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

Ramadhany, Ririn; Hirai, Itaru; Sasaki, Tadahiro; Ono, Kenichiro; Ramasoota, Pongrama; Ikuta, Kazuyoshi; Kurosu, Takeshi

doi:10.1016/j.antiviral.2015.10.012

Cited by 25 publications

(23 citation statements)

References 35 publications

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“…Antibody Fc-FcRs interactions are crucial in the design of therapeutic agents, as well as vaccines. 18,19 One of the most important antibody activities involves killing target cells by triggering antibody-dependent cell-mediated cytotoxicity (ADCC). Fc-optimized antibodies can have higher binding affinity with FcRs and achieve a higher ADCC potency.…”

Section: Introductionmentioning

confidence: 99%

Antigen binding allosterically promotes Fc receptor recognition

Zhao

Nussinov

2018

mAbs

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A key question in immunology is whether antigen recognition and Fc receptor (FcR) binding are allosterically linked. This question is also relevant for therapeutic antibody design. Antibody Fab and Fc domains are connected by flexible unstructured hinge region. Fc chains have conserved glycosylation sites at Asn297, with each conjugated to a core heptasaccharide and forming biantennary Fc glycan. The glycans modulate the Fc conformations and functions. It is well known that the antibody Fab and Fc domains and glycan affect antibody activity, but whether these elements act independently or synergistically is still uncertain. We simulated four antibody complexes: free antibody, antigen-bound antibody, FcR-bound antibody, and an antigen-antibody-FcR complex. We found that, in the antibody's "T/Y" conformation, the glycans, and the Fc domain all respond to antigen binding, with the antibody population shifting to two dominant clusters, both with the Fc-receptor binding site open. The simulations reveal that the Fc-glycan-receptor complexes also segregate into two conformational clusters, one corresponding to the antigen-free antibody-FcR baseline binding, and the other with an antigen-enhanced antibody-FcR interaction. Our study confirmed allosteric communications in antibody-antigen recognition and following FcR activation. Even though we observed allosteric communications through the IgG domains, the most important mechanism that we observed is the communication via population shift, stimulated by antigen binding and propagating to influence FcR recognition.

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Section: Introductionmentioning

confidence: 99%

Antigen binding allosterically promotes Fc receptor recognition

Zhao

Nussinov

2018

mAbs

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“…Anti-TNFα therapy totally protected the DENV-2 infected A129 mice (Martinez Gomez et al, 2016). Importantly, humanized anti-DENV antibodies engineered with mutations in Fc region were developed to prevent binding to FcR for the treatment of dengue disease in AG129 mice (Goncalvez et al, 2007; Balsitis et al, 2010; Beltramello et al, 2010; Ramadhany et al, 2015). A recent study reported plant-produced anti-dengue virus monoclonal antibodies exhibited reduced ADE activity in FcR expressing human cells (Dent et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Anti-Idiotypic Antibodies Specific to prM Monoantibody Prevent Antibody Dependent Enhancement of Dengue Virus Infection

Wang

Yang

Huang

et al. 2017

Front. Cell. Infect. Microbiol.

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Dengue virus (DENV) co-circulates as four serotypes (DENV1-4). Primary infection only leads to self-limited dengue fever. But secondary infection with another serotype carries a higher risk of increased disease severity, causing life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Serotype cross-reactive antibodies facilitate DENV infection in Fc-receptor-bearing cells by promoting virus entry via Fcγ receptors (FcγR), a process known as antibody dependent enhancement (ADE). Most studies suggested that enhancing antibodies were mainly specific to the structural premembrane protein (prM) of DENV. However, there is still no effective drugs or vaccines to prevent ADE. In this study, we firstly confirmed that both DENV-2 infected human sera (anti-DENV-2) and DENV-2 prM monoclonal antibody (prM mAb) could significantly enhance DENV-1 infection in K562 cells. Then we developed anti-idiotypic antibodies (prM-AIDs) specific to prM mAb by immunizing of Balb/c mice. Results showed that these polyclonal antibodies can dramatically reduce ADE phenomenon of DENV-1 infection in K562 cells. To further confirm the anti-ADE effect of prM-AIDs in vivo, interferon-α and γ receptor-deficient mice (AG6) were used as the mouse model for DENV infection. We found that administration of DENV-2 prM mAb indeed caused a higher DENV-1 titer as well as interleukin-10 (IL-10) and alaninea minotransferase (ALT) in mice infected with DENV-1, similar to clinical ADE symptoms. But when we supplemented prM-AIDs to DENV-1 challenged AG6 mice, the viral titer, IL-10 and ALT were obviously decreased to the negative control level. Of note, the number of platelets in peripheral blood of prM-AIDs group were significantly increased at day 3 post infection with DENV-1 compared that of prM-mAb group. These results confirmed that our prM-AIDs could prevent ADE not only in vitro but also in vivo, suggested that anti-idiotypic antibodies might be a new choice to be considered to treat DENV infection.

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“… 149 For example, a N297A mutation in the Fc region of D23-1G7C2 IgG1 was engineered to reduce the affinity of the IgG1 Fc region for FcγRs, resulting in a marked reduction in ADE activity in in vitro cell studies. 150 In another study, dengue neutralizing mAbs targeting distinct epitopes on the four DENV serotypes were engineered to prevent FcγR binding by introducing LALA (L234A-L235A) mutations in the IgG1 Fc region. The LALA variant did not enhance infection and neutralized DENV in vitro and in vivo as postexposure therapy in a mouse model of lethal DENV infection.…”

Section: Introductionmentioning

confidence: 99%

Antibody therapies for the prevention and treatment of viral infections

et al. 2017

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Antibodies are an important component in host immune responses to viral pathogens. Because of their unique maturation process, antibodies can evolve to be highly specific to viral antigens. Physicians and researchers have been relying on such high specificity in their quest to understand host–viral interaction and viral pathogenesis mechanisms and to find potential cures for viral infection and disease. With more than 60 recombinant monoclonal antibodies developed for human use in the last 20 years, monoclonal antibodies are now considered a viable therapeutic modality for infectious disease targets, including newly emerging viral pathogens such as Ebola representing heightened public health concerns, as well as pathogens that have long been known, such as human cytomegalovirus. Here, we summarize some recent advances in identification and characterization of monoclonal antibodies suitable as drug candidates for clinical evaluation, and review some promising candidates in the development pipeline.

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

Cited by 25 publications

References 35 publications

Antigen binding allosterically promotes Fc receptor recognition

Antigen binding allosterically promotes Fc receptor recognition

Anti-Idiotypic Antibodies Specific to prM Monoantibody Prevent Antibody Dependent Enhancement of Dengue Virus Infection

Antibody therapies for the prevention and treatment of viral infections

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