title: Unique carbohydrate-carbohydrate interactions are required for high affinity binding between FcgammaRIII and antibodies lacking core fucose.
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.
authors.affiliation: Pharma Research and Early Development, Roche Glycart AG, CH-8952 Schlieren, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ferrara
authors.forename: Sandra
authors.initials: S
authors.lastname: Grau
authors.forename: Christiane
authors.initials: C
authors.lastname: Jäger
authors.forename: Peter
authors.initials: P
authors.lastname: Sondermann
authors.forename: Peter
authors.initials: P
authors.lastname: Brünker
authors.forename: Inja
authors.initials: I
authors.lastname: Waldhauer
authors.forename: Michael
authors.initials: M
authors.lastname: Hennig
authors.forename: Armin
authors.initials: A
authors.lastname: Ruf
authors.forename: Arne Christian
authors.initials: AC
authors.lastname: Rufer
authors.forename: Martine
authors.initials: M
authors.lastname: Stihle
authors.forename: Pablo
authors.initials: P
authors.lastname: Umaña
authors.forename: Jörg
authors.initials: J
authors.lastname: Benz
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D001667:Binding, Competitive / Q000276:immunology; D016466:CHO Cells; D002241:Carbohydrates / Q000737:chemistry / Q000276:immunology*; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D005643:Fucose / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D017452:Receptors, IgG / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D020349:Surface Plasmon Resonance
chemical_list: D000906:Antibodies; D000936:Antigen-Antibody Complex; D002241:Carbohydrates; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D017452:Receptors, IgG; D005643:Fucose