Potent Dengue Virus Neutralization by a Therapeutic Antibody with Low Monovalent Affinity Requires Bivalent Engagement

PLoS Pathogens

Daved H. Fremont¹  Melissa A. Edeling²  S. Kyle Austin²  Bimmi Shrestha²  Michael S. Diamond²  Christopher A. Nelson²  Elizabeth A. Christian³  Manu N. Mabila³  Joseph Rucker³  Syd Johnson⁴  Kimberly A. Dowd⁵  Swati Mukherjee⁵  Theodore C. Pierson⁵ 

[1] Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America;Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America;Integral Molecular, Philadelphia, Pennsylvania, United States of America;MacroGenics, Rockville, Maryland, United States of America;Viral Pathogenesis Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America

关键词: Virions;    West Nile virus;    Antibodies;    Dengue virus;    Flaviviruses;    Enzyme-linked immunoassays;    Crystal structure;    Viral envelope;   

DOI  :  10.1371/journal.ppat.1004072

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

We recently described our most potently neutralizing monoclonal antibody, E106, which protected against lethal Dengue virus type 1 (DENV-1) infection in mice. To further understand its functional properties, we determined the crystal structure of E106 Fab in complex with domain III (DIII) of DENV-1 envelope (E) protein to 2.45 Å resolution. Analysis of the complex revealed a small antibody-antigen interface with the epitope on DIII composed of nine residues along the lateral ridge and A-strand regions. Despite strong virus neutralizing activity of E106 IgG at picomolar concentrations, E106 Fab exhibited a ∼20,000-fold decrease in virus neutralization and bound isolated DIII, E, or viral particles with only a micromolar monovalent affinity. In comparison, E106 IgG bound DENV-1 virions with nanomolar avidity. The E106 epitope appears readily accessible on virions, as neutralization was largely temperature-independent. Collectively, our data suggest that E106 neutralizes DENV-1 infection through bivalent engagement of adjacent DIII subunits on a single virion. The isolation of anti-flavivirus antibodies that require bivalent binding to inhibit infection efficiently may be a rare event due to the unique icosahedral arrangement of envelope proteins on the virion surface.

【 授权许可】

CC BY