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.
Wilkinson
Ian R
IR
School of Medicine and Biomedical Sciences, Royal Hallamshire Hospital, University of Sheffield, Sheffield S10 2JF, UK.
Ferrandis
Eric
E
Artymiuk
Peter J
PJ
Teillot
Marc
M
Soulard
Chantal
C
Touvay
Caroline
C
Pradhananga
Sarbendra L
SL
Justice
Sue
S
Wu
Zida
Z
Leung
Kin C
KC
Strasburger
Christian J
CJ
Sayers
Jon R
JR
Ross
Richard J
RJ
D000818:Animals; D019281:Dimerization; D013006:Growth Hormone / Q000737:chemistry / Q000502:physiology; D019382:Human Growth Hormone / Q000737:chemistry*; D006801:Humans; D007016:Hypophysectomy; D008024:Ligands; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry; D011487:Protein Conformation; D051381:Rats; D011986:Receptors, Somatotropin / Q000819:agonists / Q000737:chemistry* / Q000502:physiology
D008024:Ligands; D050505:Mutant Proteins; D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; D013006:Growth Hormone