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Insertion of N-Terminal Hinge Glycosylation Enhances Interactions of the Fc Region of Human IgG1 Monomers to Glycan-Dependent Receptors and Blocks Hemagglutination by the Influenza Virus

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Blundell, Pat, Lu, Dongli, Wilkinson, Mark ORCID: https://orcid.org/0000-0003-3109-6888, Dell, Anne, Hasla, Stuart and Pleass, Richard ORCID: https://orcid.org/0000-0001-7438-8296 (2019) 'Insertion of N-Terminal Hinge Glycosylation Enhances Interactions of the Fc Region of Human IgG1 Monomers to Glycan-Dependent Receptors and Blocks Hemagglutination by the Influenza Virus'. The Journal of Immunology, Vol 202, Issue 5, pp. 1595-1611.

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Abstract

In therapeutic applications in which the Fc of IgG is critically important, the receptor binding and functional properties of the Fc are lost after deglycosylation or removal of the unique Asn297 N-X-(T/S) sequon. A population of Fcs bearing sialylated glycans has been identified as contributing to this functionality, and high levels of sialylation also lead to longer serum retention times advantageous for therapy. The efficacy of sialylated Fc has generated an incentive to modify the unique N-linked glycosylation site at Asn297, either through chemical and enzymatic methods or by mutagenesis of the Fc, that disrupts the protein-Asn297 carbohydrate interface. In this study, we took an alternative approach by inserting or deleting N-linked attachment sites into the body of the Fc to generate a portfolio of mutants with tailored effector functions. For example, we describe mutants with enhanced binding to low-affinity inhibitory human Fcγ and glycan receptors that may be usefully incorporated into existing Ab engineering approaches to treat or vaccinate against disease. The IgG1 Fc fragments containing complex sialylated glycans attached to the N-terminal Asn221 sequon bound influenza virus hemagglutinin and disrupted influenza A-mediated agglutination of human erythrocytes.

Item Type: Article
Subjects: QU Biochemistry > Proteins. Amino Acids. Peptides > QU 55 Proteins
WC Communicable Diseases > Virus Diseases > Viral Respiratory Tract Infections. Respirovirus Infections > WC 515 Human influenza
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.4049/jimmunol.1801337
Depositing User: Stacy Murtagh
Date Deposited: 31 Jan 2019 18:24
Last Modified: 01 Mar 2019 10:18
URI: https://archive.lstmed.ac.uk/id/eprint/9945

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