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PLoS Negl Trop Dis. 2012;6(5):e1636. doi: 10.1371/journal.pntd.0001636. Epub 2012 May 1.

Development of a humanized antibody with high therapeutic potential against dengue virus type 2.

Author information

1
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.

Abstract

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.

PMID:
22563515
PMCID:
PMC3341331
DOI:
10.1371/journal.pntd.0001636
[Indexed for MEDLINE]
Free PMC Article
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