title: A long-acting GH receptor antagonist through fusion to GH binding protein.
abstract: Acromegaly is a human disease of growth hormone (GH) excess with considerable morbidity and increased mortality. Somatostatin analogues are first line medical treatment but the disease remains uncontrolled in up to 40% of patients. GH receptor (GHR) antagonist therapy is more effective but requires frequent high-dose injections. We have developed an alternative technology for generating a long acting potent GHR antagonist through translational fusion of a mutated GH linked to GH binding protein and tested three candidate molecules. All molecules had the amino acid change (G120R), creating a competitive GHR antagonist and we tested the hypothesis that an amino acid change in the GH binding domain (W104A) would increase biological activity. All were antagonists in bioassays. In rats all antagonists had terminal half-lives >20 hours. After subcutaneous administration in rabbits one variant displayed a terminal half-life of 40.5 hours. A single subcutaneous injection of the same variant in rabbits resulted in a 14% fall in IGF-I over 7 days.
  
  
  
  we provide proof of concept that a fusion of GHR antagonist to its binding protein generates a long acting GHR antagonist and we confirmed that introducing the W104A amino acid change in the GH binding domain enhances antagonist activity.
authors.affiliation: The University of Sheffield, Sheffield, UK.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Wilkinson
authors.affiliation: The University of Sheffield, Sheffield, UK.
authors.forename: Sarbendra L
authors.initials: SL
authors.lastname: Pradhananga
authors.affiliation: The University of Sheffield, Sheffield, UK.
authors.forename: Rowena
authors.initials: R
authors.lastname: Speak
authors.affiliation: The University of Sheffield, Sheffield, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Artymiuk
authors.affiliation: The University of Sheffield, Sheffield, UK.
authors.forename: Jon R
authors.initials: JR
authors.lastname: Sayers
authors.affiliation: The University of Sheffield, Sheffield, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ross
mesh_terms: D000172:Acromegaly / Q000188:drug therapy; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology; D019382:Human Growth Hormone / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D050505:Mutant Proteins / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011986:Receptors, Somatotropin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D050505:Mutant Proteins; D011986:Receptors, Somatotropin; D011993:Recombinant Fusion Proteins; D019382:Human Growth Hormone; C051815:somatotropin-binding protein