Glycosylation as a strategy to improve antibody-based therapeutics
Open accessAbstract
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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N-glycosylation is a critical quality attribute of biotherapeutic glycoproteins that influences efficacy, half-life and immunogenicity.
“the structure and composition of protein-linked oligosaccharides regulates the therapeutic efficacy, immunogenicity and half-life of recombinant biotherapeutics [1].”
From Glycoengineering Chinese hamster ovary cells: a short history (2021) · cites this paper as [1]
Murine cell lines NS0 and Sp2/0 produce glycan structures similar to humans but also produce immunogenic epitopes such as Galα(1-3)Gal and have high NeuGc sialic acid, which is why they are less commonly used for biotherapeutic production.
“while murine cell lines such as NS0 and Sp2/0 also produce glycan structures similar to humans, they also produce immunogenic epitopes such as the Galα(1–3)Gal epitope and they have a high content of NeuGc sialic acid, which is why they are less commonly used for biotherapeutic production [1,73].”
From Glycoengineering Chinese hamster ovary cells: a short history (2021) · cites this paper as [1]
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Chiu, M. L., Goulet, D. R., Teplyakov, A., & Gilliland, G. L. (2019) · Antibodies · doi:10.3390/antib8040055 · Cited by 646 · see citing works
“Likewise, glycosylation patterns can impact both PK and PD significantly [259,260].”
BackgroundRecent advances in (therapeutic protein) drug development
Lagassé, H. A. D., Alexaki, A., Simhadri, V. L., Katagiri, N. H., Jankowski, W., Sauna, Z. E., & Kimchi-Sarfaty, C. (2017) · F1000Research · doi:10.12688/f1000research.9970.1 · Cited by 481 · see citing works
Fc‐fusion proteins: new developments and future perspectives
Czajkowsky, D. M., Hu, J., Shao, Z., & Pleass, R. J. (2012) · EMBO Molecular Medicine · doi:10.1002/emmm.201201379 · Cited by 477 · see citing works
“…ability of IgG is consistent with the observation that decreased sialylation and galactosylation of IgG are observed in patients with arthritis (Jefferis, 2009), and modifications to the carbohydrate content of IgG have been posited as a molecular explanation for the ‘hygiene-hypothesis’…”
Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: A critical review
Maverakis, E. M., Kim, K., Shimoda, M., Gershwin, M. E., Patel, F., Wilken, R., Raychaudhuri, S. P., Ruhaak, L. R., & Lebrilla, C. B. (2015) · Journal of Autoimmunity · doi:10.1016/j.jaut.2014.12.002 · Cited by 456 · see citing works
“For example, it is nowwell established that the type of glycanpresent at residue Asn-180 of IgG1 helps dictate the effector function of the antibody, with some glycans being pro-inflammatory while others possessing anti-inflammatory properties [2,3].”
BackgroundZhong, Q., Xiao, X., Qiu, Y., Xu, Z., Chen, C., Chong, B., Zhao, X., Hai, S., Li, S., An, Z., et al. (2023) · MedComm · doi:10.1002/mco2.261 · Cited by 442 · see citing works
Glycosylation of Therapeutic Proteins
Solá, R. J., & Griebenow, K. H. (2010) · BioDrugs · doi:10.2165/11530550-000000000-00000 · Cited by 440 · see citing works
“Established technologies that have been shown to significantly improve the efficacy of protein drugs by increasing their molecular stabilities and plasma persistence times and by decreasing their pharmacodynamic responses through various mechanisms include the introduction of targeted mutations, generation of fusion p…”
BackgroundHuman plasma protein N-glycosylation
Clerc, F., Reiding, K. R., Jansen, B. C., Lageveen‐Kammeijer, G. S. M., Bondt, A., & Wuhrer, M. (2015) · Glycoconjugate Journal · doi:10.1007/s10719-015-9626-2 · Cited by 450 · see citing works
“Based on the amino acid sequence of the constant regions of the heavy chains, IgGs can be divided into four subclasses namely, IgG1 (P01857), IgG2 (P01859), IgG3 (P01860) and IgG4 (P01861) [371, 372].”
BackgroundAfucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity
Larsen, M. D., de Graaf, E. L., Sonneveld, M. E., Plomp, H. R., Nouta, J., Hoepel, W., Chen, H.-J., Linty, F., Visser, R., Brinkhaus, M., et al. (2021) · Science · doi:10.1126/science.abc8378 · Cited by 408 · see citing works
Advances in recombinant antibody manufacturing
Kunert, R., & Reinhart, D. (2016) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-016-7388-9 · Cited by 420 · see citing works
Fc glycans of therapeutic antibodies as critical quality attributes
Reusch, D., & Tejada, M. L. (2015) · Glycobiology · doi:10.1093/glycob/cwv065 · Cited by 406 · see citing works
“Depending on the recombinant expression system, this may be a complex type, hybrid type or high-mannose type structure (Durocher and Butler 2009; Jefferis 2009a).”
BackgroundInfluentialFc receptor-targeted therapies for the treatment of inflammation, cancer and beyond
Hogarth, P. M., & Pietersz, G. A. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd2909 · Cited by 348 · see citing works
“Certainly, the observation that the glycosylation state of IgG influences the pro- or anti-inflammatory nature of IgG is consistent with the clinical observation that decreased levels of sialylation and galactosylation of IgG are seen in patients with inflammatory autoimmune diseases such as rheumatoid arthritis and v…”
Post-translational Modifications Differentially Affect IgG1 Conformation and Receptor Binding*
Houde, D., Peng, Y.-C., Berkowitz, S., & Engen, J. (2010) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m900540-mcp200 · Cited by 363 · see citing works
“These effector functions are essential to many therapeutic antibodies, especially when antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity are involved in the mechanisms of action (6).”
BackgroundPharmacokinetics of monoclonal antibodies and Fc-fusion proteins
Liming, L. (2017) · Protein & Cell · doi:10.1007/s13238-017-0408-4 · Cited by 394 · see citing works
“Glycosylation patterns can impact both PK and PD significantly (Arnold et al., 2007; Jefferis, 2009a).”
BackgroundImpact of Product-Related Factors on Immunogenicity of Biotherapeutics
Singh, S. K. (2011) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.22276 · Cited by 350 · see citing works
Recombinant antibody therapeutics: the impact of glycosylation on mechanisms of action
Jefferis, R. (2009) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2009.04.007 · Cited by 329 · see citing works
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“The glycan structures of therapeutic mAbs can be of importance for the efficacy and safety of the drug [21].”
BackgroundAdvances in the assessment and control of the effector functions of therapeutic antibodies
Jiang, X., Song, A., Bergelson, S., Arroll, T. W., Parekh, B. S., May, K. M. L., Chung, S., Strouse, R., Mire‐Sluis, A. R., & Schenerman, M. A. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3365 · Cited by 300 · see citing works
“Fc glycosylation is necessary for therapeutic antibodies to elicit effector function”
BackgroundEmerging phagocytosis checkpoints in cancer immunotherapy
Liu, Y., Wang, Y., Yang, Y., Weng, L., Wu, Q., Zhang, J., Zhao, P., Fang, L., Shi, Y., & Wang, P. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01365-z · Cited by 287 · see citing works
High-sensitivity Analytical Approaches for the Structural Characterization of Glycoproteins
Alley, W. R., Mann, B. F., & Novotný, M. V. (2013) · Chemical Reviews · doi:10.1021/cr3003714 · Cited by 307 · see citing works
Chemoenzymatic Glycoengineering of Intact IgG Antibodies for Gain of Functions
Huang, W., Giddens, J. P., Fan, S., Toonstra, C., & Wang, L. (2012) · Journal of the American Chemical Society · doi:10.1021/ja3051266 · Cited by 307 · see citing works
Wilson, N. S., Yang, B., Yang, A., Loeser, S., Marsters, S. A., Lawrence, D. A., Li, Y., Pitti, R. M., Tótpál, K., Yee, S. F., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.11.012 · Cited by 247 · see citing works
“Furthermore, it may be possible to improve the potency of agonistic antibodies by modifying the amino acid or carbohydrate components of the Fc region to enhance affinity for FcgRs (Carter, 2006; Jefferis, 2009; Lazar et al., 2006; Presta et al., 2002; Satoh et al., 2006).”
BackgroundPance, K., Gramespacher, J. A., Byrnes, J. R., Salangsang, F., Serrano, J.-A. C., Cotton, A. D., Steri, V., & Wells, J. A. (2023) · Nature Biotechnology · doi:10.1038/s41587-022-01456-2 · Cited by 265 · see citing works
Considerations for the Design of Antibody-Based Therapeutics
Goulet, D. R., & Atkins, W. M. (2019) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2019.05.031 · Cited by 305 · see citing works
Mizushima, T., Yagi, H., Takemoto, E., Shibata‐Koyama, M., Isoda, Y., Iida, S., Masuda, K., Satoh, M., & Kato, K. (2011) · Genes to Cells · doi:10.1111/j.1365-2443.2011.01552.x · Cited by 246 · see citing works
“…has been achieved that may dramatically enhance effector functions through a cellular engineering technique for modifying the sugar chains displayed on the Fc region of immunoglobulin G (IgG) (Umaña et al. 1999; Kaneko et al. 2006; Jefferis 2009; Kubota et al. 2009; Yamane-Ohnuki & Satoh 2009).”
BackgroundGolay, J., Roit, F. D., Bologna, L., Ferrara, C., Leusen, J. H. W., Rambaldi, A., Klein, C., & Introna, M. (2013) · Blood · doi:10.1182/blood-2013-05-504043 · Cited by 232 · see citing works
“Glycoengineered CD20 antibodies also induced phagocytosis of CLL targets by PMNs, but not ADCC.”
BackgroundInfluentialPost-translational modifications of protein biopharmaceuticals
Walsh, G. (2010) · Drug Discovery Today · doi:10.1016/j.drudis.2010.06.009 · Cited by 263 · see citing works
Isotype and glycoform selection for antibody therapeutics
Jefferis, R. (2012) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2012.03.021 · Cited by 252 · see citing works
Self-citationZeitlin, L., Pettitt, J., Scully, C., Bohorova, N., Kim, D., Pauly, M. H., Hiatt, A., Ngo, L. H., Steinkellner, H., Whaley, K. J., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1108360108 · Cited by 229 · see citing works
“Surface plasmon resonance was also performed with recombinant FcγRIII (Table 1), a receptor important for induction of ADCC by NK cells (9, 10).”
InfluentialDesign and Production of Bispecific Antibodies
Wang, Q., Chen, Y., Park, J., Liu, X., Hu, Y., Wang, T., McFarland, K. S., & Betenbaugh, M. J. (2019) · Antibodies · doi:10.3390/antib8030043 · Cited by 280 · see citing works
“Numerous studies have demonstrated that the amino acid sequence of the CH2 and CH3 domain and the Fc conserved glycan profile both impact the antibody ADCC and CDC activities [11].”
BackgroundJunttila, T. T., Parsons, K. L., Olsson, C., Lu, Y., Xin, Y., Theriault, J., Crocker, L., Pabonan, O., Baginski, T., Meng, G., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3704 · Cited by 222 · see citing works
“org Downloaded from The ability to increase in vitro ADCC by antibody engineering is widely established (33, 34).”
BackgroundA prominent lack of IgG1-Fc fucosylation of platelet alloantibodies in pregnancy
Kapur, R., Kustiawan, I., Vestrheim, A., Koeleman, C. A. M., Visser, R., Einarsdottir, H., Porcelijn, L., Jackson, D., Kumpel, B. M., Deelder, A. M., et al. (2013) · Blood · doi:10.1182/blood-2013-09-527978 · Cited by 219 · see citing works
Washburn, N., Schwab, I., Ortiz, D., Bhatnagar, N., Lansing, J. C., Medeiros, A., Tyler, S., Mekala, D., Cochran, E., Sarvaiya, H., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1422481112 · Cited by 225 · see citing works
“Typically, this core can be further extended with fucose, galactose, sialic acid, and bisecting GlcNAc monosaccharides through selective enzymatic glycosylation reactions (12, 13).”
BackgroundSchneider‐Merck, T., van Bueren, J. J. L., Berger, S., Rossen, K., van Berkel, P. H. C., Derer, S., Beyer, T. D., Lohse, S., Bleeker, W. K., Peipp, M., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900847 · Cited by 223 · see citing works
Pharmacological significance of glycosylation in therapeutic proteins
Li, H., & d′Anjou, M. (2009) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2009.10.009 · Cited by 232 · see citing works
Glycotherapy: New Advances Inspire a Reemergence of Glycans in Medicine
Hudak, J. E., & Bertozzi, C. R. (2013) · Chemistry & Biology · doi:10.1016/j.chembiol.2013.09.010 · Cited by 228 · see citing works
“For those interested in further reading, the potential for controlling IgG-based therapeutics through glycoengineering has recently been reviewed (Jefferis, 2009).”
BackgroundKendall, S., & Teicher, J. (2008) · doi:10.1002/0471773735.ch2 · Cited by 214
Glycoconjugates: Synthesis, Functional Studies, and Therapeutic Developments
Shivatare, S. S., Shivatare, V. S., & Wong, C. (2022) · Chemical Reviews · doi:10.1021/acs.chemrev.1c01032 · Cited by 260 · see citing works
In Planta Protein Sialylation through Overexpression of the Respective Mammalian Pathway
Castilho, A., Strasser, R., Stadlmann, J., Grass, J., Jeż, J., Gattinger, P., Kunert, R., Quendler, H., Pabst, M., Leonard, R., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.088401 · Cited by 230 · see citing works
Fan, Y., del Val, I. J., Müller, C. R., Sen, J. W., Rasmussen, S. K., Kontoravdi, C., Weilguny, D., & Andersen, M. R. (2014) · Biotechnology and Bioengineering · doi:10.1002/bit.25450 · Cited by 217 · see citing works
“effectors function, immunogenicity, stability, and clearance rate (Burton and Dwek 2006; Goochee et al. 1991; Jefferis 2009a; Jefferis 2009b; Raju 2008).”
BackgroundInfluentialYu, M., Brown, D., Reed, C., Chung, S., Lutman, J., Stefanich, E., Wong, A., Stephan, J.-P., & Bayer, R. (2012) · mAbs · doi:10.4161/mabs.20737 · Cited by 203 · see citing works
“The study of antibody glycosylation is growing in importance because of the essential role carbohydrates play in modulating effector functions, which affect the safety and efficacy of therapeutic antibodies.(1,2) Induction of antibody-dependent cell-mediated cytotoxicity (ADCC) requires binding of the Fc region of the…”
BackgroundModulation of antibody galactosylation through feeding of uridine, manganese chloride, and galactose
Gramer, M. J., Eckblad, J. J., Donahue, R., Brown, J., Shultz, C., Vickerman, K., Priem, P., van den Bremer, E. T. J., Gerritsen, J., & van Berkel, P. H. C. (2011) · Biotechnology and Bioengineering · doi:10.1002/bit.23075 · Cited by 193 · see citing works
“Fortunately, antibody Fc glycosylation is relatively restricted and is typically comprised of low levels of high mannose structures with the vast majority of forms as complex, corefucosylated, biantennary structures with variable levels of terminal galactosylation and minimal sialylation (Jefferis, 2009).”
BackgroundInfluentialRecent advances in mammalian protein production
Bandaranayake, A. D., & Almo, S. C. (2014) · FEBS Letters · doi:10.1016/j.febslet.2013.11.035 · Cited by 222 · see citing works
Chemoenzymatic Methods for the Synthesis of Glycoproteins
Li, C., & Wang, L. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00238 · Cited by 248 · see citing works
Multiplexed Fc array for evaluation of antigen-specific antibody effector profiles
Brown, E. P., Dowell, K. G., Boesch, A. W., Normandin, E., Mahan, A. E., Chu, T. H., Barouch, D. H., Bailey‐Kellogg, C., Alter, G., & Ackerman, M. E. (2017) · Journal of Immunological Methods · doi:10.1016/j.jim.2017.01.010 · Cited by 197 · see citing works
“…of such effector functions has long been recognized in the fi eld of therapeutic monoclonal antibodies (Cartron et al., 2002; Liu et al., 2014; Gennari et al., 2004; Niwa et al., 2005; Pincetic et al., 2014; Taylor and Lindorfer, 2008; Clynes et al., 2000; Musolino et al., 2008; Jefferis, 2009a).”
Mimura, Y., Katoh, T., Saldova, R., O’Flaherty, R., Izumi, T., Mimura‐Kimura, Y., Utsunomiya, T., Mizukami, Y., Yamamoto, K., Matsumoto, T., et al. (2017) · Protein & Cell · doi:10.1007/s13238-017-0433-3 · Cited by 217 · see citing works
“Although the importance of glycosylation for Fc effector functions of therapeutic IgG antibodies has been previously documented (Jefferis, 2009, 2012, 2017; Mimura et al., 2009; Zhang et al., 2016), this review summarizes recent advances in antibody glycobiology that are applicable for optimization…”
BackgroundEngineered Sialylation of Pathogenic Antibodies In Vivo Attenuates Autoimmune Disease
Pagan, J. D., Kitaoka, M., & Anthony, R. M. (2017) · Cell · doi:10.1016/j.cell.2017.11.041 · Cited by 203 · see citing works
“Studies over the last decade have demonstrated the composition of the Fc glycan exerts profound influence over IgG effector functions (Jefferis, 2005, 2009a, 2009b).”
Challenges and approaches for the development of safer immunomodulatory biologics
Sathish, J. G., Sethu, S., Bielsky, M.-C., de Haan, L., French, N. S., Govindappa, K., Green, J., Griffiths, C. E. M., Holgate, S. T., Jones, D., et al. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd3974 · Cited by 186 · see citing works
“Other approaches include enhancing the effector functions of mAbs (either ADCC or CDC) through afucosylation [29] [30] [31] , by adding N-acetylglucosamine 32 and by altering the galactosylation status 33, 34 .”
BackgroundSt‐Amour, I., Paré, I., Alata, W., Coulombe, K., Goulet, C. R., Drouin‐Ouellet, J., Vandal, M., Soulet, D., Bazin, R., & Calon, F. (2013) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2013.160 · Cited by 190 · see citing works
T Lymphocytes Expressing a CD16 Signaling Receptor Exert Antibody-Dependent Cancer Cell Killing
Kudo, K., Imai, C., Lorenzini, P. A., Kamiya, T., Kono, K., Davidoff, A. M., Chng, W. J., & Campana, D. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-1365 · Cited by 187 · see citing works
“being made to further enhance the affinity of Fc fragments for FcgR, for example, by glycoengineering (23, 41).”
BackgroundDevelopment of orally active inhibitors of protein and cellular fucosylation
Okeley, N., Alley, S., Anderson, M., Boursalian, T., Burke, P., Emmerton, K., Jeffrey, S., Klussman, K., Law, C., Sussman, D., et al. (2013) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1222263110 · Cited by 177 · see citing works
Stepping stones in DNA sequencing
Taylor, M., Mulako, I., Tuffin, M., & Cowan, D. A. (2012) · Biotechnology Journal · doi:10.1002/biot.201200153 · Cited by 177 · see citing works
“2, glycoform 3) has become a focus of interest in recent years because major contributions to mAb activities have been assigned to this specific N-glycan residue (recently reviewed in [4]).”
BackgroundInfluentialExpression, Role, and Regulation of Neutrophil Fcγ Receptors
Wang, Y., & Jönsson, F. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01958 · Cited by 189 · see citing works
“Several studies have illustrated how the composition of the Fc glycan influences IgG effector functions (119, 120) (Figure 1A).”
BackgroundAntibody glycosylation in inflammation, disease and vaccination
Alter, G., Ottenhoff, T. H. M., & Joosten, S. A. (2018) · Seminars in Immunology · doi:10.1016/j.smim.2018.05.003 · Cited by 186 · see citing works
“In contrast, vaccination of HIV negative individuals with different formulations of the gp120 antigen elicited differently glycosylated IgGs.”
BackgroundInfluentialZou, G., Ochiai, H., Huang, W., Yang, Q., Li, C., & Wang, L. (2011) · Journal of the American Chemical Society · doi:10.1021/ja208390n · Cited by 167 · see citing works
Monoclonal antibody-based therapies for microbial diseases
Saylor, C., Dadachova, E., & Casadevall, A. (2009) · Vaccine · doi:10.1016/j.vaccine.2009.09.105 · Cited by 172 · see citing works
“For example, alterations in Fc region glycosylation can increase antibody-dependent cell-mediated cytotoxicity (ADCC) [101].”
Glycosylation influences on the aggregation propensity of therapeutic monoclonal antibodies.
Kayser, V., Chennamsetty, N., Voynov, V., Forrer, K., Helk, B., & Trout, B. (2011) · Biotechnology Journal · doi:10.1002/biot.201000091 · Cited by 162 · see citing works
Engineering antibody therapeutics
Chiu, M. L., & Gilliland, G. L. (2016) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2016.07.012 · Cited by 165 · see citing works
Melmer, M., Stangler, T., Premstaller, A., & Lindner, W. (2011) · Journal of Chromatography A · doi:10.1016/j.chroma.2010.10.122 · Cited by 156 · see citing works
Reusch, D., Haberger, M., Maier, B., Maier, M., Kloseck, R., Zimmermann, B., Hook, M., Szabó, Z., Tep, S., Wegstein, J., et al. (2014) · mAbs · doi:10.4161/19420862.2014.986000 · Cited by 169 · see citing works
“Additionally, they vary in galactose and sialic acid content.(4,6-8) Some therapeutic mAbs may carry additional N-glycans in the variable regions of the antigen-binding (Fab) domain and these glycans may affect antigen binding.”
Xie, H., Chakraborty, A. B., Ahn, J., Yu, Y. Q., Deepalakshmi, P. D., Gilár, M., Chen, W., Skilton, S. J., & Mazzeo, J. R. (2010) · mAbs · doi:10.4161/mabs.11986 · Cited by 145 · see citing works
Revisiting the Role of Glycosylation in the Structure of Human IgG Fc
Borrok, M. J., Jung, S. T., Kang, T. H., Monzingo, A. F., & Georgiou, G. (2012) · ACS Chemical Biology · doi:10.1021/cb300130k · Cited by 156 · see citing works
“Indeed, efforts have focused on the engineering of monoclonal antibodies with glycans optimized for various effector functions.(8, 9) For example, defucosylation of the N297 glycan has been reported to enhanced binding of FcγRIIIa and increase NK mediated ADCC by >50 fold.”
BackgroundLi, X., Fang, T., & Boons, G. (2014) · Angewandte Chemie · doi:10.1002/anie.201402606 · Cited by 151 · see citing works
Anaphylaxis syndromes related to a new mammalian cross-reactive carbohydrate determinant
Commins, S., & Platts-Mills, T. (2009) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2009.08.026 · Cited by 151 · see citing works
Antigen-Specific Antibody Glycosylation Is Regulated via Vaccination
Mahan, A. E., Jennewein, M. F., Suscovich, T. J., Dionne, K., Tedesco, J., Chung, A. W., Streeck, H., Pau, M. G., Schuitemaker, H., Francis, D., et al. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005456 · Cited by 149 · see citing works
“Thus, while the antibody therapeutics field has clearly demonstrated that alterations in antibody glycosylation is a critical mechanism for improving therapeutic efficacy via the augmentation of effector function [6,13,23] or through the alteration of inflammation in rheumatoid arthritis treatment [19], it is still un…”
BackgroundGlycosylation: impact, control and improvement during therapeutic protein production
Costa, A. R., Rodrigues, M. E., Henriques, M., Oliveira, R., & Azeredo, J. (2013) · Critical Reviews in Biotechnology · doi:10.3109/07388551.2013.793649 · Cited by 155 · see citing works
“functions through the modulation of the binding affinities for FcgR receptors (Crispin et al., 2009; Jefferis, 2009a; Li & d’Anjou, 2009; Mimura et al., 2009; Raju, 2008).”
BackgroundInfluentialJimenez del Val, I., Nagy, J. M., & Kontoravdi, C. (2011) · Biotechnology Progress · doi:10.1002/btpr.688 · Cited by 135 · see citing works
“Almost all commercial mAbs are based on the immunoglobulin (IgG) isotype.(2) All IgG-based mAbs contain a consensus N-linked glycosylation site on the Cc2 domains of their heavy chains.”
BackgroundSaxena, A., & Wu, D. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00580 · Cited by 150 · see citing works
Glycodelete engineering of mammalian cells simplifies N-glycosylation of recombinant proteins
Meuris, L., Santens, F., Elson, G., Festjens, N., Boone, M., Dos Santos, A., Devos, S., Rousseau, F., Plets, E., Houthuys, E., et al. (2014) · Nature Biotechnology · doi:10.1038/nbt.2885 · Cited by 141 · see citing works
Therapeutic antibodies, vaccines and antibodyomes
Dimitrov, D. S. (2010) · mAbs · doi:10.4161/mabs.2.3.11779 · Cited by 141 · see citing works
Size-dependent segregation controls macrophage phagocytosis of antibody-opsonized targets
Bakalar, M., Joffe, A., Schmid, E., Son, S.-M., Podolski, M., & Fletcher, D. (2018) · bioRxiv · doi:10.1101/250373 · Cited by 139
“Previous work has shown that biochemical properties of the antibody Fc domain, such as isotype and glycosylation, can produce divergent immune responses due to changes in binding specificity and affinity for activating and inhibitory Fc receptors (Jefferis, 2009; Nimmerjahn and Ravetch, 2005).”
BackgroundAntibody recognition of carbohydrate epitopes
Haji‐Ghassemi, O., Blackler, R. J., Young, N. M., & Evans, S. V. (2015) · Glycobiology · doi:10.1093/glycob/cwv037 · Cited by 145 · see citing works
“Following translation, the antibody polypeptides are modified at glycosylation sites, particularly in the constant-regions (Figure 1) where these carbohydrate moieties are involved in modulation of effector functions (Mimura et al. 2001; Jefferis 2009).”
BackgroundChemical and Chemoenzymatic Synthesis of Glycoproteins for Deciphering Functions
Wang, L., & Amin, M. A. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.01.001 · Cited by 163 · see citing works
“For example, the lack of the core fucose, as well as the attachment of a bisecting GlcNAc moiety, significantly enhances the affinity of antibody for the FcgIIIa receptor (FcgRIIIa), which is responsible for ADCC (Ferrara et al., 2011; Shields et al., 2002).”
BackgroundInfluentialdel Val, I. J., Kontoravdi, C., & Nagy, J. M. (2010) · Biotechnology Progress · doi:10.1002/btpr.470 · Cited by 139 · see citing works
Impact of Glycosylation on Effector Functions of Therapeutic IgG
Abès, R., & Teillaud, J. (2010) · Pharmaceuticals · doi:10.3390/ph3010146 · Cited by 131 · see citing works
“Engineering the Fc region of IgG1 therapeutic mAbs to modulate IgG/FcγRIIIA interactions has become a major goal over the last decade following a number of reports showing that FcγRIIIA play an important role in the efficacy of therapeutic mAbs [24].”
BackgroundNimmerjahn, F., & Ravetch, J. V. (2010) · Current topics in microbiology and immunology · doi:10.1007/82_2010_86 · Cited by 154 · see citing works
Emerging Technologies for Making Glycan-Defined Glycoproteins
Wang, L., & Lomino, J. V. (2011) · ACS Chemical Biology · doi:10.1021/cb200429n · Cited by 137 · see citing works
“Compelling evidence has shown that appropriate glycosylation is important for pharmacokinetics, cellular distributions, and biological activities of therapeutic glycoproteins (6, 7, 12-16).”
BackgroundThe Role of Fc Receptors on the Effectiveness of Therapeutic Monoclonal Antibodies
Gogesch, P., Dudek, S., van Zandbergen, G., Waibler, Z., & Anzaghe, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168947 · Cited by 152 · see citing works
“Alterations of the glycosylation pattern might therefore have a major impact on the safety and efficacy of a therapeutic mAb [82].”
BackgroundHe, H., Ye, J., Wang, Y., Liu, Q., Chung, H. S., Kwon, Y. M., Shin, M. C., Lee, K., & Yang, V. C.-M. (2014) · Journal of Controlled Release · doi:10.1016/j.jconrel.2013.12.019 · Cited by 134 · see citing works
“Possessing a relatively long half-life should be a key aspect in the clinical application of protein drugs, and various strategies, including chemical modification [16-20], fusion with other proteins or peptides [21-23], glycosylation [24-26], incorporation of protease resistant variants [27], and encapsulation into m…”
The Dawn of a New Era: Targeting the “Undruggables” with Antibody-Based Therapeutics
Qian, L., Lin, X., Gao, X., Khan, R. U., Liao, J., Du, S., Ge, J., Zeng, S., & Yao, S. Q. (2023) · Chemical Reviews · doi:10.1021/acs.chemrev.2c00915 · Cited by 156 · see citing works
Reducing Immunogenicity by Design: Approaches to Minimize Immunogenicity of Monoclonal Antibodies
Harris, C. T., & Cohen, S. (2024) · BioDrugs · doi:10.1007/s40259-023-00641-2 · Cited by 140 · see citing works
“…to some functions of antibodies, such as regulating ADCC and CDC activity, glycosylation can also alter protein therapeutic immunogenicity. mAb can bear N -glycosylation or O -glycosylation in the Fc region, typically at asparagine occupying position 297, and in the Fab region of IgG [131].”
BackgroundTrial Watch: Monoclonal antibodies in cancer therapy
Galluzzi, L., Vacchelli, E., Fridman, W. H., Galon, J., Sautès‐Fridman, C., Tartour, É., Zucman‐Rossi, J., Zitvogel, L., & Kroemer, G. (2012) · OncoImmunology · doi:10.4161/onci.1.1.17938 · Cited by 150 · see citing works
Engineering mammalian cells in bioprocessing – current achievements and future perspectives
Lim, Y., Wong, N. S. C., Lee, Y. Y., Ku, S. C. Y., Wong, D. C. F., & Yap, M. G. S. (2010) · Biotechnology and Applied Biochemistry · doi:10.1042/ba20090363 · Cited by 134 · see citing works
Boune, S., Hu, P., Epstein, A. L., & Khawli, L. A. (2020) · Antibodies · doi:10.3390/antib9020022 · Cited by 138 · see citing works
Galactosylation variations in marketed therapeutic antibodies
Raju, T., & Jordan, R. (2012) · mAbs · doi:10.4161/mabs.19868 · Cited by 126 · see citing works
“cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC).(1-9) These result from the affect of Fc glycans on antibody interactions with Fc receptors on immune effector cells and C1q in the complement system.”
BackgroundInfluentialDesigning polymers with sugar-based advantages for bioactive delivery applications
Zhang, Y., Chan, J. W., Moretti, A., & Uhrich, K. E. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.09.053 · Cited by 139 · see citing works
“As a result, hybrid technologies have emerged, such as the development of antibodies glycosylated with oligosaccharides to target sugar receptor-bearing cells [69].”
BackgroundCutting-edge mass spectrometry characterization of originator, biosimilar and biobetter antibodies.
Beck, A., Debaene, F., Diemer, H., Wagner-Rousset, E., Colas, O., van Dorsselaer, A., & Cianférani, S. (2015) · Journal of Mass Spectrometry · doi:10.1002/jms.3554 · Cited by 123 · see citing works
An endoglycosidase with alternative glycan specificity allows broadened glycoprotein remodelling.
Goodfellow, J., Baruah, K., Yamamoto, K., Bonomelli, C., Krishna, B., Harvey, D., Crispin, M., Scanlan, C. N., & Davis, B. (2012) · Journal of the American Chemical Society · doi:10.1021/ja301334b · Cited by 123 · see citing works
Fairbanks, A. (2017) · Chemical Society Reviews · doi:10.1039/c6cs00897f · Cited by 121 · see citing works
Fcγ Receptor Heterogeneity in Leukocyte Functional Responses
Rosales, C. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00280 · Cited by 139 · see citing works
“These changes in the glycosylation pattern seem to regulate IgG activity (130).”
BackgroundReusch, D., Haberger, M., Falck, D., Peter, B., Maier, B., Gassner, J., Hook, M., Wagner, K., Bonnington, L. S., Bulau, P., et al. (2015) · mAbs · doi:10.1080/19420862.2015.1045173 · Cited by 132 · see citing works
The Perfect Storm: HLA Antibodies, Complement, FcγRs and Endothelium in Transplant Rejection
Thomas, K. A., Valenzuela, N., & Reed, E. (2015) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2015.02.004 · Cited by 121 · see citing works
Liu, B., Spearman, M. A., Doering, J., Lattová, E., Perreault, H., & Butler, M. (2013) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2013.11.007 · Cited by 119 · see citing works
“The position of the conserved glycan in the restricted interstitial space between the Fc domains of the heavy chains of an antibody normally limits the accessibility of glycosyltransferase enzymes, notably galactosyltransferase and sialyltransferase (Jefferis, 2009).”
Background
- Authors
- Jefferis, R.
- Affiliations
- University of Birmingham (GB)
- Corresponding author
- Jefferis, Roy
- Venue
- Nature Reviews Drug Discovery
- Published
- 2009-03
- Volume
- 8
- Issue
- 3
- Pages
- 226-234
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- 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
- Locations
- Nature Reviews Drug Discovery (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- 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, 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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