Abstract
Glycosylation of the Fc region of IgG has a profound impact on the safety and clinical efficacy of therapeutic antibodies. While the biantennary complex-type oligosaccharide attached to Asn297 of the Fc is essential for antibody effector functions, fucose and outer-arm sugars attached to the core heptasaccharide that generate structural heterogeneity (glycoforms) exhibit unique biological activities. Hence, efficient and quantitative glycan analysis techniques have been increasingly important for the development and quality control of therapeutic antibodies, and glycan profiles of the Fc are recognized as critical quality attributes. In the past decade our understanding of the influence of glycosylation on the structure/function of IgG-Fc has grown rapidly through X-ray crystallographic and nuclear magnetic resonance studies, which provides possibilities for the design of novel antibody therapeutics. Furthermore, the chemoenzymatic glycoengineering approach using endoglycosidase-based glycosynthases may facilitate the development of homogeneous IgG glycoforms with desirable functionality as next-generation therapeutic antibodies. Thus, the Fc glycans are fertile ground for the improvement of the safety, functionality, and efficacy of therapeutic IgG antibodies in the era of precision medicine.
Highlights
Glycosylation of proteins is a complex and versatile posttranslational modification that influences biological activity, protein conformation, stability, solubility, secretion, pharmacokinetics, and antigenicity (Dwek, 1998)
immunoglobulin G (IgG) is composed of three globular domain structures, two of which are the fragments for antigen binding (Fab) and the other is the fragment crystalizable (Fc) that activates Fcγ receptors (FcγRs) on leukocytes and C1 component of complement
IgG molecules bear oligosaccharides at Asn297 of the Fc region, and the oligosaccharide plays an essential role in Fc effector functions including antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) that are among mechanisms of action of therapeutic antibodies
Summary
Glycosylation of proteins is a complex and versatile posttranslational modification that influences biological activity, protein conformation, stability, solubility, secretion, pharmacokinetics, and antigenicity (Dwek, 1998). The heterogeneous glycans can be classified into three sets (G0, G1, and G2), depending on the number of galactose residues in the outer arms of biantennary glycans Within each of these sets are four species that result from the presence or absence of core fucose and bisecting GlcNAc, namely, 16 neutral complex-type structures. Terminal α(1-3)-linked galactose (α(1-3)-Gal) and N-glycolylneuraminic acid (NeuGc) residues are frequently found in the N-glycans of recombinant IgG antibodies produced from murine myeloma cells. Such glycan structures are unnatural and potentially immunogenic in humans. It has been reported that all humans have IgG antibodies specific for the α(1-3)-Gal epitope (Galili et al, 1993) and that the anti-NeuGc activity is Glycoengineering for next-generation therapeutic antibodies
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