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

The DOI matches its Crossref record; 69 of the 78 references it cites were found in a registry or an index.

Glycosylation as a strategy to improve antibody-based therapeutics

Open access

Jefferis, Roy·2009·Nature Reviews Drug Discovery

DOI 10.1038/nrd2804

Open this paper in CoChat — free account

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.

Integrity signals

Registry

Crossref · 10.1038/nrd2804

Cites

69 of 69 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Continuous cultures of fused cells secreting antibody of predefined specificity
Köhler, G., & Milstein, C. (1975) · Nature · doi:10.1038/256495a0 · Cited by 17,200 · cited 1×
“The development of antibody therapeutics The original technology for generating MAbs of defined specificity was developed in the mouse and immediately applied to the generation of MAbs with specificity for human protein”
Method
Fcγ receptors as regulators of immune responses
Nimmerjahn, F., & Ravetch, J. V. (2008) · Nature Reviews Immunology · doi:10.1038/nri2206 · Cited by 2,947 · cited 1×
“These effector ligands include three structurally homologous cellular Fc receptor types (FcγRI, FcγRII and FcγRIII), the C1q component of complement and the neonatal Fc receptor (FcRn”
Background
FcRn: the neonatal Fc receptor comes of age
Roopenian, D. C., & Akilesh, S. (2007) · Nature Reviews Immunology · doi:10.1038/nri2155 · Cited by 2,346
Humanization of an anti-p185HER2 antibody for human cancer therapy.
Carter, P. M., Presta, L. G., Gorman, C., Ridgway, J. B., Henner, D. J., Wong, W., Rowland, A. M., Kotts, C. E., Carver, M. E., & Shepard, H. M. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.10.4285 · Cited by 1,926 · cited 1×
“The double challenge of producing rMAbs with appropriately glycosylated IgG Fc and IgG Fab sites has led to some companies engineering out VH or VL glycosylation motifs when present in candidate rMAb”
Background
Lack of Fucose on Human IgG1 N-Linked Oligosaccharide Improves Binding to Human FcγRIII and Antibody-dependent Cellular Toxicity
Shields, R. L., Lai, J., Keck, R., O'Connell, L. Y., Hong, K., Meng, Y. G., Weikert, S. H. A., & Presta, L. G. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202069200 · Cited by 1,835
Anti-Inflammatory Activity of Immunoglobulin G Resulting from Fc Sialylation
Kaneko, Y., Nimmerjahn, F., & Ravetch, J. V. (2006) · Science · doi:10.1126/science.1129594 · Cited by 1,754 · cited 1×
“Small but possibly significant differences in the affinities of sialylated and non-sialylated IgG Fc for FcγR have been reporte”
Background
Crystallographic refinement and atomic models of a human Fc fragment and its complex with fragment B of protein A from Staphylococcus aureus at 2.9- and 2.8-A resolution.
Deisenhofer, J. (1981) · Biochemistry · doi:10.1021/bi00512a001 · Cited by 1,539 · cited 1×
“X-ray crystallographic analysis reveals that the structure of the oligosaccharide is defined (as opposed to undefined owing to continuous mobility), is integral to the IgG Fc structure and forms multiple non-covalent interactions with the protein surface of the CH2 domain; thus, the conformation of the IgG Fc glycopro…”
Background
The Absence of Fucose but Not the Presence of Galactose or Bisecting N-Acetylglucosamine of Human IgG1 Complex-type Oligosaccharides Shows the Critical Role of Enhancing Antibody-dependent Cellular Cytotoxicity
Shinkawa, T., Nakamura, K., Yamane, N., Shoji-Hosaka, E., Kanda, Y., Sakurada, M., Uchida, K., Anazawa, H., Satoh, M., Yamasaki, M., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210665200 · Cited by 1,413
The Impact of Glycosylation on the Biological Function and Structure of Human Immunoglobulins
Arnold, J. N., Wormald, M. R., Sim, R. B., Rudd, P. M., & Dwek, R. A. (2006) · Annual Review of Immunology · doi:10.1146/annurev.immunol.25.022106.141702 · Cited by 1,354 · cited 1×
“It is generally reported that IgG Fc oligosaccharides of normal human IgG are predominantly devoid of terminal sialic acid residue”
Background
Potent antibody therapeutics by design
Carter, P. J. (2006) · Nature reviews. Immunology · doi:10.1038/nri1837 · Cited by 1,124 · cited 1×
“Additionally, it is estimated that ∼30% of new drugs that are likely to be licensed during the next decade will be based on antibody product”
Background
Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc
Anthony, R. M., Nimmerjahn, F., Ashline, D. J., Reinhold, V. N., Paulson, J. C., & Ravetch, J. V. (2008) · Science · doi:10.1126/science.1154315 · Cited by 849
Glycosylation changes of IgG associated with rheumatooid arthritis can activate complement via the mannose-binding protein
Malhotra, R., Wormald, M. R., Rudd, P. M., Fischer, P. B., Dwek, R. A., & Sim, R. B. (1995) · Nature Medicine · doi:10.1038/nm0395-237 · Cited by 786 · cited 1×
“The serum protein mannose-binding lectin ( MBL ) can recognize and bind arrays of N -acetylglucosamin”
Background
Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity
Umaña, P., Jean–Mairet, J., Moudry, R., Amstutz, H., & Bailey, J. E. (1999) · Nature Biotechnology · doi:10.1038/6179 · Cited by 764
The 3.2-Å crystal structure of the human IgG1 Fc fragment–FcγRIII complex
Sondermann, P., Huber, R., Oosthuizen, V., & Jacob, U. (2000) · Nature · doi:10.1038/35018508 · Cited by 735
Structural Analysis of Human IgG-Fc Glycoforms Reveals a Correlation Between Glycosylation and Structural Integrity
Krapp, S., Mimura, Y., Jefferis, R., Huber, R., & Sondermann, P. (2003) · Journal of Molecular Biology · doi:10.1016/s0022-2836(02)01250-0 · Cited by 690
Self-citation
The known unknowns of antigen processing and presentation
Vyas, J. M., van der Veen, A. G., & Ploegh, H. L. (2008) · Nature reviews. Immunology · doi:10.1038/nri2368 · Cited by 689 · cited 1×
“This is of particular interest, or concern, for the potentiation of immunogenicity, as dendritic cells are 'professional' antigen-presenting cell”
Background
Establishment of FUT8 knockout Chinese hamster ovary cells: An ideal host cell line for producing completely defucosylated antibodies with enhanced antibody‐dependent cellular cytotoxicity
Yamane‐Ohnuki, N., Kinoshita, S., Inoue‐Urakubo, M., Kusunoki, M., Iida, S., Nakano, R., Wakitani, M., Niwa, R., Sakurada, M., Uchida, K., et al. (2004) · Biotechnology and Bioengineering · doi:10.1002/bit.20151 · Cited by 572
Glycosylation of Recombinant Antibody Therapeutics
Jefferis, R. (2005) · Biotechnology Progress · doi:10.1021/bp040016j · Cited by 540 · cited 1×
“These effector ligands include three structurally homologous cellular Fc receptor types (FcγRI, FcγRII and FcγRIII), the C1q component of complement and the neonatal Fc receptor (FcRn”
BackgroundSelf-citation
Antibody production
Birch, J. R., & Racher, A. J. (2006) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2005.12.006 · Cited by 511
Glycoengineering: The effect of glycosylation on the properties of therapeutic proteins
Sinclair, A. M., & Elliott, S. (2005) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20319 · Cited by 461
Higher levels of sialylated Fc glycans in immunoglobulin G molecules can adversely impact functionality
Scallon, B. J., Tam, S. H., McCarthy, S. G., Cai, A. N., & Raju, T. S. (2006) · Molecular Immunology · doi:10.1016/j.molimm.2006.09.005 · Cited by 413
The Galα1,3Galβ1,4GlcNAc-R (α-Gal) epitope: A carbohydrate of unique evolution and clinical relevance
Macher, B. A., & Galili, U. (2008) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2007.11.003 · Cited by 404 · cited 1×
“Humans and higher primates do not have a functional gene encoding the transferase that adds galactose in α(1–3) linkage; however, owing to continual environmental exposure, humans have an IgG antibody that is specific for this antige”
Background
Development trends for monoclonal antibody cancer therapeutics
Reichert, J. M., & Valge-Archer, V. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2241 · Cited by 399 · cited 1×
“Additionally, it is estimated that ∼30% of new drugs that are likely to be licensed during the next decade will be based on antibody product”
Background
Human antibody–Fc receptor interactions illuminated by crystal structures
Woof, J. M., & Burton, D. R. (2004) · Nature reviews. Immunology · doi:10.1038/nri1266 · Cited by 397 · cited 1×
“Importantly, these technologies allow the human antibody constant region isotype — which determines the effector functions activated by immune complexes — to be selected based on its perceived suitability for a given disease indication in vivo”
Background
The Carbohydrate at FcγRIIIa Asn-162
Ferrara, C., Stuart, F., Sondermann, P., Brünker, P., & Umaña, P. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m510171200 · Cited by 360
The Structure of a Human Type III Fcγ Receptor in Complex with Fc
Radaev, S., Motyka, S. A., Fridman, W. H., Sautès‐Fridman, C., & Sun, P. D. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100350200 · Cited by 358
The influence of glycosylation on the thermal stability and effector function expression of human IgG1-Fc: properties of a series of truncated glycoforms.
Mimura, Y., Church, S., Ghirlando, R., Ashton, P., Dong, S.-C., Goodall, M., Lund, J., & Jefferis, R. (2000) · Molecular Immunology · doi:10.1016/s0161-5890(00)00105-x · Cited by 337 · cited 1×
“The influence of glycosylation on the thermal stability of human IgG1 Fc was demonstrated for a series of truncated glycoforms using differential scanning micro-calorimetry”
Self-citation
Recommendations on risk-based strategies for detection and characterization of antibodies against biotechnology products.
Koren, E., Smith, H. W., Shores, E., Shankar, G., Finco-Kent, D., Rup, B., Barrett, Y., Devanarayan, V., Gorovits, B., Gupta, S., et al. (2008) · JIM - Journal of Immunological Methods · doi:10.1016/j.jim.2008.01.001 · Cited by 332 · cited 1×
“Such antibody responses can prejudice treatment if they are neutralizing, if they result in clearance of the therapeutic as immune complexes or if they sensitize the patient for severe reactions on re-exposur”
Background
Expression of GnTIII in a recombinant anti‐CD20 CHO production cell line: Expression of antibodies with altered glycoforms leads to an increase in ADCC through higher affinity for FCγRIII
Davies, J., Jiang, L., Pan, L., LaBarre, M. J., Anderson, D., & Reff, M. (2001) · Biotechnology and Bioengineering · doi:10.1002/bit.1119 · Cited by 327 · cited 1×
“Subsequently, two groups engineered the CHO cell line to express the GnTIII enzyme that adds bisecting N -acetylglucosamine residues, and demonstrated that ADCC improved by two or more orders of magnitude for a rituximab-like produc”
Background
Diversity in Specificity, Abundance and Composition of Anti-Neu5Gc Antibodies in Normal Humans: Potential Implications for Disease
Padler-karavani, V., Yu, H., Cao, H.-Z., Chokhawala, H. A., Karp, F., Varki, N., Chen, X., & Varki, A. (2008) · Glycobiology · doi:10.1093/glycob/cwn072 · Cited by 322 · cited 1×
“Similarly, CHO, NS0 and Sp2/0 cells can add an α(2–3)-linked N -glycylneuraminic acid that is not present in humans and that might also be immunogeni”
Background
Modulation of therapeutic antibody effector functions by glycosylation engineering: Influence of Golgi enzyme localization domain and co‐expression of heterologous β1, 4‐N‐acetylglucosaminyltransferase III and Golgi α‐mannosidase II
Ferrara, C., Brünker, P., Suter, T., Moser, S., Püntener, U., & Umaña, P. (2006) · Biotechnology and Bioengineering · doi:10.1002/bit.20777 · Cited by 305
Structural characterization of N-linked oligosaccharides on monoclonal antibody cetuximab by the combination of orthogonal matrix-assisted laser desorption/ionization hybrid quadrupole–quadrupole time-of-flight tandem mass spectrometry and sequential enzymatic digestion
Qian, J., Liu, T., Yang, L., Daus, A., Crowley, R., & Zhou, Q. (2007) · Analytical Biochemistry · doi:10.1016/j.ab.2007.01.023 · Cited by 294
The effect of the removal of sialic acid, galactose and total carbohydrate on the functional activity of Campath-1H
Boyd, P. N., Lines, A. C., & Patel, A. K. (1995) · Molecular Immunology · doi:10.1016/0161-5890(95)00118-2 · Cited by 283 · cited 1×
“Removal of terminal galactose residues from the chimeric mouse–human IgG1 antibody alemtuzumab was shown to reduce CDC but to be without effect on FcγR-mediated function”
Background
Structural Comparison of Fucosylated and Nonfucosylated Fc Fragments of Human Immunoglobulin G1
Matsumiya, S., Yamaguchi, Y., Saito, J., Nagano, M., Sasakawa, H., Otaki, S., Satoh, M., Shitara, K., & Kato, K. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.02.034 · Cited by 279 · cited 1×
“These studies map the binding site for all four of these ligands to the hinge-proximal and lower hinge region of the CH2 domai”
Background
The antiinflammatory activity of IgG: the intravenous IgG paradox
Nimmerjahn, F., & Ravetch, J. V. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20061788 · Cited by 278 · cited 1×
“; for example, in a complex mouse model of inflammation, polyclonal human IgGs bearing Fc sialyl sugar residues were shown to be anti-inflammator”
Background
IgG subclass-independent improvement of antibody-dependent cellular cytotoxicity by fucose removal from Asn297-linked oligosaccharides
Niwa, R., Natsume, A., Uehara, A., Wakitani, M., Iida, S., Uchida, K., Satoh, M., & Shitara, K. (2005) · Journal of Immunological Methods · doi:10.1016/j.jim.2005.08.009 · Cited by 249
Role of Oligosaccharide Residues of IgG1-Fc in FcγRIIb Binding
Mimura, Y., Sondermann, P., Ghirlando, R., Lund, J., Young, S. P., Goodall, M., & Jefferis, R. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m107478200 · Cited by 236
Self-citation
Antibody fucosylation differentially impacts cytotoxicity mediated by NK and PMN effector cells
Peipp, M., van Bueren, J. J. L., Schneider‐Merck, T., Bleeker, W. K., Dechant, M., Beyer, T. D., Repp, R., van Berkel, P. H. C., Vink, T., van de Winkel, J. G. J., et al. (2008) · Blood · doi:10.1182/blood-2008-03-144600 · Cited by 227 · cited 1×
“The industry is beginning to respond to the perceived advantages of non-fucosylated antibodies for cancer therapies, but a recent report suggests that there are contrary indication”
Background
Structural and numerical variations of the carbohydrate moiety of immunoglobulin G.
Mizuochi, T., Taniguchi, T., Shimizu, A., & Kobata, A. (1982) · Journal of Immunology · doi:10.4049/jimmunol.129.5.2016 · Cited by 211
Nonfucosylated Therapeutic IgG1 Antibody Can Evade the Inhibitory Effect of Serum Immunoglobulin G on Antibody-Dependent Cellular Cytotoxicity through its High Binding to FcγRIIIa
Iida, S., Misaka, H., Inoue, M., Shibata, M., Nakano, R., Yamane-Ohnuki, N., Wakitani, M., Yano, K., Shitara, K., & Satoh, M. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-2619 · Cited by 206
Immunogenicity of anti-tumor necrosis factor antibodies-toward improved methods of anti-antibody measurement.
Aarden, L., Ruuls, S., & Wolbink, G. (2008) · Current Opinion in Immunology · doi:10.1016/j.coi.2008.06.011 · Cited by 198 · cited 1×
“Such antibody responses can prejudice treatment if they are neutralizing, if they result in clearance of the therapeutic as immune complexes or if they sensitize the patient for severe reactions on re-exposur”
Background
Differential glycosylation of polyclonal IgG, IgG-Fc and IgG-Fab isolated from the sera of patients with ANCA-associated systemic vasculitis
Holland, M., Yagi, H., Takahashi, N., Kato, K., Savage, C. O. S., Goodall, D. M., & Jefferis, R. (2005) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2005.11.021 · Cited by 191 · cited 1×
“Approximately 30% of polyclonal human IgG molecules bear N -linked oligosaccharides in the IgG Fab region, in addition to those attached at the conserved glycosylation site at Asn297 in the IgG F”
BackgroundSelf-citation
Development of a simple and rapid method for producing non‐fucosylated oligomannose containing antibodies with increased effector function
Zhou, Q., Shankara, S., Roy, A. J., Qiu, H., Estes, S. D., McVie-Wylie, A. J., Culm-Merdek, K., Park, A., Pan, C. Q., & Edmunds, T. (2007) · Biotechnology and Bioengineering · doi:10.1002/bit.21598 · Cited by 189 · cited 1×
“Opportunities are also opening up for the generation of synthetic IgG Fc glycoforms that might allow the development of probes to further dissect the complexities of inflammatory responses mediated by the humoral immune syste”
Background
Glycosylation and biological activity of CAMPATH-1H expressed in different cell lines and grown under different culture conditions.
Lifely, M. R., Hale, C., Boyce, S., Keen, M., & Phillips, J. (1995) · Glycobiology · doi:10.1093/glycob/5.8.813 · Cited by 173
A comparative study of the N-linked oligosaccharide structures of human IgG subclass proteins.
Jefferis, R., Lund, J., Mizutani, H., Nakagawa, H., Kawazoe, Y., Arata, Y., & Takahashi, N. (1990) · Biochemical Journal · doi:10.1042/bj2680529 · Cited by 166
Self-citation
Untitled work
Imai-Nishiya (2007) · doi:10.1186/1472-6750-7-84 · Cited by 157 · cited 1×
“The most widely used production cell lines are CHO, NS0 and Sp2/0, in various engineered form”
Method
Impact of variable domain glycosylation on antibody clearance: an LC/MS characterization.
Huang, L.-H., Biolsi, S., Bales, K., & Kuchibhotla, U. (2006) · Analytical Biochemistry · doi:10.1016/j.ab.2005.11.012 · Cited by 153 · cited 1×
“However, 11 oligosaccharides were released from the IgG Fab, including diantennary and triantennary oligosaccharides bearing gal α(1–3) gal, N -glycylneuraminic acid and N -acetylgalactosamine residue”
Background
Mannan binding lectin and its interaction with immunoglobulins in health and in disease.
Arnold, J. N., Dwek, R., Rudd, P., & Sim, R. B. (2006) · Immunology Letters · doi:10.1016/j.imlet.2006.05.007 · Cited by 148 · cited 1×
“The serum protein mannose-binding lectin ( MBL ) can recognize and bind arrays of N -acetylglucosamin”
Background
Site-specific glycosylation of human immunoglobulin G is altered in four rheumatoid arthritis patients.
Youings, A., Chang, S.-C., Dwek, R., & Scragg, I. (1996) · Biochemical Journal · doi:10.1042/bj3140621 · Cited by 142
Selective clearance of glycoforms of a complex glycoprotein pharmaceutical caused by terminal N-acetylglucosamine is similar in humans and cynomolgus monkeys
Jones, A. J. S., Papac, D. I., Chin, E. H., Keck, R. G., Baughman, S. A., Lin, Y. S., Kneer, J., & Battersby, J. E. (2007) · Glycobiology · doi:10.1093/glycob/cwm017 · Cited by 137 · cited 1×
“The TNFR55 component has three glycosylation sites, and glycoforms with exposed N -acetylglucosamine residues were shown to be cleared though the mannose receptor and to have a shorter half-life than IgG F”
Background
Optimizing engagement of the immune system by anti-tumor antibodies: an engineer's perspective
Desjarlais, J. R., Lazar, G. A., Zhukovsky, E. A., & Chu, S. Y. (2007) · Drug Discovery Today · doi:10.1016/j.drudis.2007.08.009 · Cited by 134 · cited 1×
“These studies map the binding site for all four of these ligands to the hinge-proximal and lower hinge region of the CH2 domai”
Background
High concentrations of therapeutic IgG1 antibodies are needed to compensate for inhibition of antibody-dependent cellular cytotoxicity by excess endogenous immunoglobulin G
Preithner, S., Elm, S., Lippold, S., Locher, M., Wolf, A., da Silva, A. J., Baeuerle, P. A., & Prang, N. S. (2005) · Molecular Immunology · doi:10.1016/j.molimm.2005.07.010 · Cited by 131
Paradigms for glycan-binding receptors in cell adhesion
Taylor, M. E., & Drickamer, K. (2007) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2007.09.004 · Cited by 119 · cited 1×
“The mannose receptor is a C-type lectin, expressed at the surface of macrophages, endothelial cells and dendritic cells, that recognizes arrays of mannose and N -acetylglucosamine residue”
Background
Contrasting glycosylation profiles between Fab and Fc of a human IgG protein studied by electrospray ionization mass spectrometry
Mimura, Y., Ashton, P. R., Takahashi, N., Harvey, D. J., & Jefferis, R. (2007) · Journal of Immunological Methods · doi:10.1016/j.jim.2007.07.014 · Cited by 114 · cited 1×
“Approximately 30% of polyclonal human IgG molecules bear N -linked oligosaccharides in the IgG Fab region, in addition to those attached at the conserved glycosylation site at Asn297 in the IgG F”
BackgroundSelf-citation
The therapeutic use of rituximab in non‐Hodgkin's lymphoma
Marcus, R., & Hagenbeek, A. (2006) · European journal of haematology. Supplementum · doi:10.1111/j.1600-0579.2004.00340.x-i1 · Cited by 114 · cited 1×
“It is approved for the treatment of non-Hodgkin's lymphoma, in which the target is neoplastic CD20-expressing B lymphocyte”
Background
A Nonfucosylated Anti-HER2 Antibody Augments Antibody-Dependent Cellular Cytotoxicity in Breast Cancer Patients
Suzuki, E., Niwa, R., Saji, S., Muta, M., Hirose, M., Iida, S., Shiotsu, Y., Satoh, M., Shitara, K., Kondo, M., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-1335 · Cited by 111
Cell type-specific glycoforms of Fc gamma RIIIa (CD16): differential ligand binding.
Edberg, J., & Kimberly, R. (1997) · Journal of Immunology · doi:10.4049/jimmunol.159.8.3849 · Cited by 103
Interactions of immunoglobulins outside the antigen-combining site.
Nezlin, R., & Ghetie, V. (2004) · Advances in Immunology · doi:10.1016/s0065-2776(04)82004-2 · Cited by 82 · cited 1×
“Importantly, these technologies allow the human antibody constant region isotype — which determines the effector functions activated by immune complexes — to be selected based on its perceived suitability for a given disease indication in vivo”
Background
The Potential Role of Mannan‐Binding Lectin in the Clearance of Self‐Components Including Immune Complexes
Saevarsdottir, S., Vikingsdottir, T., & Valdimarsson, H. (2004) · Scandinavian Journal of Immunology · doi:10.1111/j.0300-9475.2004.01437.x · Cited by 79 · cited 1×
“The serum protein mannose-binding lectin ( MBL ) can recognize and bind arrays of N -acetylglucosamin”
Background
Quantitation of the oligosaccharides of human serum IgG from patients with rheumatoid arthritis: a critical evaluation of different methods.
Routier, F., Hounsell, E. F., Rudd, P., Takahashi, N., Bond, A., Hay, F. C., Alavi, A., Axford, J. S., & Jefferis, R. (1998) · JIM - Journal of Immunological Methods · doi:10.1016/s0022-1759(98)00032-5 · Cited by 77 · cited 1×
“It is generally reported that IgG Fc oligosaccharides of normal human IgG are predominantly devoid of terminal sialic acid residue”
BackgroundSelf-citation
Characterization of a complex glycoprotein whose variable metabolic clearance in humans is dependent on terminal N-acetylglucosamine content
Keck, R. G., Nayak, N., Lerner, L. E., Raju, S., Ma, S., Schreitmueller, T., Chamow, S., Moorhouse, K., Kotts, C. E., & Jones, A. J. S. (2007) · Biologicals · doi:10.1016/j.biologicals.2007.05.004 · Cited by 72 · cited 1×
“The TNFR55 component has three glycosylation sites, and glycoforms with exposed N -acetylglucosamine residues were shown to be cleared though the mannose receptor and to have a shorter half-life than IgG F”
Background
Reduced Susceptibility of Recombinant Polyclonal Antibodies to Inhibitory Anti-Variable Domain Antibody Responses
Klitgaard, J. L., Coljee, V. W., Andersen, P. S., Rasmussen, L. K., Nielsen, L. S., Haurum, J., & Bregenholt, S. (2006) · Journal of Immunology · doi:10.4049/jimmunol.177.6.3782 · Cited by 71
Compensation of endogenous IgG mediated inhibition of antibody-dependent cellular cytotoxicity by glyco-engineering of therapeutic antibodies
Nechansky, A., Schuster, M., Jost, W. H., Siegl, P., Wiederkum, S., Gorr, G., & Kircheis, R. (2006) · Molecular Immunology · doi:10.1016/j.molimm.2006.08.013 · Cited by 70 · cited 1×
“The enhanced ADCC observed for afucosylated IgG Fc results, in part, from the increased affinity for FcγRIIIa — this allows the afucosylated IgG Fc to overcome the competition from high concentrations of fucosylated IgG in normal seru”
Background
Glycosylation profiling of a therapeutic recombinant monoclonal antibody with two N-linked glycosylation sites using liquid chromatography coupled to a hybrid quadrupole time-of-flight mass spectrometer.
Lim, A., Reed-Bogan, A., & Harmon, B. J. (2008) · Analytical Biochemistry · doi:10.1016/j.ab.2008.01.003 · Cited by 63 · cited 1×
“; however, present reports suggest that CHO cells can glycosylate VH and/or VL motifs in a manner similar to that observed for normal polyclonal Ig”
Result
Glycosylation of polyclonal and paraprotein IgG in multiple myeloma
Farooq, M., Takahashi, N., Arrol, H., Drayson, M., & Jefferis, R. (1997) · Glycoconjugate Journal · doi:10.1023/a:1018555619519 · Cited by 33 · cited 1×
“Analysis of monoclonal human IgG proteins isolated from the sera of patients with multiple myeloma revealed individual (and unique) glycoform profiles, including major differences in the levels of galactosylation, fucosylation and the addition of bisecting N -acetylglucosamine residue”
BackgroundSelf-citation
Variability factors in the clinical response to recombinant antibodies and IgG Fc-containing fusion proteins
Watier, H. (2005) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.5.1.s29 · Cited by 26 · cited 1×
“It is approved for the treatment of non-Hodgkin's lymphoma, in which the target is neoplastic CD20-expressing B lymphocyte”
Background
Substances reactive with mannose-binding protein (MBP) in sera of patients with rheumatoid arthritis.
Sato, R., Matsushita, M., Miyata, M., Sato, Y., Kasukawa, R., & Fujita, T. (1997) · Fukushima Journal of Medical Science · doi:10.11501/3101354 · Cited by 21
Remodelling the oligosaccharide of human IgG antibodies: effects on biological activities.
Abadeh, S., Church, S., Dong, S.-C., Lund, J., Goodall, M., & Jefferis, R. (1997) · Biochemical Society Transactions · doi:10.1042/bst025s661 · Cited by 12
Self-citation
Meeting report & News from academia
Moutel, S., & Perez, F. (2008) · Biotechnology Journal · doi:10.1002/biot.200800011 · Cited by 9

Research works printed but not linked: 7

Mirik, G. R., Bradt, B. M., Denardo, S. J. & Denardo, G. L. A review of human anti-globulin antibody (HAGA, HAMA, HACA, HAHA) responses to monoclonal antibodies. Not four letter words. Q. J. Nucl. Med. Mol. Imaging 48, 251–257 (2004).
Jefferis, R. Antibody therapeutics: isotype and glycoform selection. Expert Opin. Biol. Ther. 7, 1401–1413 (2007). · DOI
van Sorge, N. M., van der Pol, W. L. & van de Winkel, J. G. FcγR polymorphisms: implications for function, disease susceptibility and immunotherapy. Tissue Antigens 61, 189–202 (2003). · DOI
Chung, C. H. et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-α-1,3-galactose. N. Engl. J. Med. 358, 1109–1117 (2008). Important report of hypersensitivity reactions to a recombinant therapeutic due to production in Sp2/0 cells in which gal a (1–3) gal is added. · DOI · Paper page
Garred, P. et al. J. Two edged role of mannose binding lectin in rheumatoid arthritis: a cross sectional study. J. Rheumatol. 27, 26–34 (2000).
Harris, R. J. Heterogeneity of recombinant antibodies: linking structure to function. Dev. Biol. (Basel) 122, 117–127 (2005).
Watt, G. et al. Synthesis of homogeneous neoglycoforms of IgG-Fc molecules and their functional properties. Hum. Antibodies 11, 29–30 (2002). · DOI

Sorted by citations

Biological roles of glycans
Varki, A. (2017) · Glycobiology · doi:10.1093/glycob/cww086 · Cited by 2,635
Glycosylation in health and disease
Reily, C., Stewart, T. J., Renfrow, M. B., & Novak, J. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0129-4 · Cited by 2,075
Therapeutic antibodies for autoimmunity and inflammation
Chan, A. C., & Carter, P. J. (2010) · Nature reviews. Immunology · doi:10.1038/nri2761 · Cited by 846
“A second widely applicable and comparably successful method for increasing the IgG ADCC activity is through tailoring of Fc glycosylatio”
Method
Strategies and challenges for the next generation of therapeutic antibodies
Beck, A., Wurch, T., Bailly, C., & Corvaı̈a, N. (2010) · Nature reviews. Immunology · doi:10.1038/nri2747 · Cited by 868
“, and the associated properties of the Fc can also be modulated by engineering at several levels: altering the glycosylation status to regulate anti- and pro-inflammatory propertie”
Background
Open Peer Review
Ferguson, C. L. (2016) · Serials review · doi:10.6084/m9.figshare.2066868.v1 · Cited by 564

See all 829

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Glycosylation as a strategy to improve antibody-based therapeutics

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Metadata

Record

About these checks