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Cited by 770Monoclonal and Polyclonal Antibodies ResearchGlycosylation and Glycoproteins ResearchImmune Cell Function and Interaction

Unique carbohydrate-carbohydrate interactions are required for high affinity binding between FcγRIII and antibodies lacking core fucose

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Ferrara, Claudia, Grau, Sandra, Jäger, Christiane, Sondermann, Peter, Brünker, Peter, Waldhauer, Inja, Hennig, Michael, Ruf, Armin +4 more·2011·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1108455108PMC PMC3150898
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Abstract

Antibody-mediated cellular cytotoxicity (ADCC), a key immune effector mechanism, relies on the binding of antigen–antibody complexes to Fcγ receptors expressed on immune cells. Antibodies lacking core fucosylation show a large increase in affinity for FcγRIIIa leading to an improved receptor-mediated effector function. Although afucosylated IgGs exist naturally, a next generation of recombinant therapeutic, glycoenginereed antibodies is currently being developed to exploit this finding. In this study, the crystal structures of a glycosylated Fcγ receptor complexed with either afucosylated or fucosylated Fc were determined allowing a detailed, molecular understanding of the regulatory role of Fc-oligosaccharide core fucosylation in improving ADCC. The structures reveal a unique type of interface consisting of carbohydrate–carbohydrate interactions between glycans of the receptor and the afucosylated Fc. In contrast, in the complex structure with fucosylated Fc, these contacts are weakened or nonexistent, explaining the decreased affinity for the receptor. These findings allow us to understand the higher efficacy of therapeutic antibodies lacking the core fucose and also suggest a unique mechanism by which the immune system can regulate antibody-mediated effector functions.

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  • Core-fucose weakens carbohydrate-carbohydrate interactions necessary for high-affinity binding between antibodies and glycosylated FcγRIIIa, making core-fucosylation undesirable in mAbs that mediate ADCC.

    “Core-fucose weakens carbohydrate-carbohydrate interactions necessary for high-affinity binding between antibodies and glycosylated FcγRIIIa, which is why core-fucosylation is undesirable in mAbs that mediate antibody-dependent cell cytotoxicity (ADCC), a mechanism exploited for the selective clearing of tumour cells by immune cells after antibody engagement [14].”

    From Glycoengineering Chinese hamster ovary cells: a short history (2021) · cites this paper as [14]

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Research works printed but not linked: 34

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Authors
Ferrara, C., Grau, S., Jäger, C., Sondermann, P., Brünker, P., Waldhauer, I., Hennig, M., Ruf, A., Rufer, A. C., Stihle, M., Umaña, P., & Benz, J.
Affiliations
F. Hoffmann-La Roche AG (CH)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2011-07-18
Volume
108
Issue
31
Pages
12669-12674
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1108455108
PMC
PMC3150898
OpenAlex
W1969824500
Cited by
770
References
6
Citations by year
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FWCI
31.34
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • DORA PSI (Paul Scherrer Institute) (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 › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
Keywords
FcγRIIIa, antibody-dependent cellular cytotoxicity, core fucosylation, carbohydrate-carbohydrate interactions, effector function
MeSH terms
Animals, Antibodies, Antibody-Dependent Cell Cytotoxicity, Antigen-Antibody Complex, Binding, Competitive, Carbohydrates, Cells, Cultured, Cricetulus, Fucose, Glycosylation, Cricetinae, Humans, Immunoglobulin G, Immunoglobulin Fc Fragments, Kinetics, Leukocytes, Mononuclear, Models, Molecular, Protein Binding, Molecular Structure, CHO Cells, Protein Structure, Tertiary, Receptors, IgG, Crystallography, X-Ray, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Surface Plasmon Resonance

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