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Cell. 2015 Jul 30;162(3):493-504. doi: 10.1016/j.cell.2015.06.057. Epub 2015 Jul 16.

Structure-Guided Design of an Anti-dengue Antibody Directed to a Non-immunodominant Epitope.

Author information

  • 1Visterra Inc., One Kendall Square, Suite B3301, Cambridge, MA 02139, USA; Department of Biological Engineering, Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge MA 02139; USA.
  • 2Department of Biological Engineering, Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge MA 02139; USA.
  • 3Visterra Inc., One Kendall Square, Suite B3301, Cambridge, MA 02139, USA.
  • 4Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore.
  • 5Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857.
  • 6School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
  • 7Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore; Department of Microbiology, National University of Singapore, 5 Science Drive 2, Blk MD4, Level 3, Singapore 117545.
  • 8Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore; Department of Biology, Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge MA 02139, USA.
  • 9Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore; Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857.
  • 10Department of Biological Engineering, Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge MA 02139; USA; Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore. Electronic address: rams@mit.edu.

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.

PMID:
26189681
PMCID:
PMC4758460
DOI:
10.1016/j.cell.2015.06.057
[PubMed - indexed for MEDLINE]
Free PMC Article
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