Impact of Glycosylation on Effector Functions of Therapeutic IgG

Abstract

Human IgG has only one conserved glycosylation site located in the Cγ2 domain of the Fc region that accounts for the presence of two sugar moieties per IgG. These IgG sugar cores play a critical role in a number of IgG effector functions. In the present review, we describe the main characteristics of IgG Fc glycosylation and some abnormalities of serum IgG glycosylation. We also discuss how glycosylation impacts on monoclonal antibodies (mAbs) and IVIg effector functions and how these molecules can be engineered. Several therapeutic antibodies have now been engineered to be no- or low-fucose antibodies and are currently tested in clinical trials. They exhibit an increased binding to activating FcγRIIIA and trigger a strong antibody-dependent cell cytotoxicity (ADCC) as compared to their highly-fucosylated counterparts. They represent a new generation of therapeutic antibodies that are likely to show a better clinical efficacy in patients, notably in cancer patients where cytotoxic antibodies are needed.

Keywords: Fc receptor; IgG; antibody; glycosylation.

Figure 1

Mechanisms of action of IVIg. Enlarged representation of the Asn297-linked oligosaccharide complex is shown [Fucα1-6: fucose(α1-6); Man: mannose; GlcNAc: N-acetyl-glucosamine; Gal: galactose; NANA: sialic acid]. IVIg mechanisms of action can be divided in two categories: (A) Fab-mediated activity against immunoregulatory or pathogen-related molecules, or presence of anti-idiotype (Id) antibodies that can neutralize autoantibodies and inhibit Id⁺ FcγRIIb⁺ pathogenic B cells. (B) Fc-mediated activity of IVIg through different mechanisms: (i) competitive blockade of FcRn, (ii) competitive blockade of activating FcγR and up-regulation of FcγRIIB and (iii) C3b and C4b binding leading to an indirect inhibition of membrane attack complex (MAC) formation. These molecular mechanisms trigger (i) an increased clearance of pathogenic endogenous antibodies, (ii) the modulation of DC, granulocyte, T and NK cell activity and (iii) a decrease of complement-dependent tissue destruction, respectively. Altogether, Fc-mediated mechanisms ultimately lead to anti-inflammatory activity.