Tian-Ying Zhang1, Quan Yuan1, Jing-Hua Zhao1, Ya-Li Zhang2, Lun-Zhi Yuan1, Ying Lan1, Yu-Chieh Lo3, Cheng-Pu Sun3, Chang-Ru Wu4, Jun-Fang Zhang1, Ying Zhang1, Jia-Li Cao1, Xue-Ran Guo1, Xuan Liu1, Xiao-Bing Mo5, Wen-Xin Luo1, Tong Cheng1, Yi-Xin Chen1, Mi-Hua Tao3, James Wk Shih1, Qin-Jian Zhao1, Jun Zhang1, Pei-Jer Chen4, Y Adam Yuan6, Ning-Shao Xia1. 1. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Science & School of Public Health, Xiamen University, Xiamen, China National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science & School of Public Health, Xiamen University, Xiamen, China. 2. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Science & School of Public Health, Xiamen University, Xiamen, China National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science & School of Public Health, Xiamen University, Xiamen, China Xiamen Blood Services, Xiamen 361002, China. 3. Academia Sinica, Institute of Biomedical Sciences, Taipei, Taiwan. 4. Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. 5. Department of Biological Sciences and Center for Bioimaging Sciences, National University of Singapore, Singapore, 117543, Singapore National University of Singapore (Suzhou) Research Institute, Suzhou 215123, China. 6. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Science & School of Public Health, Xiamen University, Xiamen, China National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science & School of Public Health, Xiamen University, Xiamen, China Department of Biological Sciences and Center for Bioimaging Sciences, National University of Singapore, Singapore, 117543, Singapore National University of Singapore (Suzhou) Research Institute, Suzhou 215123, China.
Abstract
OBJECTIVE: This study aimed to investigate the therapeutic potential of monoclonal antibody (mAb) against HBV as a novel treatment approach to chronic hepatitis B (CHB) in mouse models. METHODS: Therapeutic effects of mAbs against various epitopes on viral surface protein were evaluated in mice mimicking persistent HBV infection. The immunological mechanisms of mAb-mediated viral clearance were systematically investigated. RESULTS: Among 11 tested mAbs, a novel mAb E6F6 exhibited the most striking therapeutic effects in several HBV-persistent mice. Single-dose administration of E6F6 could profoundly suppress the levels of hepatitis B surface antigen (HBsAg) and HBV DNA for several weeks in HBV-transgenic mice. E6F6 regimen efficiently prevented initial HBV infection, and reduced viral dissemination from infected hepatocytes in human-liver-chimeric mice. E6F6-based immunotherapy facilitated the restoration of anti-HBV T-cell response in hydrodynamic injection (HDI)-based HBV carrier mice. Immunological analyses suggested that the Fcγ receptor-dependent phagocytosis plays a predominant role in E6F6-mediated viral suppression. Molecular analyses suggested that E6F6 recognises an evolutionarily conserved epitope (GPCK(R)TCT) and only forms a smaller antibody-viral particle immune complex with limited interparticle crosslinking when it binds to viral particles. This unique binding characteristic of E6F6 to HBV was possibly associated with its effective in vivo opsonophagocytosis for viral clearance. CONCLUSIONS: These results provided new insight into understanding the therapeutic role and mechanism of antibody against persistent viral infection. The E6F6-like mAbs may provide a novel immunotherapeutic agent against human chronic HBV infection. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
OBJECTIVE: This study aimed to investigate the therapeutic potential of monoclonal antibody (mAb) against HBV as a novel treatment approach to chronic hepatitis B (CHB) in mouse models. METHODS: Therapeutic effects of mAbs against various epitopes on viral surface protein were evaluated in mice mimicking persistent HBV infection. The immunological mechanisms of mAb-mediated viral clearance were systematically investigated. RESULTS: Among 11 tested mAbs, a novel mAb E6F6 exhibited the most striking therapeutic effects in several HBV-persistent mice. Single-dose administration of E6F6 could profoundly suppress the levels of hepatitis B surface antigen (HBsAg) and HBV DNA for several weeks in HBV-transgenic mice. E6F6 regimen efficiently prevented initial HBV infection, and reduced viral dissemination from infected hepatocytes in human-liver-chimeric mice. E6F6-based immunotherapy facilitated the restoration of anti-HBV T-cell response in hydrodynamic injection (HDI)-based HBV carrier mice. Immunological analyses suggested that the Fcγ receptor-dependent phagocytosis plays a predominant role in E6F6-mediated viral suppression. Molecular analyses suggested that E6F6 recognises an evolutionarily conserved epitope (GPCK(R)TCT) and only forms a smaller antibody-viral particle immune complex with limited interparticle crosslinking when it binds to viral particles. This unique binding characteristic of E6F6 to HBV was possibly associated with its effective in vivo opsonophagocytosis for viral clearance. CONCLUSIONS: These results provided new insight into understanding the therapeutic role and mechanism of antibody against persistent viral infection. The E6F6-like mAbs may provide a novel immunotherapeutic agent against human chronic HBV infection. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Authors: Qiao Wang; Eleftherios Michailidis; Yingpu Yu; Zijun Wang; Arlene M Hurley; Deena A Oren; Christian T Mayer; Anna Gazumyan; Zhenmi Liu; Yunjiao Zhou; Till Schoofs; Kai-Hui Yao; Jan P Nieke; Jianbo Wu; Qingling Jiang; Chenhui Zou; Mohanmmad Kabbani; Corrine Quirk; Thiago Oliveira; Kalsang Chhosphel; Qianqian Zhang; William M Schneider; Cyprien Jahan; Tianlei Ying; Jill Horowitz; Marina Caskey; Mila Jankovic; Davide F Robbiani; Yumei Wen; Ype P de Jong; Charles M Rice; Michel C Nussenzweig Journal: Cell Host Microbe Date: 2020-06-05 Impact factor: 21.023
Authors: Loghman Salimzadeh; Nina Le Bert; Charles-A Dutertre; Upkar S Gill; Evan W Newell; Christian Frey; Magdeleine Hung; Nikolai Novikov; Simon Fletcher; Patrick Tf Kennedy; Antonio Bertoletti Journal: J Clin Invest Date: 2018-08-07 Impact factor: 14.808