title: A bispecific antibody effectively neutralizes all four serotypes of dengue virus by simultaneous blocking virus attachment and fusion.
abstract: Although dengue virus (DENV) infection severely threatens the health of humans, no specific antiviral drugs are currently approved for clinical use against DENV infection. Attachment and fusion are 2 critical steps for the flavivirus infection, and the corresponding functional epitopes are located at E protein domain III (E-DIII) and domain II (E-DII), respectively. Here, we constructed a bispecific antibody (DVD-1A1D-2A10) based on the 2 well-characterized anti-DENV monoclonal antibodies 1A1D-2 (1A1D) and 2A10G6 (2A10). The 1A1D antibody binds E-DIII and can block the virus attaching to the cell surface, while the 2A10 antibody binds E-DII and is able to prevent the virus from fusing with the endosomal membrane. Our data showed that DVD-1A1D-2A10 retained the antigen-binding activity of both parental antibodies. Importantly, it was demonstrated to be significantly more effective at neutralizing DENV than its parental antibodies both in vitro and in vivo, even better than the combination of them. To eliminate the potential antibody-dependent enhancement (ADE) effect, this bispecific antibody was successfully engineered to prevent Fc-γ-R interaction. Overall, we generated a bispecific anti-DENV antibody targeting both attachment and fusion stages, and this bispecific antibody broadly neutralized all 4 serotypes of DENV without risk of ADE, suggesting that it has great potential as a novel antiviral strategy against DENV.
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.
authors.forename: Xin
authors.initials: X
authors.lastname: Shi
authors.affiliation: b Department of Virology , Beijing Institute of Microbiology and Epidemiology , Beijing , China.|c State Key Laboratory of Pathogen and Biosecurity , Beijing , China.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Deng
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.
authors.forename: Huajing
authors.initials: H
authors.lastname: Wang
authors.affiliation: e Department of Traditional Chinese Medicine , Navy General Hospital , Beijing , China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Ji
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Tan
authors.affiliation: b Department of Virology , Beijing Institute of Microbiology and Epidemiology , Beijing , China.|c State Key Laboratory of Pathogen and Biosecurity , Beijing , China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: b Department of Virology , Beijing Institute of Microbiology and Epidemiology , Beijing , China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Li
authors.affiliation: b Department of Virology , Beijing Institute of Microbiology and Epidemiology , Beijing , China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.
authors.forename: Tian
authors.initials: T
authors.lastname: Xia
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Meng
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Yu
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.|d State Key Laboratory of Antibody Medicine and Targeting Therapy , Shanghai , China.
authors.forename: Bohua
authors.initials: B
authors.lastname: Li
authors.affiliation: b Department of Virology , Beijing Institute of Microbiology and Epidemiology , Beijing , China.
authors.forename: E-De
authors.initials: ED
authors.lastname: Qin
authors.affiliation: a International Joint Cancer Institute, Second Military Medical University , Shanghai , China.|d State Key Laboratory of Antibody Medicine and Targeting Therapy , Shanghai , China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Dai
authors.affiliation: b Department of Virology , Beijing Institute of Microbiology and Epidemiology , Beijing , China.|c State Key Laboratory of Pathogen and Biosecurity , Beijing , China.
authors.forename: Cheng-Feng
authors.initials: CF
authors.lastname: Qin
authors.affiliation: d State Key Laboratory of Antibody Medicine and Targeting Therapy , Shanghai , China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D000914:Antibodies, Viral / Q000276:immunology / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003715:Dengue / Q000276:immunology; D003716:Dengue Virus / Q000276:immunology*; D006801:Humans; D051379:Mice; D065288:Serogroup; D053585:Virus Attachment / Q000187:drug effects*
chemical_list: D018033:Antibodies, Bispecific; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral
keywords: Attachment; bispecific antibody; dengue virus; fusion; monoclonal antibody; neutralizing activity