Development of a Humanized Antibody with High Therapeutic Potential against Dengue Virus Type 2

Details

• Alternative Title:
  PLoS Negl Trop Dis
• Personal Author:
  Li, Pi-Chun ; Liao, Mei-Ying ; Cheng, Ping-Chang ; Liang, Jian-Jong ; Liu, I-Ju ; Chiu, Chien-Yu ; Lin, Yi-Ling ; Chang, Gwong-Jen J. ; Wu, Han-Chung
• Description:
  Background
  
  Dengue virus (DENV) is a significant public health threat in tropical and subtropical regions of the world. A therapeutic antibody against the viral envelope (E) protein represents a promising immunotherapy for disease control.
  
  Methodology/Principal Findings
  
  We generated seventeen novel mouse monoclonal antibodies (mAbs) with high reactivity against E protein of dengue virus type 2 (DENV-2). The mAbs were further dissected using recombinant E protein domain I-II (E-DI-II) and III (E-DIII) of DENV-2. Using plaque reduction neutralization test (PRNT) and mouse protection assay with lethal doses of DENV-2, we identified four serotype-specific mAbs that had high neutralizing activity against DENV-2 infection. Of the four, E-DIII targeting mAb DB32-6 was the strongest neutralizing mAb against diverse DENV-2 strains. Using phage display and virus-like particles (VLPs) we found that residue K310 in the E-DIII A-strand was key to mAb DB32-6 binding E-DIII. We successfully converted DB32-6 to a humanized version that retained potency for the neutralization of DENV-2 and did not enhance the viral infection. The DB32-6 showed therapeutic efficacy against mortality induced by different strains of DENV-2 in two mouse models even in post-exposure trials.
  
  Conclusions/Significance
  
  We used novel epitope mapping strategies, by combining phage display with VLPs, to identify the important A-strand epitopes with strong neutralizing activity. This study introduced potential therapeutic antibodies that might be capable of providing broad protection against diverse DENV-2 infections without enhancing activity in humans.
  
  
• Subjects:
  Animals Antibodies, Monoclonal Antibodies, Monoclonal, Humanized Antibodies, Neutralizing Antibodies, Viral Antiviral Agents Dengue Dengue Virus Disease Models, Animal Epitope Mapping Female Humans Immunotherapy Mice Mice, Inbred BALB C Neutralization Tests Survival Analysis Viral Plaque Assay

  More +
• Source:
  PLoS Negl Trop Dis. 2012; 6(5).
• Document Type:
  Journal Article
• Volume:
  6
• Issue:
  5
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:7c0bf6eaea168c419e8731547bff0fd4c6042d2519b2570dc9f4d36121035e50
• Download URL:
  https://stacks.cdc.gov/view/cdc/8126/cdc_8126_DS1.pdf
• File Type:
  [PDF - 2.31 MB ]