Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/86830
Title: Molecular basis for dengue virus broad cross-neutralization by humanized monoclonal antibody 513
Authors: Wong, Yee Hwa
Kumar, Akshita
Liew, Chong Wai
Tharakaraman, Kannan
Srinivasaraghavan, Kannan
Sasisekharan, Ram
Verma, Chandra
Lescar, Julien
Keywords: Dengue Virus
Humanized Monoclonal Antibody 513
Issue Date: 2018
Source: Wong, Y. H., Kumar, A., Liew, C. W., Tharakaraman, K., Srinivasaraghavan, K., Sasisekharan, R., et al. (2018). Molecular basis for dengue virus broad cross-neutralization by humanized monoclonal antibody 513. Scientific Reports, 8(1), 8449-.
Series/Report no.: Scientific Reports
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 GluH55 using site-directed mutagenesis followed by isothermal titration calorimetry measurements.
URI: https://hdl.handle.net/10356/86830
http://hdl.handle.net/10220/45324
ISSN: 2045-2322
DOI: 10.1038/s41598-018-26800-y
Rights: © 2018 The Author(s) (Nature Publishing Group). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

Google ScholarTM

Check

Altmetric


Plumx

Items in DR-NTU are protected by copyright, with all rights reserved, unless otherwise indicated.