The history of IgG glycosylation and where we are now

Abstract

IgG glycosylation is currently at the forefront of both immunology and glycobiology, likely due in part to the widespread and growing use of antibodies as drugs. For over four decades, it has been recognized that the conserved N-linked glycan on asparagine 297 found within the second Ig domain of the heavy chain (CH2) that helps to comprise Fc region of IgG plays a special role in IgG structure and function. Changes in galactosylation, fucosylation and sialylation are now well-established factors, which drive differential IgG function, ranging from inhibitory/anti-inflammatory to activating complement and promoting antibody-dependent cellular cytotoxicity. Thus, if we are to truly understand how to design and deploy antibody-based drugs with maximal efficacy and evaluate proper vaccine responses from a protective and functional perspective, a deep understanding of IgG glycosylation is essential. This article is intended to provide a comprehensive review of the IgG glycosylation field and the impact glycans have on IgG function, beginning with the earliest findings over 40 years ago, in order to provide a robust foundation for moving forward.

Keywords: IgG; glycan; glycosylation; sialylation.

Fig. 1

IgG glycans. Schematic showing common glycoforms found on mouse and human IgG molecules. These are typically biantennary with (A) terminal GlcNAcs, (B) monogalactosylated, (C) digalactosylated, (D) one sialic acid or (E) two sialic acids, and each of these with or without core fucose and bisecting GlcNAc. Other glycoforms are known to exist, but these are the major classes. (This figure is available in black and white in print and in colour at Glycobiology online.)

Fig. 2

Structural impact of α2,6-sialylation on IgG Fc. Crystal structures of a normally glycosylated (nonenriched) wild-type Fc domain [PDB: 4Q7D] (red ribbons) compared to the structure of the same Fc carrying fully sialylated N-glycans [PDB: 4Q6Y] (gray ribbons), demonstrating the difference in conformation. (A) A broad view of the full structure highlights the close similarity of the CH1 domains but the divergence in conformation and position of the CH2 domains. (B) A closer view of the two structures, including a molecular surface rendering of the glycans (gold) from the disialylated Fc structure (gray). (C) The complete structure of the Fc with disialylated glycans. (D) The structure of the wild-type Fc with the glycan from the disialylated Fc structure to illustrate the change in the CH2 domain position relative to the glycan. (This figure is available in black and white in print and in colour at Glycobiology online.)