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.