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 Blood, 15 September 2008, Vol. 112, No. 6, pp. 2390-2399.
Prepublished online as a Blood First Edition Paper on June 19, 2008; DOI 10.1182/blood-2008-03-144600.

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IMMUNOBIOLOGY

Antibody fucosylation differentially impacts cytotoxicity mediated by NK and PMN effector cells

Matthias Peipp1,*, Jeroen J. Lammerts van Bueren2,*, Tanja Schneider-Merck3, Wim W. K. Bleeker2, Michael Dechant3, Thomas Beyer3, Roland Repp1, Patrick H. C. van Berkel2, Tom Vink2, Jan G. J. van de Winkel2,4, Paul W. H. I. Parren2, and Thomas Valerius3

1 Division of Stem Cell Transplantation and Immunotherapy, Christian-Albrechts-University, Kiel, Germany; 2 Genmab, Utrecht, The Netherlands; 3 Division of Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany; and 4 Immunotherapy Laboratory, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

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 IgG1 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.


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