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Switching constant domains enhances agonist activities of antibodies to a thrombopoietin receptor

Nature Biotechnology volume 26, pages 209–211 (2008)Cite this article

Abstract

We enhanced the activities of two agonist antibodies specific for the thrombopoietin receptor (c-MPL) by switching domains within their constant regions to those of different antibody isotypes. Our results suggest the importance of the hinge region in modulating agonist activity. The antibodies' thrombopoietin-like activity in vitro and in vivo, as well as the desirable pharmacokinetic profile conferred by retaining the whole-IgG structure, suggests that they provide a valuable option for treating thrombocytopenia.

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Figure 1: Improving anti-c-MPL agonist antibodies MA01 and MA02 by domain subclass conversion.
Figure 2: In vivo efficacy of MA01G4344U in human c-MPL transgenic mouse model.

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Acknowledgements

The authors wish to thank Norio Komatsu for kindly providing UT-7/TPO; Tomoyuki Tahara, Eiji Mori, Tomoaki Kuwaki, Yoshimasa Inagaki, Takashi Kato, Hitoshi Yoshida, Nobuaki Takahashi, Ralph Kubo and Jun-ichi Koumegawa for discussions and suggestions; Kazuma Tomizuka and Makoto Kakitani for technical advice on making the transgenic mouse; Keiko Nakahashi and Masumi Goto for advice and assistance on PK analysis; Katsumi Yazaki for kindly providing research materials; Naoko Tago, Tomoko Nagasaka, Junko Inuzuka, Sayuri Negishi, Yumi Takeuchi, Mayu Hosono and Jeremy Young for excellent technical assistance. This research was financially supported by Kirin Pharma Co., Ltd.

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Authors and Affiliations

  1. Discovery Research Laboratories, Kirin Pharma Co., Ltd., 3 Miyahara, Takasaki, 370-1295, Gunma, Japan

    Masayuki Kai, Kazuhiro Motoki, Hideaki Yoshida, Chie Emuta, Yukiko Chisaka, Kumi Tsuruhata, Chisato Endo, Mari Muto, Hiroshi Miyazaki & Shiro Kataoka

  2. Research Division, Development Research Laboratories, Kirin Pharma Co., Ltd., 3 Miyahara, Takasaki, 370-1295, Gunma, Japan

    Munetake Shimabe & Uichi Nishiyama

  3. Frontier Laboratory, Kirin Pharma Co., Ltd., 3 Miyahara, Takasaki, 370-1295, Gunma, Japan

    Tetsuya Hagiwara

  4. Production Division, CMC R&D Laboratories, Kirin Pharma Co., Ltd., 100-1 Hagiwara-cho, Takasaki, 370-0013, Gunma, Japan

    Atsushi Matsumoto

Authors
  1. Masayuki Kai
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  2. Kazuhiro Motoki
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  13. Hiroshi Miyazaki
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  14. Shiro Kataoka
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Contributions

M.K., K.M. and H.Y. designed and conducted research, collected data, analyzed data and wrote the paper; M.S., K.T., C. Emuta, M.M., C. Endo and Y.C. performed experiments, collected and analyzed data; U.N., T.H., A.M., H.M. and S.K. designed and conducted research.

Corresponding author

Correspondence to Shiro Kataoka.

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All the authors are employees of Kirin Pharma Co., Ltd.

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Supplementary Figures 1–5, Supplementary Table 1 (PDF 5193 kb)

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Kai, M., Motoki, K., Yoshida, H. et al. Switching constant domains enhances agonist activities of antibodies to a thrombopoietin receptor. Nat Biotechnol 26, 209–211 (2008). https://doi.org/10.1038/nbt1376

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