Molecular basis for dengue virus broad cross-neutralization by humanized monoclonal antibody 513
Name
s41598-018-26800-y.pdf
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6.5 MB
Format
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Checksum (MD5)
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Author(s)
Wong, Yee Hwa
Kumar, Akshita
Liew, Chong Wai
Tharakaraman, Kannan
Srinivasaraghavan, Kannan
Sasisekharan, Ram
Verma, Chandra
Lescar, Julien
Date Issued
May 2018
Journal
Scientific Reports
Publisher
Nature Publishing Group
Citation
Wong, Yee Hwa et al. “Molecular Basis for Dengue Virus Broad Cross-Neutralization by Humanized Monoclonal Antibody 513.” Scientific Reports 8, 1 (May 2018): © 2018 The Author(s)
Version
Final published version
Abstract
Dengue is a widespread viral disease with 3.6 billion people at risk worldwide. Humanized monoclonal antibody (mAb) 513, currently undergoing clinical trials in Singapore, targets an epitope on the envelope protein domain III exposed at the surface of the viral particle. This antibody potently neutralizes all four dengue virus serotypes in a humanized mouse model that recapitulates human dengue infection, without signs of antibody-mediated enhancement of the disease. The crystal structure of single-chain variable fragment (scFv) 513 bound to the envelope protein domain III from dengue virus serotype 4 was used as a template to explore the molecular origins of the broader cross-reactivity and increased in vivo potency of mAb 513, compared to the parent murine mAb 4E11, using molecular dynamics simulations and network analyses. These two methods are a powerful complement to existing structural and binding data and detail specific interactions that underpin the differential binding of the two antibodies. We found that a Glu at position H55 (GluH55) from the second Complementarity Determining Region of the Heavy chain (CDR-H2) which corresponds to Ala in 4E11, is a major contributor to the enhancement in the interactions of mAb 513 compared to 4E11. Importantly, we also validate the importance of GluH55using site-directed mutagenesis followed by isothermal titration calorimetry measurements.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Terms of Use
Creative Commons Attribution 4.0 International License
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DOI of Published Version
https://doi.org/10.1038/s41598-018-26800-y
