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Molecular basis for dengue virus broad cross-neutralization by humanized monoclonal antibody 513
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Molecular basis for dengue virus broad cross-neutralization by humanized monoclonal antibody 513
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Journal Article
Molecular basis for dengue virus broad cross-neutralization by humanized monoclonal antibody 513
2018
Overview
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 (Glu
H55
) 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 Glu
H55
using site-directed mutagenesis followed by isothermal titration calorimetry measurements.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
