicri:noCountry></affiliation><affiliation><mods:affiliation>Departments of Pediatrics and Medicine, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester</mods:affiliation><wicri:noCountry code="subField">Worcester</wicri:noCountry></affiliation><affiliation><mods:affiliation>Departments of Pediatrics and Medicine, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester</mods:affiliation><wicri:noCountry code="subField">Worcester</wicri:noCountry></affiliation>Le document en format XML
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Greenough</name><affiliation><mods:affiliation>Departments of Pediatrics and Medicine, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester</mods:affiliation><wicri:noCountry code="subField">Worcester</wicri:noCountry></affiliation></author><author><name sortKey="Babcock, Gregory J" sort="Babcock, Gregory J" uniqKey="Babcock G" first="Gregory J." last="Babcock">Gregory J. Babcock</name><affiliation><mods:affiliation>Massachusetts Biologic Laboratories, University of Massachusetts Medical School, Jamaica Plain</mods:affiliation><wicri:noCountry code="subField">Plain</wicri:noCountry></affiliation></author><author><name sortKey="Roberts, Anjeanette" sort="Roberts, Anjeanette" uniqKey="Roberts A" first="Anjeanette" last="Roberts">Anjeanette Roberts</name><affiliation wicri:level="2"><mods:affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</mods:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Hernandez, Hector J" sort="Hernandez, Hector J" uniqKey="Hernandez H" first="Hector J." last="Hernandez">Hector J. Hernandez</name><affiliation><mods:affiliation>Massachusetts Biologic Laboratories, University of Massachusetts Medical School, Jamaica Plain</mods:affiliation><wicri:noCountry code="subField">Plain</wicri:noCountry></affiliation></author><author><name sortKey="Thomas, William D" sort="Thomas, William D" uniqKey="Thomas W" first="William D." last="Thomas">William D. Thomas</name><affiliation><mods:affiliation>Massachusetts Biologic Laboratories, University of Massachusetts Medical School, Jamaica Plain</mods:affiliation><wicri:noCountry code="subField">Plain</wicri:noCountry></affiliation></author><author><name sortKey="Coccia, Jennifer A" sort="Coccia, Jennifer A" uniqKey="Coccia J" first="Jennifer A." last="Coccia">Jennifer A. Coccia</name><affiliation><mods:affiliation>Massachusetts Biologic Laboratories, University of Massachusetts Medical School, Jamaica Plain</mods:affiliation><wicri:noCountry code="subField">Plain</wicri:noCountry></affiliation></author><author><name sortKey="Graziano, Robert F" sort="Graziano, Robert F" uniqKey="Graziano R" first="Robert F." last="Graziano">Robert F. Graziano</name><affiliation wicri:level="2"><mods:affiliation>Medarex, Inc., Bloomsbury, New Jersey</mods:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">New Jersey</region></placeName><wicri:cityArea>Medarex, Inc., Bloomsbury</wicri:cityArea></affiliation></author><author><name sortKey="Srinivasan, Mohan" sort="Srinivasan, Mohan" uniqKey="Srinivasan M" first="Mohan" last="Srinivasan">Mohan Srinivasan</name><affiliation wicri:level="2"><mods:affiliation>Medarex, Inc., Bloomsbury, New Jersey</mods:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">New Jersey</region></placeName><wicri:cityArea>Medarex, Inc., Bloomsbury</wicri:cityArea></affiliation></author><author><name sortKey="Lowy, Israel" sort="Lowy, Israel" uniqKey="Lowy I" first="Israel" last="Lowy">Israel Lowy</name><affiliation wicri:level="2"><mods:affiliation>Medarex, Inc., Bloomsbury, New Jersey</mods:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">New Jersey</region></placeName><wicri:cityArea>Medarex, Inc., Bloomsbury</wicri:cityArea></affiliation></author><author><name sortKey="Finberg, Robert W" sort="Finberg, Robert W" uniqKey="Finberg R" first="Robert W" last="Finberg">Robert W. Finberg</name><affiliation><mods:affiliation>Departments of Pediatrics and Medicine, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester</mods:affiliation><wicri:noCountry code="subField">Worcester</wicri:noCountry></affiliation></author><author><name sortKey="Subbarao, Kanta" sort="Subbarao, Kanta" uniqKey="Subbarao K" first="Kanta" last="Subbarao">Kanta Subbarao</name><affiliation wicri:level="2"><mods:affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</mods:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Vogel, Leatrice" sort="Vogel, Leatrice" uniqKey="Vogel L" first="Leatrice" last="Vogel">Leatrice Vogel</name><affiliation wicri:level="2"><mods:affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</mods:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Somasundaran, Mohan" sort="Somasundaran, Mohan" uniqKey="Somasundaran M" first="Mohan" last="Somasundaran">Mohan Somasundaran</name><affiliation><mods:affiliation>Departments of Pediatrics and Medicine, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester</mods:affiliation><wicri:noCountry code="subField">Worcester</wicri:noCountry></affiliation></author><author><name sortKey="Luzuriaga, Katherine" sort="Luzuriaga, Katherine" uniqKey="Luzuriaga K" first="Katherine" last="Luzuriaga">Katherine Luzuriaga</name><affiliation><mods:affiliation>Departments of Pediatrics and Medicine, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester</mods:affiliation><wicri:noCountry code="subField">Worcester</wicri:noCountry></affiliation></author><author><name sortKey="Sullivan, John L" sort="Sullivan, John L" uniqKey="Sullivan J" first="John L." last="Sullivan">John L. Sullivan</name><affiliation><mods:affiliation>Departments of Pediatrics and Medicine, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester</mods:affiliation><wicri:noCountry code="subField">Worcester</wicri:noCountry></affiliation></author><author><name sortKey="Ambrosino, Donna M" sort="Ambrosino, Donna M" uniqKey="Ambrosino D" first="Donna M." last="Ambrosino">Donna M. Ambrosino</name><affiliation><mods:affiliation>Massachusetts Biologic Laboratories, University of Massachusetts Medical School, Jamaica Plain</mods:affiliation></affiliation><affiliation wicri:level="1"><mods:affiliation>E-mail: donna.ambrosino@umassmed.edu</mods:affiliation><country wicri:rule="url">États-Unis</country></affiliation><affiliation wicri:level="2"><mods:affiliation>Reprints or correspondence: Dr. Donna M. Ambrosino, Massachusetts Biologic Laboratories, 305 South St., Jamaica Plain, MA 02130 (donna.ambrosino@umassmed.edu).</mods:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Reprints or correspondence: Dr. Donna M. Ambrosino, Massachusetts Biologic Laboratories, 305 South St., Jamaica Plain</wicri:cityArea></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">The Journal of Infectious Diseases</title><title level="j" type="abbrev">The Journal of Infectious Diseases</title><idno type="ISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><publisher>The University of Chicago Press</publisher><date type="published">2005</date><biblScope unit="vol">191</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="507">507</biblScope><biblScope unit="page" to="514">514</biblScope></imprint><idno type="ISSN">0022-1899</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-1899</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Background. Severe acute respiratory syndrome (SARS) remains a significant public health concern after the epidemic in 2003. Human monoclonal antibodies (MAbs) that neutralize SARS-associated coronavirus (SARSCoV) could provide protection for exposed individuals. Methods. Transgenic mice with human immunoglobulin genes were immunized with the recombinant major surface (S) glycoprotein ectodomain of SARS-CoV. Epitopes of 2 neutralizing MAbs derived from these mice were mapped and evaluated in a murine model of SARS-CoV infection. Results. Both MAbs bound to S glycoprotein expressed on transfected cells but differed in their ability to block binding of S glycoprotein to Vero E6 cells. Immunoprecipitation analysis revealed 2 antibody-binding epitopes: one MAb (201) bound within the receptor-binding domain at aa 490–510, and the other MAb (68) bound externally to the domain at aa 130–150. Mice that received 40 mg/kg of either MAb prior to challenge with SARS-CoV were completely protected from virus replication in the lungs, and doses as low as 1.6 mg/kg offered significant protection. Conclusions. Two neutralizing epitopes were defined for MAbs to SARS-CoV S glycoprotein. Antibodies to both epitopes protected mice against SARS-CoV challenge. Clinical trials are planned to test MAb 201, a fully human MAb specific for the epitope within the receptor-binding region.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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