title: Compensation of endogenous IgG mediated inhibition of antibody-dependent cellular cytotoxicity by glyco-engineering of therapeutic antibodies.
abstract: A major limitation to the application of therapeutic IgG antibodies (Abs) is their reduced in vivo efficacy compared to their high efficacy as measured in vitro. Recently, Preithner et al. showed that the high amount of endogenous serum IgG impairs the antibody-dependent cellular cytotoxicity effector function (ADCC) of therapeutic Abs in vivo by competing for binding to Fcgamma-RIII on the effector cells. Modification of the glycosylation moieties attached to the Fc part of the Ab, e.g. de-fucosylation, has been shown to increase ADCC activity. We here show that the ADCC activity of a fucose-deficient, moss-produced therapeutic IgG is not impaired by normal human serum. The increased ADCC activity of the fucose-deficient Ab variant even in the presence of high endogenous IgG indicates that glyco-engineering of Abs may translate into improved clinical efficacy. Noteworthy, moss production of glyco-modified Abs should be applicable to a broad variety of therapeutic Abs currently in use indicative for the potential of this technology platform.
authors.forename: Andreas
authors.initials: A
authors.lastname: Nechansky
authors.forename: Manfred
authors.initials: M
authors.lastname: Schuster
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jost
authors.forename: Petra
authors.initials: P
authors.lastname: Siegl
authors.forename: Susanne
authors.initials: S
authors.lastname: Wiederkum
authors.forename: Gilbert
authors.initials: G
authors.lastname: Gorr
authors.forename: Ralf
authors.initials: R
authors.lastname: Kircheis
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology* / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D006031:Glycosylation; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D011487:Protein Conformation; D015202:Protein Engineering; D017452:Receptors, IgG / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; C496124:FCGR3A protein, human; C510956:IGN 311; D007074:Immunoglobulin G; D017452:Receptors, IgG