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:10.1371/journal.ppat.1010469

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

Medicine

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

Abstract

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.

Original language	English
Article number	e1010469
Journal	PLoS Pathogens
Volume	18
Issue number	4
DOIs	https://doi.org/10.1371/journal.ppat.1010469
Publication status	Published - Apr 2022

Bibliographical note

Funding Information:
This work was supported by MOST Grants 106-3114-B-006-003 (YSL, SWW, TMY), 108-2321-B-006-013 (YSL, SWW, TMY), 109-2320-B-006-068 (SWW) and 109-2327-B-006-010 and 110-2327-B-006-005 (SWW, TMY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
Copyright: © 2022 Tien et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ASJC Scopus Subject Areas

Parasitology
Microbiology
Immunology
Molecular Biology
Genetics
Virology

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.ppat.1010469

Cite this

Tien, S. M., Chang, P. C., Lai, Y. C., Chuang, Y. C., Tseng, C. K., Kao, Y. S., Huang, H. J., Hsiao, Y. P., Liu, Y. L., Lin, H. H., Chu, C. C., Cheng, M. H., Ho, T. S., Chang, C. P., Ko, S. F., Shen, C. P., Anderson, R., Lin, Y. S., Wan, S. W., & Yeh, T. M. (2022). Therapeutic efficacy of humanized monoclonal antibodies targeting dengue virus nonstructural protein 1 in the mouse model. PLoS Pathogens, 18(4), Article e1010469. https://doi.org/10.1371/journal.ppat.1010469

Tien, SM, Chang, PC, Lai, YC, Chuang, YC, Tseng, CK, Kao, YS, Huang, HJ, Hsiao, YP, Liu, YL, Lin, HH, Chu, CC, Cheng, MH, Ho, TS, Chang, CP, Ko, SF, Shen, CP, Anderson, R, Lin, YS, Wan, SW & Yeh, TM 2022, 'Therapeutic efficacy of humanized monoclonal antibodies targeting dengue virus nonstructural protein 1 in the mouse model', PLoS Pathogens, vol. 18, no. 4, e1010469. https://doi.org/10.1371/journal.ppat.1010469

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title = "Therapeutic efficacy of humanized monoclonal antibodies targeting dengue virus nonstructural protein 1 in the mouse model",

abstract = "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.",

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

note = "Funding Information: This work was supported by MOST Grants 106-3114-B-006-003 (YSL, SWW, TMY), 108-2321-B-006-013 (YSL, SWW, TMY), 109-2320-B-006-068 (SWW) and 109-2327-B-006-010 and 110-2327-B-006-005 (SWW, TMY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: Copyright: {\textcopyright} 2022 Tien et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

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AU - Kao, Yu San

AU - Huang, Hong Jyun

AU - Hsiao, Yu Peng

AU - Liu, Yi Ling

AU - Lin, Hsing Han

AU - Chu, Chien Chou

AU - Cheng, Miao Huei

AU - Ho, Tzong Shiann

AU - Chang, Chih Peng

AU - Ko, Shu Fen

AU - Shen, Che Piao

AU - Anderson, Robert

AU - Lin, Yee Shin

AU - Wan, Shu Wen

AU - Yeh, Trai Ming

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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

UN SDGs

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