Comparison of biological activity among nonfucosylated therapeutic IgG1 antibodies with three different N-linked Fc oligosaccharides: the high-mannose, hybrid, and complex types
Abstract
The structure of asparagine-linked oligosaccharides attached to the antibody constant region (Fc) of human immunoglobulin G1 (IgG1) has been shown to affect the pharmacokinetics and antibody effector functions of antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, it is still unclear how differences in the N-linked oligosaccharide structures impact the biological activities of antibodies, especially those lacking core fucose. Here, we succeeded in generating core fucose-lacking human IgG1 antibodies with three different N-linked Fc oligosaccharides, namely, a high-mannose, hybrid, and complex type, using the same producing clone, and compared their activities. Cultivation of an alpha-1,6-fucosyltransferase (FUT8) knockout Chinese hamster ovary cell line in the presence or absence of a glycosidase inhibitor (either swainsonine or kifunensine) yielded antibody production of each of the three types without contamination by the others. Two of three types of nonnaturally occurring atypical oligosaccharide IgG1, except the complex type, reduced the affinity for both human lymphocyte receptor IIIa (FcgammaRIIIa) and the C1q component of the complement, resulting in reduction of ADCC and CDC. The bulky structure of the nonreducing end of N-linked Fc oligosaccharides is considered to contribute the CDC change, whereas the structural change in the reducing end, i.e. the removal of core fucose, causes ADCC enhancement through improved FcgammaRIIIa binding. In the pharmacokinetic profile, although no significant difference of human neonatal Fc receptor (FcRn)-binding affinity was observed among the three types, the complex type showed longer serum half-lives than the other types irrespective of core fucosylation in mice, which also suggests the contribution of the nonreducing end structure. The present study provides basic information on the effects of core fucose-lacking N-linked Fc oligosaccharides on antibody biological activities.
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Therapeutic mAbs with high terminal mannose glycans exhibit fast elimination from systemic circulation and lower efficacy.
“For example, therapeutic mAbs with high terminal mannose glycans exhibit fast elimination from systemic circulation and lower efficacy.43, 44”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [44]
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- Authors
- Kanda, Y., Yamada, T., Mori, K., Okazaki, A., Inoue, M., Kitajima-Miyama, K., Kuni-Kamochi, R., Nakano, R., Yano, K., Kakita, S., Shitara, K., & Satoh, M.
- Venue
- Glycobiology
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-09-29
- Volume
- 17
- Issue
- 1
- Pages
- 104-118
- ISSN
- 0959-6658 (ISSN-L)
- 1460-2423
- OpenAlex
- W2124847934
- Cited by
- 372
- References
- 48
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 16 · 2023: 21 · 2022: 12 · 2021: 30 · 2020: 13 · 2019: 20 · 2018: 29 · 2017: 21 · 2016: 36 · 2015: 26 · 2014: 20 · 2013: 17 · 2012: 22
- FWCI
- 11.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Glycobiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
- Keywords
- IgG1 antibodies, Fc glycosylation, core fucose, N-glycans, complex types, antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, FcγRIIIa, C1q binding, FcRn binding, pharmacokinetics, swainsonine, kifunensine
- MeSH terms
- Rituximab, Animals, Antibodies, Monoclonal, Antibody-Dependent Cell Cytotoxicity, Carbohydrate Sequence, Complement System Proteins, Cricetulus, Cytotoxicity, Immunologic, Female, Fucosyltransferases, Cricetinae, Humans, Immunoglobulin G, Immunoglobulin Fc Fragments, Immunologic Factors, Mannans, Metabolic Clearance Rate, Molecular Sequence Data, Multiple Myeloma, Oligosaccharides, Protein Binding, Receptors, Fc, Structure-Activity Relationship, Histocompatibility Antigens Class I, Complement C1q, CHO Cells, Receptors, IgG, Organisms, Genetically Modified, Mice, Antibodies, Monoclonal, Murine-Derived
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