title: Plant-produced anti-dengue virus monoclonal antibodies exhibit reduced antibody-dependent enhancement of infection activity.
abstract: The mAb E60 has the potential to be a desirable therapeutic molecule since it efficiently neutralizes all four serotypes of dengue virus (DENV). However, mammalian-cell-produced E60 exhibits antibody-dependent enhancement of infection (ADE) activity, rendering it inefficacious in vivo, and treated animals more susceptible to developing more severe diseases during secondary infection. In this study, we evaluated a plant-based expression system for the production of therapeutically suitable E60. The mAb was transiently expressed in Nicotiana benthamianaWT and a ∆XFT line, a glycosylation mutant lacking plant-specific N-glycan residues. The mAb was efficiently expressed and assembled in leaves and exhibited highly homogenous N-glycosylation profiles, i.e. GnGnXF3 or GnGn structures, depending on the expression host. Both E60 glycovariants demonstrated equivalent antigen-binding specificity and in vitro neutralization potency against DENV serotypes 2 and 4 compared with their mammalian-cell-produced counterpart. By contrast, plant-produced E60 exhibited reduced ADE activity in Fc gamma receptor expressing human cells. Our results suggest the ability of plant-produced antibodies to minimize ADE, which may lead to the development of safe and highly efficacious antibody-based therapeutics against DENV and other ADE-prone viral diseases. Our study provides so far unknown insight into the relationship between mAb N-glycosylation and ADE, which contributes to our understanding of how sugar moieties of antibodies modulate Fc-mediated functions and viral pathogenesis.
authors.affiliation: The Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Dent
authors.affiliation: The Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hurtado
authors.affiliation: Department of Biological Sciences, University of Southern Mississippi, Hattiesburg, MS, USA.
authors.forename: Amber M
authors.initials: AM
authors.lastname: Paul
authors.affiliation: The Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Sun
authors.affiliation: The Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ, USA.
authors.forename: Huafang
authors.initials: H
authors.lastname: Lai
authors.affiliation: The Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.affiliation: The Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Esqueda
authors.affiliation: Department of Biological Sciences, University of Southern Mississippi, Hattiesburg, MS, USA.
authors.forename: Fengwei
authors.initials: F
authors.lastname: Bai
authors.affiliation: Department of Applied Genetics and Cell Biology, University of Natural Resources and Applied Life Sciences, Vienna, Austria.
authors.forename: Herta
authors.initials: H
authors.lastname: Steinkellner
authors.affiliation: The Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
mesh_terms: D000911:Antibodies, Monoclonal / Q000235:genetics* / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology; D000914:Antibodies, Viral / Q000235:genetics* / Q000276:immunology*; D019067:Antibody-Dependent Enhancement / Q000276:immunology*; D003715:Dengue / Q000276:immunology* / Q000821:virology; D003716:Dengue Virus / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression; D006801:Humans; D014026:Nicotiana / Q000235:genetics* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral