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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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.
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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