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A ligand-receptor fusion of growth hormone forms a dimer and is a potent long-acting agonist

Nature Medicine volume 13, pages 1108–1113 (2007)Cite this article

Abstract

Cytokine hormones have a short plasma half-life and require frequent administration. For example, growth hormone replacement involves daily injections. In common with other cytokines, the extracellular domain of the growth hormone receptor circulates as a binding protein, which naturally prolongs the biological half-life of growth hormone. Here we have studied the biological actions of a ligand-receptor fusion of growth hormone and the extracellular domain of its receptor. The genetically engineered ligand-receptor fusion protein was purified from mammalian cell culture. In rats, the ligand-receptor fusion had a 300-times reduced clearance as compared to native growth hormone, and a single injection promoted growth for 10 d, far exceeding the growth seen after administration of native growth hormone. The ligand-receptor fusion forms a reciprocal, head-to-tail dimer that provides a reservoir of inactive hormone similar to the natural reservoir of growth hormone and its binding protein. In conclusion, a ligand-receptor fusion of cytokine to its extracellular receptor generates a potent, long-acting agonist with exceptionally slow absorption and elimination. This approach could be easily applied to other cytokines.

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Figure 1: Relationship between growth hormone, GHBP, the ligand-receptor (LR) fusion and the GHR on the basis of published structures27 (pdb3HHR).
Figure 2: Characterization and bioactivity of the ligand-receptor (LR) fusion.
Figure 3: Profiles of growth hormone (GH) and ligand-receptor (LR) fusion measured after subcutaneous and intravenous administration.
Figure 4: Body weight change in rats after subcutaneous administration of growth hormone (GH) and the ligand-receptor (LR) fusion.

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Acknowledgements

We are grateful to ARC BioServ and particularly to S. Smith and I. Phillips for their support in protein production. This work was supported through an Asterion Ltd. contract with the University of Sheffield.

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Author notes

  1. Ian R Wilkinson, Eric Ferrandis and Peter J Artymiuk: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Medicine and Biomedical Sciences, Royal Hallamshire Hospital, University of Sheffield, Sheffield, S10 2JF, UK

    Ian R Wilkinson, Sarbendra L Pradhananga, Sue Justice & Richard J Ross

  2. Institut Henri Beaufour, Ipsen, 5 Avenue du Canada, Les Ulis Cedex, 91966, France

    Eric Ferrandis, Marc Teillot, Chantal Soulard & Caroline Touvay

  3. Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, S10 2JF, UK

    Peter J Artymiuk

  4. Department of Medicine, Campus Mitte Charite-Universitatsmedizim, Berlin, 10117, Germany

    Zida Wu & Christian J Strasburger

  5. Pituitary Research Unit, Garvan Institute of Medical Research, Sydney, 2010, New South Wales, Australia

    Kin C Leung

  6. Unit of Infection and Immunity, Royal Hallamshire Hospital, University of Sheffield, Sheffield, S10 2JF, UK

    Jon R Sayers

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Contributions

I.R.W., S.L.P. and S.J. cloned, purified, tested and analyzed the fusion proteins. Z.W., K.C.L. and C.J.S. contributed to the characterization of the fusion proteins. E.F., M.T., C.S. and C.T. performed and analyzed the in vivo studies. E.F., P.J.A., J.R.S. and R.J.R. were responsible for the concepts, data analysis and writing of the manuscript. R.J.R. supervised the project.

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Correspondence to Richard J Ross.

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Competing interests

S.J., Z.W., K.C.L. and C.J.S. have no competing interests to declare. I.W., P.J.A., S.L.P., J.R.S. and R.J.R. have an equity interest in Asterion Ltd., and P.J.A., J.R.S. and R.J.R. are directors of Asterion Ltd. E.F., M.T., C.S. and C.T. are employed by Ipsen. This work was supported through an Asterion Ltd. contract with the University of Sheffield.

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Wilkinson, I., Ferrandis, E., Artymiuk, P. et al. A ligand-receptor fusion of growth hormone forms a dimer and is a potent long-acting agonist. Nat Med 13, 1108–1113 (2007). https://doi.org/10.1038/nm1610

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