Antibody fucosylation differentially impacts cytotoxicity mediated by NK and PMN effector cells.
Glycosylation of the antibody Fc fragment is essential for Fc receptor-mediated activity. Carbohydrate heterogeneity is known to modulate the activity of effector cells in the blood, in which fucosylation particularly affects NK cell-mediated killing. Here, we investigated how the glycosylation profile of 2F8, a human IgG(1) monoclonal antibody against epidermal growth factor receptor in clinical development, impacted effector function. Various 2F8 batches differing in fucosylation, galactosylation, and sialylation of the complex-type oligosaccharides in the Fc fragment were investigated. Our results confirmed that low fucose levels enhance mononuclear cell-mediated antibody-mediated cellular cytotoxicity (ADCC). In contrast, polymorphonuclear cells were found to preferentially kill via high-fucosylated antibody. Whole blood ADCC assays, containing both types of effector cells, revealed little differences in tumor cell killing between both batches. Significantly, however, high-fucose antibody induced superior ADCC in blood from granulocyte colony-stimulating factor-primed donors containing higher numbers of activated polymorphonuclear cells. In conclusion, our data demonstrated for the first time that lack of fucose does not generally increase the ADCC activity of therapeutic antibodies and that the impact of Fc glycosylation on ADCC is critically dependent on the recruited effector cell type.
Peipp
Matthias
M
Division of Stem Cell Transplantation and Immunotherapy, Christian-Albrechts-University, Kiel, Germany.
Lammerts van Bueren
Jeroen J
JJ
Schneider-Merck
Tanja
T
Bleeker
Wim W K
WW
Dechant
Michael
M
Beyer
Thomas
T
Repp
Roland
R
van Berkel
Patrick H C
PH
Vink
Tom
T
van de Winkel
Jan G J
JG
Parren
Paul W H I
PW
Valerius
Thomas
T
D000906:Antibodies / Q000276:immunology / Q000378:metabolism*; D000920:Antibody-Dependent Cell Cytotoxicity; D002460:Cell Line; D005643:Fucose / Q000276:immunology* / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*
D000906:Antibodies; D007141:Immunoglobulin Fc Fragments; D005643:Fucose