Structure-Guided Design of an Anti-dengue Antibody Directed to a Non-immunodominant Epitope
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Author(s)
Tharakaraman, Kannan
Rowley, Kirk J.
Costa, Vivian V.
Chan, Kuan Rong
Wong, Yee Hwa
Ong, Li Ching
Tan, Hwee Cheng
Koch, Tyree
Viswanathan, Karthik
Liew, Chong Wai
Date Issued
July 2015
Journal
Cell
Publisher
Elsevier
Citation
Robinson, Luke N., Kannan Tharakaraman, Kirk J. Rowley, Vivian V. Costa, Kuan Rong Chan, Yee Hwa Wong, Li Ching Ong, et al. “Structure-Guided Design of an Anti-Dengue Antibody Directed to a Non-Immunodominant Epitope.” Cell 162, no. 3 (July 2015): 493–504.
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Author's final manuscript
Abstract
Dengue is the most common vector-borne viral disease, causing nearly 400 million infections yearly. Currently there are no approved therapies. Antibody epitopes that elicit weak humoral responses may not be accessible by conventional B cell panning methods. To demonstrate an alternative strategy to generating a therapeutic antibody, we employed a non-immunodominant, but functionally relevant, epitope in domain III of the E protein, and engineered by structure-guided methods an antibody directed to it. The resulting antibody, Ab513, exhibits high-affinity binding to, and broadly neutralizes, multiple genotypes within all four serotypes. To assess therapeutic relevance of Ab513, activity against important human clinical features of dengue was investigated. Ab513 mitigates thrombocytopenia in a humanized mouse model, resolves vascular leakage, reduces viremia to nearly undetectable levels, and protects mice in a maternal transfer model of lethal antibody-mediated enhancement. The results demonstrate that Ab513 may reduce the public health burden from dengue.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1016/j.cell.2015.06.057
