Cited by 829Monoclonal and Polyclonal Antibodies ResearchGlycosylation and Glycoproteins ResearchViral Infectious Diseases and Gene Expression in Insects

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Glycosylation as a strategy to improve antibody-based therapeutics

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Jefferis, Roy·2009·Nature Reviews Drug Discovery

DOI 10.1038/nrd2804

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Abstract

To date, more than 20 recombinant immunoglobulin G (IgG) antibody therapeutics are licensed for the treatment of various diseases. The mechanism of action of recombinant monoclonal antibodies (rMAbs) has been extensively investigated and several distinct pathways have been defined; selective activation of specific pathways may optimize clinical outcomes for different diseases, such as cancer and chronic inflammation. Human IgG is a glycoprotein with oligosaccharides attached at a single site. These are essential to the mode of action of rMAbs, and the antibody efficacy can vary depending on the particular oligosaccharide that is attached. Methods are now becoming available that allow the production of rMAbs bearing pre-selected oligosaccharides - glycoforms - to provide maximum efficacy for a given disease indication. This Review summarizes current knowledge of these methods and avenues for their exploitation in the clinic.

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Background
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Background
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Background
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Background

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Background
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Background
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Background
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Background
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Background
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BackgroundInfluential
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BackgroundMethod
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Background
Key protection factors against tetanus: Anti-tetanus toxin antibody affinity and its ability to prevent tetanus toxin - ganglioside interaction.
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Background
Bespoke affinity ligands for the purification of therapeutic proteins
Khoury, G. E., Khogeer, B., Chen, C., Ng, K., Jacob, S. I., & Lowe, C. (2015) · Pharmaceutical Bioprocessing · doi:10.4155/pbp.14.60 · Cited by 17
Removal of a C-terminal serine residue proximal to the inter-chain disulfide bond of a human IgG1 lambda light chain mediates enhanced antibody stability and antibody dependent cell-mediated cytotoxicity
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Antibodies as key mediators of protection against Mycobacterium tuberculosis
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“Additionally, LTBI patients exhibited increased levels of di-galactosylation and sialylation, along with lower agalactosylation on IgG compared to ATB patients, indicating a heightened in ﬂ ammatory state in ATB (13, 72 – 74).”
Background
Unexpected Arabinosylation after Humanization of Plant Protein N-Glycosylation
Bohlender, L. L., Parsons, J., Hoernstein, S. N. W., Bangert, N., Rodríguez-Jahnke, F., Reski, R., & Decker, E. L. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.838365 · Cited by 19
“The impact of terminal N-glycan residues on efficacy and functional role of protein therapeutics has been extensively reviewed (Jefferis, 2009; Li and d’Anjou, 2009; Solá and Griebenow, 2010).”
Background
Recent advances and trends in sample preparation and chemical modification for glycan analysis.
Kinoshita, M., & Yamada, K. (2021) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2021.114424 · Cited by 16
Strategic feeding of NS0 and CHO cell cultures to control glycan profiles and immunogenic epitopes of monoclonal antibodies
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“Insights into the role of glycosylation in the regulation of antibodymediated immune functions have been applied to glyco-engineer therapeutic monoclonal antibodies to enhance or alter their effector functions (Jefferis, 2009).”
Background
Key Challenges in Designing CHO Chassis Platforms
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“In particular for monoclonal antibodies, the specific glycan structure plays an important role in the immunoactivity of the product [182] which led to the development of production cell lines that lack, for instance, fucosyltransferase FUT8, or that overexpress enzymes to generate more complex glycan structures [183,1…”
Background
Comparison of two glycoengineering strategies to control the fucosylation of a monoclonal antibody
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Data-independent oxonium ion profiling of multi-glycosylated biotherapeutics
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N -Glycosyltransferase from Aggregatibacter aphrophilus synthesizes glycopeptides with relaxed nucleotide-activated sugar donor selectivity
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Understanding Glycomechanics Using Mathematical Modeling: A Review of Current Approaches to Simulate Cellular Glycosylation Reaction Networks
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“Figure 3; sialylation is modest with < 10 % of structures being monosialylated or disialylated (Jefferis et al., 1990; Rudd et al., 1997; Routier et al., 1998; Jefferis 2009).”
BackgroundMethodInfluentialSelf-citation
Glycan engineering reveals interrelated effects of terminal galactose and core fucose on antibody‐dependent cell‐mediated cytotoxicity
Zhang, Q., Joubert, M. K., Polozova, A., Guzman, R. D., Lakamsani, K., Kinderman, F. S., Xiang, D., Shami, A. S. E., Miscalichi, N., Flynn, G. C., et al. (2020) · Biotechnology Progress · doi:10.1002/btpr.3045 · Cited by 19
“Next, terminal galactose was added to G0F species through enzymatic remodeling of mAbs with β (1, 4) galactosyltransferase.”
BackgroundMethodInfluential
Glyco-Engineering of Plant-Based Expression Systems
Fischer, R., Holland, T., Sack, M., Schillberg, S., Stöger, E., Twyman, R. M., & Buyel, J. F. (2018) · Advances in biochemical engineering, biotechnology · doi:10.1007/10_2018_76 · Cited by 21
Chemoenzymatic Glycan Remodeling of Natural and Recombinant Glycoproteins
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“…exhibit enhanced binding to FcγIIIa receptor, which translates into a 50–100 fold increase in antibody-dependent cellular *Corresponding author: wang518@umd.edu. uthor M anuscript A uthor M anuscript A uthor M anuscript cytotoxicity (ADCC) (Arnold, Wormald, Sim, Rudd, & Dwek, 2007; Jefferis, 2009).”
Background
Human Cell Line-Derived Monoclonal IgA Antibodies for Cancer Immunotherapy
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“In addition, while CHO-derived N-glycans exclusively possess α2,3-linked sialic acid, the majority of human serum IgA is linked in α2,6 configuration [24,29].”
BackgroundResultInfluential
GlycoPep MassList: Software to Generate Massive Inclusion Lists for Glycopeptide Analyses
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“IgG is also a very important recombinantly expressed biotherapeutic [43].”
Different Glycosylation Pattern of Human I g G 1 and I g G 3 Antibodies Isolated from Transiently as well as Permanently Transfected Cell Lines
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scFv-Based “Grababody” as a General Strategy to Improve Recruitment of Immune Effector Cells to Antibody-Targeted Tumors
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“Depending on cell culture conditions, the produced monoclonal antibodies can have varied glycosylation (3), which can either extend or shorten the serum half-life of the antibodies (4-6), and cause side effects in some antibody –based treatments (7).”
Background
Application of Quality by Design Paradigm to the Manufacture of Protein Therapeutics
del Val, I. J., Philip, M., Exley, K., Sou, S. N., Kyriakopoulos, S., Polizzi, K. M., & Kontoravdi, C. (2012) · InTech eBooks · doi:10.5772/50261 · Cited by 12
“The majority of approved biopharmaceuticals are produced in mammalian cell culture systems, since they are the sole means to deliver proteins with desired glycosylation patterns and thus ensure reduced immunogenicity and higher in vivo efficacy and stability [32, 107, 108].”
Background
Purification of human monoclonal antibodies and their fragments.
Müller-Späth, T., & Morbidelli, M. (2014) · Methods in molecular biology · doi:10.1007/978-1-62703-586-6_17 · Cited by 15
Single cell RNA sequencing improves the next generation of approaches to AML treatment: challenges and perspectives
Khosroabadi, Z., Azaryar, S., Dianat‐Moghadam, H., Amoozgar, Z., & Sharifi, M. (2025) · Molecular Medicine · doi:10.1186/s10020-025-01085-w · Cited by 18
Divergent Enzymatic Assembly of a Comprehensive 64‐Membered IgG N‐Glycan Library for Functional Glycomics
Ma, W., Xu, Z., Jiang, Y., Liu, J.-L., Xu, D.-D., Huang, W., & Li, T.-H. (2023) · Advancement of science · doi:10.1002/advs.202303832 · Cited by 14
IgE glycans promote anti-IgE IgG autoantibodies that facilitate IgE serum clearance via Fc Receptors
Plattner, K., Gharailoo, Z., Zinkhan, S., Engeroff, P., Bachmann, M. F., & Vogel, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1069100 · Cited by 15
“Moreover, glycosylation of proteins influences their serum kinetic (45, 46).”
Background
Desalting paper spray mass spectrometry (DPS-MS) for rapid detection of glycans and glycoconjugates
Chiu, K.-Y., Wang, Q., Gunawardena, H. P., Held, M., Faik, A., & Chen, H. (2021) · International Journal of Mass Spectrometry · doi:10.1016/j.ijms.2021.116688 · Cited by 18
Comparative studies on the substrate specificity and defucosylation activity of three α-L-fucosidases using synthetic fucosylated glycopeptides and glycoproteins as substrates
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Afucosylated IgG Targets FcγRIV for Enhanced Tumor Therapy in Mice
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“The Fc domain of mammalian IgG has a highly conserved N-linked glycosylation site in the second heavy chain constant domain (CH2) at the asparagine at position 297 (Asn297, EU numbering aligned to humans IgG) [9,10].”
Background
Multiplexed Comparative Analysis of Intact Glycopeptides using Electron-Transfer Dissociation (ETD) and Synchronous Precursor Selection (SPS) -based Triple-Stage Mass Spectrometry (MS3).
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Glycosylation of random IgG distinguishes seropositive and seronegative rheumatoid arthritis
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“The exposure of fucose and of branching GlcNAc is greatly influencing the ADCC of Ab preparation, and thus a main target during the design of efficient monoclonal Ab [25].”
Background
Structural consequences of aglycosylated IgG Fc variants evolved for FcγRI binding
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Background
Decoding the mannose receptor-mAb interaction: the importance of high-mannose N-glycans and glycan-pairing
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New Opportunities in Glycan Engineering for Therapeutic Proteins
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Background
Recent advances on the one-pot synthesis to assemble size-controlled glycans and glycoconjugates and polysaccharides
Han, X., Shen, B., Qiao, M., Linhardt, R. J., & Zhang, X. (2021) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2021.117672 · Cited by 15
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Background
Glycan dependent refolding activity of ER glucosyltransferase (UGGT).
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“Typically N-glycans are released by action of chemical or enzyme (peptide N-glycosidase F (PNGase-F)), which cleaves selectively nonfucosylated and α-[1-6]-corefucosylated N-glycans between Asn residue and GlcNAc of oligosaccharides.”
Background
Comparison of Traditional 2-AB Fluorescence LC-MS/MS and Automated LC-MS for the Comparative Glycan Analysis of Monoclonal Antibodies.
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Generating novel recombinant prokaryotic lectins with altered carbohydrate binding properties through mutagenesis of the PA-IL protein from Pseudomonas aeruginosa.
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“For example, serum IgG's, unlike many other serum glycoproteins, are not heavily sialylated, and the N-linked glycans present in the Fc region of the glycoproteins usually bear biantennary glycans terminating in LacNAc [42,43].”
Background
Glycoengineering in cancer therapeutics
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Authors: Jefferis, R.
Affiliations: University of Birmingham (GB)
Corresponding author: Jefferis, Roy
Venue: Nature Reviews Drug Discovery
Publisher: Springer Science and Business Media LLC
Published: 2009-03
Volume: 8
Issue: 3
Pages: 226-234
ISSN: 1474-1776 (ISSN-L)
1474-1784
DOI: 10.1038/nrd2804
OpenAlex: W1986197388
Cited by: 829
References: 78
Citations by year: 2026: 23 · 2025: 29 · 2024: 24 · 2023: 30 · 2022: 31 · 2021: 53 · 2020: 49 · 2019: 42 · 2018: 61 · 2017: 69 · 2016: 76 · 2015: 51 · 2014: 56 · 2013: 67 · 2012: 63
FWCI: 8.21
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.springer.com/tdm (tdm)
Locations: Nature Reviews Drug Discovery (publishedVersion, cc-by)
PubMed (publishedVersion)
University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
Topics: Life Sciences › Immunology and Microbiology › Immunology › 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, recombinant monoclonal antibodies, antibody effector functions, glycoforms, oligosaccharides, IgG, therapeutic antibodies, glycoengineering, antibody mechanism of action, cancer immunotherapy, chronic inflammation
MeSH terms: Animals, Antibodies, Monoclonal, Glycosylation, Humans, Immunoglobulin G, Inflammation, Neoplasms, Oligosaccharides

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Glycosylation as a strategy to improve antibody-based therapeutics

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