Therapeutic efficacy of antibodies lacking FcγR against lethal dengue virus infection is due to neutralizing potency and blocking of enhancing antibodies

Williams, Katherine L.; Sukupolvi-Petty, Soila; Beltramello, Martina; Johnson, Syd; Sallusto, Federica; Lanzavecchia, Antonio; Diamond, Michael S.; Harris, Eva

doi:10.1371/journal.ppat.1003157

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Journal article

Therapeutic efficacy of antibodies lacking FcγR against lethal dengue virus infection is due to neutralizing potency and blocking of enhancing antibodies

Williams, Katherine L. Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, California, United States of America
Sukupolvi-Petty, Soila Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
Beltramello, Martina Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Johnson, Syd Macrogenics, Inc., Rockville, Maryland, United States of America
Sallusto, Federica Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Lanzavecchia, Antonio Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Diamond, Michael S. Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
Harris, Eva Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, California, United States of America

14.02.2013

Published in:

Plos pathogens. - 2013, vol. 9, no. 2, p. e1003157

English Dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) are life-threatening complications following infection with one of the four serotypes of dengue virus (DENV). At present, no vaccine or antiviral therapies are available against dengue. Here, we characterized a panel of eight human or mouse-human chimeric monoclonal antibodies (MAbs) and their modified variants lacking effector function and dissected the mechanism by which some protect against antibody-enhanced lethal DENV infection. We found that neutralizing modified MAbs that recognize the fusion loop or the A strand epitopes on domains II and III of the envelope protein, respectively, act therapeutically by competing with and/or displacing enhancing antibodies. By analyzing these relationships, we developed a novel in vitro suppression-of- enhancement assay that predicts the ability of modified MAbs to act therapeutically against antibody-enhanced disease in vivo. These studies provide new insight into the biology of DENV pathogenesis and the requirements for antibodies to treat lethal DENV disease.

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