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Glycobiology Advance Access published online on September 29, 2006
Glycobiology, doi:10.1093/glycob/cwl057
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Received August 23, 2006
Revised September 25, 2006
Accepted September 25, 2006

Article

Comparison of biological activity among non-fucosylated therapeutic IgG1 antibodies with three different N-linked Fc oligosaccharides: the high-mannose, hybrid, and complex types

Yutaka Kanda 1, Tsuyoshi Yamada 1, Katsuhiro Mori 1, Akira Okazaki 1, Miho Inoue 1, Kazuko Kitajima-Miyama 1, Reiko Kuni-Kamochi 1, Ryosuke Nakano 1, Keiichi Yano 1, Shingo Kakita 1, Kenya Shitara 1, and Mitsuo Satoh 1 *

1 Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., 3-6-6 Asahi-machi, Machida-shi, Tokyo 194-8533, Japan

* To whom correspondence should be addressed.
Mitsuo Satoh, E-mail: msatoh{at}kyowa.co.jp


  Abstract

The structure of asparagine-linked oligosaccharides attached to the antibody constant region (Fc) of human immunoglobulin G1 (IgG1) has been shown to affect the pharmacokinetics and antibody effector functions of antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, it is still unclear how differences in the N-linked oligosaccharide structures impact the biological activities of antibodies, especially those lacking core fucose. Here, we succeeded in generating core fucose-lacking human IgG1 antibodies with three different N-linked Fc oligosaccharides, namely, a high-mannose, hybrid, and complex type, using the same producing clone, and directly compared their activities. Cultivation of an {alpha}-1,6-fucosyltransferase (FUT8) knockout Chinese hamster ovary (CHO) cell line in the presence or absence of a glycosidase inhibitor (either swainsonine or kifunensine) yielded antibody production of each of the three types without contamination by the others. Two of three types of non-naturally occurring atypical oligosaccharide IgG1, except the complex type, reduced the affinity for both human lymphocyte receptor IIIa (Fc{gamma}RIIIa) and the C1q component of the complement, resulting in reduction of ADCC and CDC. The bulky structure of the non-reducing end of N-linked Fc oligosaccharides is considered to contribute the CDC change, whereas the structural change in the reducing end, i.e., the removal of core fucose, causes ADCC enhancement through improved Fc{gamma}RIIIa binding. In the pharmacokinetic profile, although no significant difference of human neonatal Fc receptor (FcRn)-binding affinity was observed among the three types, the complex type showed longer serum half-lives than the other types irrespective of core fucosylation in mice, which also suggests the contribution of the non-reducing end structure. The present study provides basic information on the effects of core fucose-lacking N-linked Fc oligosaccharides on antibody biological activities.

Keywords: antibody effector functions; Fc oligosaccharides; IgG1 lacking core-fucosylation; N-linked oligosaccharide structure; pharmacokinetics.
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