title: Antibody with an engineered Fc region as a therapeutic agent against dengue virus infection.
abstract: Antibody-dependent enhancement (ADE) of dengue virus (DENV) infectivity is thought to play a crucial role in severe dengue disease. It occurs when pre-existing sub-neutralizing anti-DENV antibody (Ab) produced from a primary infection encounters a DENV serotype different from that of the initial infection and forms immune complexes, which enable the efficient infection of Fcγ receptor-bearing cells. However, the exact role played by Abs during a secondary infection of patients remains unknown. We previously obtained a broadly cross-reactive neutralizing IgG1 human monoclonal anti-DENV envelope (E) Ab (HuMAb) D23-1G7C2-IgG1 from a DENV-infected patient; however, D23-1G7C2-IgG1 had ADE activity. With the aim of being able to reduce the ADE activity, we exchanged the Fc region of D23-1G7C2 to generate Abs bearing each of the three other IgG subclasses (IgG2-4). In addition, N297A, a mutation known to reduce the affinity of the IgG1 Fc region for Fcγ receptors, was introduced into D23-1G7C2-IgG1. Swapping D23-1G7C2-IgG1 to IgG2 or IgG4 subclasses reduced ADE activity in FcγRI and FcγRII-bearing THP-1 cells. By contrast, in FcγRII-bearing K562 cells, the change to IgG2 increased ADE activity. Introducing the N297A mutation into D23-1G7C2-IgG1 resulted in a marked reduction in ADE activity in both cell types. Compared to D23-1G7C2-IgG1, D23-1G7C2-IgG1-N297A was less protective in IFN-α/β/γ receptor knockout mice infected with a lethal dose of recombinant chimeric DENV, carrying prME of DENV-2 in Japanese encephalitis virus (80% vs. 40% survival, respectively). These observations provide valuable information regarding the use of recombinant Abs as therapeutics.
authors.affiliation: Research Institute of Microbial Disease, Osaka University, Japan.
authors.forename: Ririn
authors.initials: R
authors.lastname: Ramadhany
authors.affiliation: Faculty of Medicine, University of the Ryukyu, Okinawa, Japan.
authors.forename: Itaru
authors.initials: I
authors.lastname: Hirai
authors.affiliation: Research Institute of Microbial Disease, Osaka University, Japan.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Medical and Biological Laboratories Corporation Ltd., Japan.
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Ono
authors.affiliation: Center of Excellence of Antibody Research, Department of Social and Environment Medicine, Faculty of Tropical Medicine, Mahidol University, Thailand.
authors.forename: Pongrama
authors.initials: P
authors.lastname: Ramasoota
authors.affiliation: Research Institute of Microbial Disease, Osaka University, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Ikuta
authors.affiliation: Research Institute of Microbial Disease, Osaka University, Japan. Electronic address: tkurosu@biken.osaka-u.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kurosu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D000914:Antibodies, Viral / Q000276:immunology / Q000494:pharmacology*; D019067:Antibody-Dependent Enhancement / Q000187:drug effects; D003429:Cross Reactions; D003715:Dengue / Q000628:therapy* / Q000821:virology*; D003716:Dengue Virus / Q000187:drug effects* / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D020014:K562 Cells; D051379:Mice; D009154:Mutation; D015202:Protein Engineering; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*; D019595:Severe Dengue / Q000276:immunology; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D007074:Immunoglobulin G; D017452:Receptors, IgG; D014759:Viral Envelope Proteins
keywords: Antibody-dependent enhancement; Dengue; Human monoclonal antibody; IgG subclass; Neutralization