A Monosaccharide Residue Is Sufficient to Maintain Mouse and Human IgG Subclass Activity and Directs IgG Effector Functions to Cellular Fc Receptors

• Published in: Cell reports (Cambridge) 2015-12, Vol.13 (11), p.2376-2385
• Main Authors: Kao, Daniela, Danzer, Heike, Collin, Mattias, Groß, Andrea, Eichler, Jutta, Stambuk, Jerko, Lauc, Gordan, Lux, Anja, Nimmerjahn, Falk
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD20 - immunology; Basic Medicine; Cell Line, Tumor; CHO Cells; Complement C1q - chemistry; Complement C1q - metabolism; Cricetinae; Cricetulus; cytotoxic antibodies; Fcγ receptors; Female; Glycopeptides - analysis; Glycoside Hydrolases - metabolism; Glycosylation; Humans; IgG; Immunoglobulin G - chemistry; Immunoglobulin G - metabolism; Immunologi inom det medicinska området; Immunology in the medical area; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - transplantation; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; Mice, Inbred C57BL; Mice, Knockout; Monosaccharides - metabolism; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase - metabolism; Protein Binding; Receptors, Fc - genetics; Receptors, Fc - metabolism; Receptors, IgG - deficiency; Receptors, IgG - genetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.11.027

Immunoglobulin G (IgG) glycosylation modulates antibody activity and represents a major source of heterogeneity within antibody preparations. Depending on their glycosylation pattern, individual IgG glycovariants present in recombinant antibody preparations may trigger effects ranging from enhanced pro-inflammatory activity to increased anti-inflammatory activity. In contrast, reduction of IgG glycosylation beyond the central mannose core is generally believed to result in impaired IgG activity. However, this study reveals that a mono- or disaccharide structure consisting of one N-acetylglucosamine with or without a branching fucose residue is sufficient to retain the activity of the most active human and mouse IgG subclasses in vivo and further directs antibody activity to cellular Fcγ receptors. Notably, the activity of minimally glycosylated antibodies is not predicted by in vitro assays based on a monomeric antibody-Fcγ-receptor interaction analysis, whereas in vitro assay systems using immune complexes are more suitable to predict IgG activity in vivo. [Display omitted] •Select IgG subclasses maintain full activity in a monosaccharide variant•Monosaccharide antibodies mediate effector functions via FcγRs•Monosaccharide antibodies lose complement activating activity•Monomeric IgG-FcγR interaction analysis does not predict IgG activity Lack of IgG glycosylation is generally thought to impair IgG activity. Kao et al. now show that the most active mouse and human IgG subclasses maintain their in vivo activity even if they only contain a mono- or disaccharide sugar residue but lose their capacity to activate the complement pathway.