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Journal of Biochemistry Advance Access originally published online on October 12, 2006
Journal of Biochemistry 2006 140(6):777-783; doi:10.1093/jb/mvj207
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© 2006 The Japanese Biochemical Society.

ARTICLE

Enhanced Fc-Dependent Cellular Cytotoxicity of Fc Fusion Proteins Derived from TNF Receptor II and LFA-3 by Fucose Removal from Asn-Linked Oligosaccharides

Emi Shoji-Hosaka1, Yukari Kobayashi2, Masako Wakitani1, Kazuhisa Uchida1, Rinpei Niwa1, Kazuyasu Nakamura2 and Kenya Shitara1,*

1 Department of Antibody Research, Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd., Machida-shi, Tokyo 194-8533; and 2 BioFrontier Laboratory, Kyowa Hakko Kogyo Co., Ltd., Machida-shi, Tokyo 194-8533

* To whom correspondence should be addressed. Phone: +81-42-725-0857, Fax: +81-42-726-8330, E-mail: kshitara{at}kyowa.co.jp


  Abstract

Fucose removal from complex-type oligosaccharide of human IgGs results in a major enhancement of Fc-dependent cellular cytotoxicity. The aim of this study was to determine the effect of fucose removal on the effector function of another class of clinically important molecules that can effect cellular cytotoxicity, Fc fusion proteins. The receptors chosen for study were TNF receptor II and LFA-3, both of which have therapeutic significance. The fucosylated versions of these fusion proteins were produced in unmodified CHO cells, whereas the nonfucosylated counterparts were produced in CHO cells with {alpha}-1,6-fucosyltransferase, an enzyme required for fucosylation, knocked-out. Whilst binding activity of TNFRII-Fc and LFA-3-Fc were unchanged by fucose-removal, nonfucosylated Fc fusion proteins exhibited significantly higher Fc receptor {gamma}IIIa–binding and increased Fc-mediated cytotoxicity on target cells compared to fucosylated counterparts. Notably, in case of TNFRII-Fc, only the nonfucosylated protein exhibited potent Fc dependent cytotoxicity to transmembrane TNF-{alpha} expressing cells. These results prove that enhancement of Fc dependent cellular cytotoxicity by fucose-removal is effective in not only whole IgG but also Fc fusion proteins, and thus widens the potential of Fc-fusion proteins as therapeutic candidates.


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