Role of Fc Core Fucosylation in the Effector Function of IgG1 Antibodies

Abstract

The presence of fucose on IgG1 Asn-297 N-linked glycan is the modification of the human IgG1 Fc structure with the most significant impact on FcɣRIII affinity. It also significantly enhances the efficacy of antibody dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells in vitro, induced by IgG1 therapeutic monoclonal antibodies (mAbs). The effect of afucosylation on ADCC or antibody dependent phagocytosis (ADCP) mediated by macrophages or polymorphonuclear neutrophils (PMN) is less clear. Evidence for enhanced efficacy of afucosylated therapeutic mAbs in vivo has also been reported. This has led to the development of several therapeutic antibodies with low Fc core fucose to treat cancer and inflammatory diseases, seven of which have already been approved for clinical use. More recently, the regulation of IgG Fc core fucosylation has been shown to take place naturally during the B-cell immune response: A decrease in α-1,6 fucose has been observed in polyclonal, antigen-specific IgG1 antibodies which are generated during alloimmunization of pregnant women by fetal erythrocyte or platelet antigens and following infection by some enveloped viruses and parasites. Low IgG1 Fc core fucose on antigen-specific polyclonal IgG1 has been linked to disease severity in several cases, such as SARS-CoV 2 and Dengue virus infection and during alloimmunization, highlighting the in vivo significance of this phenomenon. This review aims to summarize the current knowledge about human IgG1 Fc core fucosylation and its regulation and function in vivo, in the context of both therapeutic antibodies and the natural immune response. The parallels in these two areas are informative about the mechanisms and in vivo effects of Fc core fucosylation, and may allow to further exploit the desired properties of this modification in different clinical contexts.

Keywords: ADCC; IgG; N-glycan; NK cells; fucosylation; humoral response; therapeutic antibodies; virus.

Figure 1

The IgG Asn-297 N-glycan heterogeneity. Panel (A) major types of N-glycosylation observed in IgG. Panel (B) detail of complex type glycosylation with percentage of circulating IgG containing either fucose or bisecting N-Acetylglucosamine. The orange circle indicates the core structure. The blue broken lines and text indicate the heterogeneity of complex N-glycans, carrying either no Gal (G0), 1-2 Gal (G1/2), 1-2 Sialic acids (S1/2), with (F) or without core α-1,6-fucose.

Figure 2

Simplified scheme of enzymatic reactions involved in N-linked glycosylation of IgG. The major glycosylation steps and enzymes involved in N- linked glycosylation of IgGs taking place in ER and Golgi are shown. GnT, N-Acetyl glucosamine transferase; FUT, Fucosyl transferase; Man, Mannose; Gal, Galactose; GlcNAcm N-acetylglucosamine; SA, sialic acid (N-Acetylneuraminic Acid).

Figure 3

Major pathways of GDP-fucose biosynthesis and IgG Fc core fucosylation. FUK, Fucose Kinase; GDPP, GDP-fucose-pyrophosphorylase; GMD, GDP-mannose 4,6 dehydratase; FX, GDP-4-keto 6-deoxymannose 3,5-epimerase-4-reductase; FUT, Fucosyltransferase.

Figure 4

Major mechanisms of action of Fc core afucosylated IgG1 antibodies. IgG1 antibodies lacking Fc core α-1,6-fucose show a 10-100 fold increased binding to FcɣRIIIA and FcɣRIIIB on the indicated immune cells (NK, monocytes/macrophages and PMN), which results in increased ADCC by NK cells, enhanced competition with plasma IgGs, increased PMN activation, increased inhibition of FcγRIIA-mediated ADCC by PMN, induced by some antibodies (e.g. anti-EGFR mAbs). The effect of monocyte/macrophage induced ADCP is less clear. Low Fc core fucose can also increase release of cytokines, such as IL-6, TNF-α and IL-8, both in vitro and in vivo.