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

作者：Wilkinson Ian R; Ferrandis Eric; Artymiuk Peter J; Teillot Marc; Soulard Chantal; Touvay Caroline; Pradhananga Sarbendra L; Justice Sue; Wu Zida; Leung Kin C; Stra**urger Christian J; Sayers Jon R; Ross Richard J^*

来源：Nature Medicine, 2007, 13(9): 1108-1113.

DOI：10.1038/nm1610

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 ligandreceptor 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.

• 出版日期2007-9
• 单位河北医科大学