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Non-fucosylated Therapeutic Antibodies: The Next Generation of Therapeutic Antibodies

  • Mitsuo Satoh
  • Shigeru Iida
  • Naoko Yamane-Ohnuki
  • Katsuhiro Mori
  • Yutaka Kanda
  • Reiko Kuni-Kamochi
  • Ryosuke Nakano
  • Harue Imai-Nishiya
  • Akira Okazaki
  • Toyohide Shinkawa
  • Akihito Natsume
  • Rinpei Niwa
  • Kenya Shitara
Conference paper
Part of the Animal Cell Technology: Basic & Applied Aspects book series (ANICELLTECH, volume 15)

Abstract

Therapeutic antibody IgG1 has two N-linked oligosaccharide chains bound to the Fc region. The oligosaccharides are of the complex biantennary type, composed of a trimannosyl core structure with the presence or absence of core fucose, bisecting N-acetylglucosamine (GlcNAc), galactose, and terminal sialic acid, which gives rise to structural heterogeneity. Both human serum IgG and therapeutic antibodies are well known to be heavily fucosulated. Recently, ­antibody-dependent cellular cytotoxicity (ADCC), a lytic attack on antibody-targeted cells, has been found to be one of the critical effector functions responsible for the clinical efficacy of therapeutic antibodies such as anti-CD20 IgG1 rituximab (RituxanR) and anti-Her2/neu IgG1 trastuzumab (HerceptinR). ADCC is triggered upon the binding of lymphocyte receptors (FcγRs) to the antibody Fc region. The activity is dependent on the amount of fucose attached to the innermost GlcNAc of N-linked Fc oligosaccharide via an α-1,6-linkage, and is dramatically enhanced by a reduction in fucose. Non-fucosylated therapeutic antibodies show more potent efficacy than their fucosylated counterparts both in vitro and in vivo [7, 8, 9, 10, 11, 12, 13, 14], and are not likely to be immunogenic because their carbohydrate structures are a normal component of natural human serum IgG. Thus, the application of non-fucosylated antibodies is expected to be a powerful and elegant approach to the design of the next generation therapeutic antibodies with improved efficacy. In this review, we discuss the importance of the oligosaccharides attached to the Fc region of therapeutic antibodies, especially regarding the inhibitory effect of fucosylated therapeutic antibodies on the efficacy of non-fucosylated counterparts in one medical agent. The impact of completely non-fucosylated therapeutic antibodies on therapeutic fields will be also discussed.

Keywords

Therapeutic antibody N-linked Fc oligosaccharide core-fucosylation α-1,6-fucosyltransferase (FUT8) knockout Chinese hamster ovary (CHO) ADCC FcγRIIIa binding human plasma IgG 

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Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Mitsuo Satoh
    • 1
  • Shigeru Iida
    • 1
  • Naoko Yamane-Ohnuki
    • 1
  • Katsuhiro Mori
    • 1
  • Yutaka Kanda
    • 1
  • Reiko Kuni-Kamochi
    • 1
  • Ryosuke Nakano
    • 1
  • Harue Imai-Nishiya
    • 1
  • Akira Okazaki
    • 1
  • Toyohide Shinkawa
    • 1
  • Akihito Natsume
    • 1
  • Rinpei Niwa
  • Kenya Shitara
    • 1
  1. 1.Tokyo Research laboratoriesKyowa Hakko Kogyo Co., Ltd.TokyoJapan

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