Lack of Fucose on Human IgG1 N-Linked Oligosaccharide Improves Binding to Human FcγRIII and Antibody-dependent Cellular Toxicity*

By R. Shields, Jadine Lai, R. Keck, L. O'connell, Kyu Hong, Y. Meng, S. Weikert, L. Presta. Journal of Biological Chemistry, 2002

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Lec13 cells, a variant Chinese hamster ovary cell line, were used to produce human IgG1 that were deficient in fucose attached to the Asn297-linked carbohydrate but were otherwise similar to that found in IgG1 produced in normal Chinese hamster ovary cell lines and from human serum. Lack of fucose on the IgG1 had no effect on binding to human FcγRI, C1q, or the neonatal Fc receptor. Although no change in affinity was found for the His131 polymorphic form of human FcγRIIA, a slight improvement in binding was evident for FcγRIIB and the Arg131 FcγRIIA polymorphic form. In contrast, binding of the fucose-deficient IgG1 to human FcγRIIIA was improved up to 50-fold. Antibody-dependent cellular cytotoxicity assays using purified peripheral blood monocytes or natural killer cells from several donors showed enhanced cytotoxicity, especially evident at lower antibody concentrations. When combined with an IgG1 Fc protein variant that exhibited enhanced antibody-dependent cellular cytotoxicity, the lack of fucose was synergistic.

Subfields: Genetics, Molecular Biology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/7b27035c095dcbb8e43ec3a8315f1fdfc61900ea

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Citations in the corpus

• Crystal structure of mammalian α1,6-fucosyltransferase, FUT8 (2007, background): “The lack of core fucose on the IgG1 molecule results in an enhancement in ADCC activity of up to 100-fold, suggesting that this core fucose-deficient IgG1 would be useful in terms of antibody therapy in cancer treatment.”
• Optimal and consistent protein glycosylation in mammalian cell culture. (2009, methodology): “Biowa Inc. utilized gene knock-down technology to remove α(1,6)-linked Fuc sugars from N-glycans in a CHO cell line to create Potelligent R© cells that produce fucose-free antibodies with 50 to 100 times enhanced ADCC activity with the same growth and productivity as in the parental cell line.”
• Effects of Drug Loading on the Antitumor Activity of a Monoclonal Antibody Drug Conjugate (2004, background): “For example several approaches have been shown to enhance the ability of an antibody to mediate antibody-dependent cell-mediated cytotoxicity by optimizing the structure of the Fc-associated N-linked oligosaccharide (2, 3).”
• IgG Subclasses and Allotypes: From Structure to Effector Functions (2014, background): “FUCOSYLATION It has been known for quite some time that core fucosylation of the IgG-Fc affects binding to FcγRIIIa (112), with non-fucosylated antibodies binding FcγRIIIa much stronger.”
• Therapeutic antibodies for autoimmunity and inflammation (2010, background): “Decreasing the fucose content of the carbohydrates in the Fc region can also enhance ADC”