High-mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans
Abstract
Glycan structures attached to the C(H)2 domain of the Fc region of immunoglobulin G (IgG) are essential for specific effector functions but their role in modulating clearance is less clear. Clearance is of obvious importance for therapeutic monoclonal antibodies (Mabs) as it directly impacts efficacy. Here, we study the impact of Fc glycan structure on the clearance of four therapeutic human IgGs (one IgG1 and three IgG2s) in humans. The therapeutic IgGs were affinity purified from serum samples from human pharmacokinetic studies, and changes to the glycan profile over time were determined by peptide mapping employing high-resolution mass spectrometry. Relative levels of high-mannose 5 (M5) glycan decreased as a function of circulation time, whereas other glycans remained constant. These results demonstrate that therapeutic IgGs containing Fc high-mannose glycans are cleared more rapidly in humans than other glycan forms. The quantitative effect of this on pharmacokinetic area under the curve was calculated and shown to be relatively minor for three of the four molecules studied, but, depending on the dosing regimen and the relative level of the high-mannose glycan, this can also have significant impact. High-mannose content of therapeutic Mabs should be considered an important product quality attribute which may affect pharmacokinetic properties of therapeutic antibodies.
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High-mannose structures are cleared more rapidly from circulation in humans and mice, likely due to uptake by endogenous receptors such as the mannose receptor.
“Pharmacokinetic studies in both humans and mice revealed that high-mannose structures were cleared more rapidly from circulation, which is likely to be a result of uptake by endogenous receptors such as the mannose receptor [29,30].”
From Glycoengineering Chinese hamster ovary cells: a short history (2021) · cites this paper as [29]
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 [43]
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- Authors
- Goetze, A. M., Liu, Y. D., Zhang, Z., Shah, B., Lee, E., Bondarenko, P. V., & Flynn, G. C.
- Affiliations
- Amgen (United States) (US)
- Corresponding author
- Goetze, A. M.
- Venue
- Glycobiology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-03-18
- Volume
- 21
- Issue
- 7
- Pages
- 949-959
- ISSN
- 0959-6658 (ISSN-L)
- 1460-2423
- OpenAlex
- W2155819450
- Cited by
- 467
- References
- 35
- Citations by year
- 2026: 24 · 2025: 21 · 2024: 30 · 2023: 35 · 2022: 31 · 2021: 43 · 2020: 41 · 2019: 30 · 2018: 48 · 2017: 33 · 2016: 36 · 2015: 34 · 2014: 21 · 2013: 14 · 2012: 22
- FWCI
- 14.92
- 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 › Protein purification and stability
- Keywords
- Fc glycosylation, high-mannose glycans, therapeutic monoclonal antibodies, IgG clearance, serum clearance, pharmacokinetics, Fc fragment, IgG1, IgG2, product quality attributes, dosing regimen
- MeSH terms
- Adult, Antibodies, Monoclonal, Chromatography, Liquid, Glycopeptides, Glycoproteins, Humans, Immunoglobulin G, Immunoglobulin Fc Fragments, Mannose, Metabolic Clearance Rate, Polysaccharides, Clinical Trials, Phase I as Topic, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Serum
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