A ligand-receptor fusion of growth hormone forms a dimer and is a potent long-acting agonist
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.
|Authors||Wilkinson, I. R.;Ferrandis, E.;Artymiuk, P. J.;Teillot, M.;Soulard, C.;Touvay, C.;Pradhananga, S. L.;Justice, S.;Wu, Z.;Leung, K. C.;Strasburger, C. J.;Sayers, J. R.;Ross, R. J. :|
|Publisher Name||NAT MED|
|Published Date||2007-01-01 00:00:00|
|OpenAccess Link||https://publications.gimr.garvan.org.au/download.php?2305_11022/07 Wilkinson NM.pdf|