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
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.Show more [+] Less [-]