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Glycobiology Advance Access originally published online on October 24, 2008
Glycobiology 2009 19(2):126-134; doi:10.1093/glycob/cwn110
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

The N-linked oligosaccharide at Fc{gamma}RIIIa Asn-45: an inhibitory element for high Fc{gamma}RIIIa binding affinity to IgG glycoforms lacking core fucosylation

Mami Shibata-Koyama2, Shigeru Iida2, Akira Okazaki2, Katsuhiro Mori2, Kazuko Kitajima-Miyama2, Seiji Saitou2, Shingo Kakita2, Yutaka Kanda2, Kenya Shitara2, Koichi Kato3,4 and Mitsuo Satoh1,2

2 Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd, 3-6-6 Asahi-machi, Machida-shi, Tokyo 194-8533
3 Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya 467-8603
4 Okazaki Institute for Integrative Bioscience and Institute for Molecular Science, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787, Japan

1 To whom correspondence should be addressed: Tel: +81-42-725-2556; Fax: +81-42-726-8330; e-mail: msatoh{at}kyowa.co.jp

Received on August 22, 2008; revised on October 9, 2008; accepted on October 10, 2008

Human leukocyte receptor IIIa (Fc{gamma}RIIIa) plays an important role in mediating therapeutic antibodies’ antibody-dependent cellular cytotoxicity (ADCC), which is closely related to the clinical efficacy of anticancer processes in humans in vivo. The removal of the core fucose from oligosaccharides attached to the Fc region of antibodies improves Fc{gamma}RIIIa binding, allowing the antibodies to enhance dramatically the antibody effector functions of ADCC. In this study, the contribution of Fc{gamma}RIIIa oligosaccharides to the strength of the Fc{gamma}RIIIa/antibody complex was analyzed using a serial set of soluble human recombinant Fc{gamma}RIIIa lacking the oligosaccharides. A nonfucosylated antibody IgG1 appeared to have a significantly higher affinity to the wild-type Fc{gamma}RIIIa fully glycosylated at its five N-linked oligosaccharide sites than did the fucosylated IgG1, and this increased binding was almost abolished once all of the Fc{gamma}RIIIa glycosylation was removed. Our gain-of-function analysis in the Fc{gamma}RIIIa oligosaccharide at Asn-162 (N-162) confirmed that N-162 is the element required for the high binding affinity to nonfucosylated antibodies, as previously revealed by loss-of-function analyses. Interestingly, beyond our expectation, the Fc{gamma}RIIIa modified by N-162 alone showed a significantly higher binding affinity to nonfucosylated IgG1 than did the wild-type Fc{gamma}RIIIa. Attachment of the other four oligosaccharides, especially the Fc{gamma}RIIIa oligosaccharide at Asn-45 (N-45), hindered the high binding affinity of Fc{gamma}RIIIa to nonfucosylated IgG1. Our data clearly demonstrated that N-45 is an inhibitory element for the high Fc{gamma}RIIIa binding affinity mediated by N-162 to nonfucosylated antibodies. This information can be exploited for the structural-based functional study of Fc{gamma}RIIIa.

Key words: Fc{gamma}RIIIa Asn-45 / Fc{gamma}RIIIa binding affinity / IgG1 lacking core fucosylation / N-linked Fc oligosaccharides / N-linked Fc{gamma}RIIIa oligosaccharides


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