Technical Report abstract
Nature Medicine 13, 1108 - 1113 (2007)
Published online: 26 August 2007 | doi:10.1038/nm1610
A ligand-receptor fusion of growth hormone forms a dimer and is a potent long-acting agonist
Ian R Wilkinson1,7, Eric Ferrandis2,7, Peter J Artymiuk3,7, Marc Teillot2, Chantal Soulard2, Caroline Touvay2, Sarbendra L Pradhananga1, Sue Justice1, Zida Wu4, Kin C Leung5, Christian J Strasburger4, Jon R Sayers6 & Richard J Ross1
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.
- School of Medicine and Biomedical Sciences, Royal Hallamshire Hospital, University of Sheffield, Sheffield S10 2JF, UK.
- Institut Henri Beaufour, Ipsen, 5 Avenue du Canada, 91966 Les Ulis Cedex, France.
- Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2JF, UK.
- Department of Medicine, Campus Mitte Charite-Universitatsmedizim, 10117 Berlin, Germany.
- Pituitary Research Unit, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
- Unit of Infection and Immunity, Royal Hallamshire Hospital, University of Sheffield, Sheffield S10 2JF, UK.
- These authors contributed equally to this work.
Correspondence to: Richard J Ross1 e-mail: r.j.ross@sheffield.ac.uk
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