Your browser doesn't support javascript.
loading
Analysis of a Therapeutic Antibody Cocktail Reveals Determinants for Cooperative and Broad Ebolavirus Neutralization.
Gilchuk, Pavlo; Murin, Charles D; Milligan, Jacob C; Cross, Robert W; Mire, Chad E; Ilinykh, Philipp A; Huang, Kai; Kuzmina, Natalia; Altman, Pilar X; Hui, Sean; Gunn, Bronwyn M; Bryan, Aubrey L; Davidson, Edgar; Doranz, Benjamin J; Turner, Hannah L; Alkutkar, Tanwee; Flinko, Robin; Orlandi, Chiara; Carnahan, Robert; Nargi, Rachel; Bombardi, Robin G; Vodzak, Megan E; Li, Sheng; Okoli, Adaora; Ibeawuchi, Morris; Ohiaeri, Benjamin; Lewis, George K; Alter, Galit; Bukreyev, Alexander; Saphire, Erica Ollmann; Geisbert, Thomas W; Ward, Andrew B; Crowe, James E.
Afiliação
  • Gilchuk P; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Murin CD; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • Milligan JC; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • Cross RW; Galveston National Laboratory, Galveston, TX 77550, USA; Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • Mire CE; Galveston National Laboratory, Galveston, TX 77550, USA; Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • Ilinykh PA; Galveston National Laboratory, Galveston, TX 77550, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • Huang K; Galveston National Laboratory, Galveston, TX 77550, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • Kuzmina N; Galveston National Laboratory, Galveston, TX 77550, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • Altman PX; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • Hui S; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • Gunn BM; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
  • Bryan AL; Integral Molecular, Inc., Philadelphia, PA 19104, USA.
  • Davidson E; Integral Molecular, Inc., Philadelphia, PA 19104, USA.
  • Doranz BJ; Integral Molecular, Inc., Philadelphia, PA 19104, USA.
  • Turner HL; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • Alkutkar T; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • Flinko R; Division of Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • Orlandi C; Division of Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • Carnahan R; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Nargi R; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Bombardi RG; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Vodzak ME; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Li S; Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA.
  • Okoli A; First Consultants Medical Center, Lagos, Nigeria.
  • Ibeawuchi M; First Consultants Medical Center, Lagos, Nigeria.
  • Ohiaeri B; First Consultants Medical Center, Lagos, Nigeria.
  • Lewis GK; Division of Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • Alter G; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
  • Bukreyev A; Galveston National Laboratory, Galveston, TX 77550, USA; Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • Saphire EO; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • Geisbert TW; Galveston National Laboratory, Galveston, TX 77550, USA; Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • Ward AB; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • Crowe JE; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Immunity ; 52(2): 388-403.e12, 2020 02 18.
Article em En | MEDLINE | ID: mdl-32023489
ABSTRACT
Structural principles underlying the composition of protective antiviral monoclonal antibody (mAb) cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic mAb cocktail against Ebola virus. We systematically analyzed the antibody repertoire in human survivors and identified a pair of potently neutralizing mAbs that cooperatively bound to the ebolavirus glycoprotein (GP). High-resolution structures revealed that in a two-antibody cocktail, molecular mimicry was a major feature of mAb-GP interactions. Broadly neutralizing mAb rEBOV-520 targeted a conserved epitope on the GP base region. mAb rEBOV-548 bound to a glycan cap epitope, possessed neutralizing and Fc-mediated effector function activities, and potentiated neutralization by rEBOV-520. Remodeling of the glycan cap structures by the cocktail enabled enhanced GP binding and virus neutralization. The cocktail demonstrated resistance to virus escape and protected non-human primates (NHPs) against Ebola virus disease. These data illuminate structural principles of antibody cooperativity with implications for development of antiviral immunotherapeutics.
Assuntos
Palavras-chave
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Glicoproteínas / Doença pelo Vírus Ebola / Ebolavirus / Anticorpos Neutralizantes / Anticorpos Monoclonais / Anticorpos Antivirais Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Glicoproteínas / Doença pelo Vírus Ebola / Ebolavirus / Anticorpos Neutralizantes / Anticorpos Monoclonais / Anticorpos Antivirais Idioma: En Ano de publicação: 2020 Tipo de documento: Article