Antibody with an engineered Fc region as a therapeutic agent against dengue virus infection

• Main Authors: Ririn Ramadhany, Itaru Hirai, Tadahiro Sasaki, Ken Ichiro Ono, Pongrama Ramasoota, Kazuyoshi Ikuta, Takeshi Kurosu
• Other Authors: Osaka University
• Format: Article
• Published: 2018
• Subjects: Immunology and Microbiology
• Online Access: https://repository.li.mahidol.ac.th/handle/123456789/36043
• Institution: Mahidol University

© 2015 Published by Elsevier B.V. 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.