PLoS Pathogens (Apr 2022)

Therapeutic efficacy of humanized monoclonal antibodies targeting dengue virus nonstructural protein 1 in the mouse model.

  • Sen-Mao Tien,
  • Po-Chun Chang,
  • Yen-Chung Lai,
  • Yung-Chun Chuang,
  • Chin-Kai Tseng,
  • Yu-San Kao,
  • Hong-Jyun Huang,
  • Yu-Peng Hsiao,
  • Yi-Ling Liu,
  • Hsing-Han Lin,
  • Chien-Chou Chu,
  • Miao-Huei Cheng,
  • Tzong-Shiann Ho,
  • Chih-Peng Chang,
  • Shu-Fen Ko,
  • Che-Piao Shen,
  • Robert Anderson,
  • Yee-Shin Lin,
  • Shu-Wen Wan,
  • Trai-Ming Yeh

DOI
https://doi.org/10.1371/journal.ppat.1010469
Journal volume & issue
Vol. 18, no. 4
p. e1010469

Abstract

Read online

Dengue virus (DENV) which infects about 390 million people per year in tropical and subtropical areas manifests various disease symptoms, ranging from fever to life-threatening hemorrhage and even shock. To date, there is still no effective treatment for DENV disease, but only supportive care. DENV nonstructural protein 1 (NS1) has been shown to play a key role in disease pathogenesis. Recent studies have shown that anti-DENV NS1 antibody can provide disease protection by blocking the DENV-induced disruption of endothelial integrity. We previously demonstrated that anti-NS1 monoclonal antibody (mAb) protected mice from all four serotypes of DENV challenge. Here, we generated humanized anti-NS1 mAbs and transferred them to mice after DENV infection. The results showed that DENV-induced prolonged bleeding time and skin hemorrhage were reduced, even several days after DENV challenge. Mechanistic studies showed the ability of humanized anti-NS1 mAbs to inhibit NS1-induced vascular hyperpermeability and to elicit Fcγ-dependent complement-mediated cytolysis as well as antibody-dependent cellular cytotoxicity of cells infected with four serotypes of DENV. These results highlight humanized anti-NS1 mAb as a potential therapeutic agent in DENV infection.