Production, characterization, and pharmacokinetic properties of antibodies with N-linked mannose-5 glycans
Open accessAbstract
The effector functions of therapeutic antibodies are strongly affected by the specific glycans added to the Fc domain during post-translational processing. Antibodies bearing high levels of N-linked mannose-5 glycan (Man5) have been reported to exhibit enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) compared with antibodies with fucosylated complex or hybrid glycans. To better understand the relationship between antibodies with high levels of Man5 and their biological activity in vivo, we developed an approach to generate substantially homogeneous antibodies bearing the Man5 glycoform. A mannosidase inhibitor, kifunensine, was first incorporated in the cell culture process to generate antibodies with a distribution of high mannose glycoforms. Antibodies were then purified and treated with a mannosidase for trimming to Man5 in vitro. This 2-step approach can consistently generate antibodies with > 99% Man5 glycan. Antibodies bearing varying levels of Man5 were studied to compare ADCC and Fcγ receptor binding, and they showed enhanced ADCC activity and increased binding affinity to the FcγRIIIA. In addition, the clearance rate of antibodies bearing Man8/9 and Man5 glycans was determined in a pharmacokinetics study in mice. When compared with historical data, the antibodies bearing the high mannose glycoform exhibited faster clearance rate compared with antibodies bearing the fucosylated complex glycoform, while the pharmacokinetic properties of antibodies with Man8/9 and Man5 glycoforms appeared similar. In addition, we identified the presence of a mannosidase in mouse serum that converted most Man8/9 to Man6 after 24 h.
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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 [30]
Oligomannose glycans (Man5-9GlcNAc2) increase FcγRIIIa binding and ADCC of mAbs compared with fucosylated complex glycans, but decrease CDC activity and binding affinity to FcγRIIa/b.
“While oligomannose glycans (Man5–9GlcNAc2) have been shown to increase the FcγRIIIa binding and ADCC of mAbs compared with fucosylated complex glycans, the CDC activity was decreased together with the binding affinity to FcγRIIa/b [30].”
From Glycoengineering Chinese hamster ovary cells: a short history (2021) · cites this paper as [30]
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“Also, high mannose glycoforms exhibit higher FcgRIIIa binding, but show reduced CDC activity.(64,65)”
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“Glycosylation patterns of mAbs or Fc-fusion proteins can significantly affect their PK and pharmacodynamics behaviors.(9,10,46) To determine the effects of glycosylation on transcytosis, two sets of Fc-containing molecules were tested.”
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“The mannosidase present in mouse serum converts most Man8/9 to Man6 after 24 h (Yu et al. 2012).”
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Glycoform-resolved FcɣRIIIa affinity chromatography–mass spectrometry
Lippold, S., Nicolardi, S., Domínguez‐Vega, E., Heidenreich, A.-K., Vidarsson, G., Reusch, D., Haberger, M., Wuhrer, M., & Falck, D. (2019) · mAbs · doi:10.1080/19420862.2019.1636602 · Cited by 53 · see citing works
“glycoforms over 2x fucosylated complex glycoforms, and similar or decreased affinities and activities compared to afucosylated complex glycoforms.(12,13,27) Identity and affinity of the M5/M5 were confirmed by glycoengineering (Supplemental Figure 6 and 7).”
BackgroundPharmacokinetic and Pharmacodynamic Considerations in the Design of Therapeutic Antibodies
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“High mannose content (Man5/8/9) has been associated with affinity for FcγRIIIA and enhanced ADCC activity, but this may rather be due to afucosylation, because high- mannose glycans do not have core fucosylation similar to bisecting GlcNAc- variants.(63,90)”
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Alga‐Made Anti‐Hepatitis B Antibody Binds to Human Fcγ Receptors
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The Formidable Challenge of Controlling High Mannose-Type N-Glycans in Therapeutic mAbs
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Controlling the time evolution of mAb N‐linked glycosylation, Part I: Microbioreactor experiments
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Therapeutic antibody glycosylation impacts antigen recognition and immunogenicity
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Pharmacokinetic de-risking tools for selection of monoclonal antibody lead candidates
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Glycoengineering of pertuzumab and its impact on the pharmacokinetic/pharmacodynamic properties
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Mannose metabolism in recombinant CHO cells and its effect on IgG glycosylation
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Constrained global sensitivity analysis for bioprocess design space identification
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Real‐time product attribute control to manufacture antibodies with defined N‐linked glycan levels
Zupke, C., Brady, L. J., Slade, P. G., Clark, P. C. T., Caspary, R. G., Livingston, B., Taylor, L. D., Bigham, K., Morris, A. E., & Bailey, R. W. (2015) · Biotechnology Progress · doi:10.1002/btpr.2136 · Cited by 40 · see citing works
“presence of High Mannose on the Fc domain has been shown to impact antibody clearance(9) and effector function activity.(10)”
BackgroundHilliard, M., Alley, W. R., McManus, C. A., Yu, Y. Q., Hallinan, S., Gebler, J. C., & Rudd, P. M. (2017) · mAbs · doi:10.1080/19420862.2017.1377381 · Cited by 40 · see citing works
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“68,72 However, the impact of these modifications on mAb clearance by mannose receptors on liver macrophages and endothelial cells needs to be considered, 73 as does the impact of enhanced binding to FcγR on mAb clearance in general.”
Self-citationGlycoengineered hepatitis B virus-like particles with enhanced immunogenicity
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“HM structures are a critical quality attribute within biopharmaceutical protein production[41] and can accumulate during cell culture performance.”
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“The similar comparative analysis revealed the highest FcγRIIIa affinity with the afucosylated complex-type glycan [54], and thus this enhancement is likely due to the afucosylated glycan [55].”
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“In mammalian cell culture, kifunensine was successfully employed to produce protein with >90% high-mannose content [28,29,33,34].”
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Rapid intensification of an established CHO cell fed‐batch process
Schulze, M., Niemann, J., Wijffels, R. H., Matuszczyk, J., & Martens, D. E. (2021) · Biotechnology Progress · doi:10.1002/btpr.3213 · Cited by 33 · see citing works
“A study investigating the impact of in vitro trimmed mannosylated mAb1 isoforms on its effector functions, showed that while antibody-dependent cellular cytotoxicity (ADCC) was increased by about 6-fold, complementdependent cytotoxicity (CDC) was decreased by 50%.(35) Still, the respectively investigated mannosylation…”
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“The level of high mannose is very low in recombinant monoclonal antibodies, but there are cases in which up to 10% has been observed.25,26 In human endogenous IgG, high mannose is present at only around 0.1%.24 D/H exchange revealed that the major structural difference between antibodies with high mannose and complex…”
BackgroundInfluentialGlycosylation-dependent opsonophagocytic activity of staphylococcal protein A antibodies
Chen, X., Shi, M., Tong, X., Kim, H. K., Wang, L., Schneewind, O., & Missiakas, D. M. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2003621117 · Cited by 31 · see citing works
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“…that impact the pharmacokinetics of mAbs and Fc-fusion proteins, such as FcRn binding (Suzuki et al., 2010), isoelectric point (Igawa et al., 2010b), immunogenicity (Karmiris et al., 2009), off-target binding (Bumbaca et al., 2011; Vugmeyster et al., 2011) and glycosylation (Yu et al., 2012).”
BackgroundA robust method for increasing Fc glycan high mannose level of recombinant antibodies
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Popp, O., Moser, S., Zielonka, J., Rüger, P., Hansen, S., & Plöttner, O. (2017) · mAbs · doi:10.1080/19420862.2017.1405203 · Cited by 30 · see citing works
“In general, high levels of high mannose should be avoided due to a greater risk for altering the antibody effector function and faster clearance in vivo.(48,49) A previous study has shown the influence of cell culture medium osmolality and the level of high mannose glycan species.”
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Glycoengineering of Therapeutic Antibodies with Small Molecule Inhibitors
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Fc-GDF15 glyco-engineering and receptor binding affinity optimization for body weight regulation
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Multivariate data analysis of growth medium trends affecting antibody glycosylation
Powers, D. N., Trunfio, N., Velugula‐Yellela, S. R., Angart, P. A., Faustino, A. M., & Agarabi, C. D. (2019) · Biotechnology Progress · doi:10.1002/btpr.2903 · Cited by 24 · see citing works
“glycoforms which can be characteristic of cellular stress and causes incomplete processing during N-glycan biosynthesis.(6,23,24) This cellular”
BackgroundSvecla, M., Nour, J., Bladergroen, M. R., Nicolardi, S., Zhang, T., Beretta, G., Wuhrer, M., Norata, G. D., & Falck, D. (2023) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2023.100615 · Cited by 23 · see citing works
“Furthermore, accessible oligomannose sites should be rapidly trimmed down to Man5 by circulating mannosidase 1—a 1A and 1B variant exist—while the oligomannose portion of TPNG is dominated by Man9 (70, 71).”
BackgroundShapiro, M. A. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1379738 · Cited by 22 · see citing works
Arabinosylation of recombinant human immunoglobulin-based protein therapeutics
Hossler, P., Chumsae, C., Racicot, C., Ouellette, D., Ibraghimov, A. R., Serna, D., Mora, A., McDermott, S., Labkovsky, B., Scesney, S. M., et al. (2017) · mAbs · doi:10.1080/19420862.2017.1294295 · Cited by 22 · see citing works
“Decreasing the levels of mannose is potentially beneficial because the high mannose forms exhibit potentially increased immunogenicity and shorter systemic half-life.(5,6)”
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Kang, S., Zhang, Z., Richardson, J., Shah, B., Gupta, S., Huang, C., Qiu, J., Le, N., Lin, H. C., & Bondarenko, P. V. (2015) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2015.03.002 · Cited by 22 · see citing works
The therapeutic potential of sialylated Fc domains of human IgG
Pleass, R. J. (2021) · mAbs · doi:10.1080/19420862.2021.1953220 · Cited by 21 · see citing works
Marco, F. D., Berger, T., Esser‐Skala, W., Rapp, E., Regl, C., & Huber, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22169072 · Cited by 22 · see citing works
“Furthermore, oligomannose type and core-afucosylation increase ADCC activity, strengthening the FcγIIIa receptor binding affinity [49,50].”
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The Impact of Immunoglobulin G1 Fc Sialylation on Backbone Amide H/D Exchange
Kuhne, F., Bonnington, L. S., Malik, S., Thomann, M., Avenal, C., Cymer, F., Wegele, H., Reusch, D., Mormann, M., & Bulau, P. (2019) · Antibodies · doi:10.3390/antib8040049 · Cited by 20 · see citing works
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“On the other hand, high mannose glycoforms increase the affinity of antibodies for the FcgIII receptor thus increasing ADCC activity of certain antibodies (Yu et al., 2012).”
BackgroundStructural characterization of the Man5 glycoform of human IgG3 Fc
Shah, I. S., Lovell, S., Mehzabeen, N., Battaile, K. P., & Tolbert, T. J. (2017) · Molecular Immunology · doi:10.1016/j.molimm.2017.10.001 · Cited by 20 · see citing works
“Man5-IgG1 is reported to have higher binding affinity to FcγRIIIA and higher Antibody Dependent Cellular Cytotoxicity (ADCC) when compared to IgG1 bearing complex-type glycoforms (Yu et al., 2012).”
BackgroundWoodall, D. W., Dillon, T. M., Kalenian, K., Padaki, R., Kuhns, S. T., Semin, D. J., & Bondarenko, P. V. (2022) · mAbs · doi:10.1080/19420862.2021.2004982 · Cited by 20 · see citing works
“This finding is consistent with previous studies and serves as a benchmark for the method.(32,33,34) Several of the glycoforms contain multiple peaks in the XMCs, for example, G1F/G1F.”
BackgroundResultGlycan profiling of proteins using lectin binding by Surface Plasmon Resonance
Wang, W., Soriano, B., & Chen, Q. (2017) · Analytical Biochemistry · doi:10.1016/j.ab.2017.09.014 · Cited by 20 · see citing works
Computational tools for predicting and controlling the glycosylation of biopharmaceuticals
Kontoravdi, C., & Jimenez del Val, I. (2018) · Current Opinion in Chemical Engineering · doi:10.1016/j.coche.2018.08.007 · Cited by 18 · see citing works
- Authors
- Yu, M., Brown, D., Reed, C., Chung, S., Lutman, J., Stefanich, E., Wong, A., Stephan, J.-P., & Bayer, R.
- Affiliations
- Genentech (US)
- Illumina (United States) (US)
- Genomics Institute of the Novartis Research Foundation (US)
- Corresponding author
- Bayer, Robert
- Venue
- mAbs
- Publisher
- Informa UK Limited
- Published
- 2012-07
- Volume
- 4
- Issue
- 4
- Pages
- 475-487
- ISSN
- 1942-0862 (ISSN-L)
- 1942-0870
- PMC
- PMC3499342
- OpenAlex
- W2057390178
- Cited by
- 203
- References
- 39
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 13 · 2023: 13 · 2022: 11 · 2021: 24 · 2020: 22 · 2019: 21 · 2018: 18 · 2017: 19 · 2016: 10 · 2015: 15 · 2014: 7 · 2013: 4 · 2012: 2
- FWCI
- 6.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- mAbs (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (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
- antibody glycosylation, antibody-dependent cellular cytotoxicity, FcγRIIIa binding, kifunensine, antibody clearance, pharmacokinetics, therapeutic antibodies
- MeSH terms
- Alkaloids, Animals, Antibodies, Monoclonal, Antibody-Dependent Cell Cytotoxicity, Binding, Competitive, Cell Survival, Cells, Cultured, Cricetulus, Enzyme-Linked Immunosorbent Assay, Female, Cricetinae, Humans, Immunoglobulin Fc Fragments, Mannose, Mannosidases, Metabolic Clearance Rate, Mice, Nude, Polysaccharides, CHO Cells, Receptors, IgG, Area Under Curve, Spectrometry, Mass, Electrospray Ionization, Cell Line, Tumor, Mice
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