A Novel Long-Acting Human Growth Hormone Fusion Protein (VRS-317): Enhanced In Vivo Potency and Half-Life
| Autor: | Susan E. Alters, Jeffrey L. Cleland, Jerome A. Moore, Brian C. Rogers, Benjamin Spink, Chai-Wei Wang, Volker Schellenberger, Willem P. C. Stemmer, Nathan Geething |
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| Rok vydání: | 2012 |
| Předmět: |
Male
growth hormone deficiency safety protein delivery medicine.medical_specialty Swine Recombinant Fusion Proteins Gene Expression Pharmaceutical Science long acting Pharmacology Biology Cell Line Growth hormone deficiency Pharmacokinetics In vivo Internal medicine pharmacodynamics glomerular filtration medicine Animals Humans Potency Cloning Molecular Receptor Lipoatrophy hormones Human Growth Hormone Haplorhini Receptors Somatotropin medicine.disease Rats Endocrinology Pharmacodynamics growth hormone Female pharmacokinetics Half-Life Biotechnology Hormone |
| Zdroj: | Journal of Pharmaceutical Sciences |
| ISSN: | 0022-3549 |
| Popis: | A novel recombinant human growth hormone (rhGH) fusion protein (VRS-317) was designed to minimize receptor-mediated clearance through a reduction in receptor bind- ing without mutations to rhGH by genetically fusing with XTEN amino acid sequences to the N-terminus and the C-terminus of the native hGH sequence. Although in vitro potency of VRS- 317 was reduced approximately 12-fold compared with rhGH, in vivo potency was increased because of the greatly prolonged exposure to the target tissues and organs. VRS-317 was three- fold more potent than daily rhGH in hypophysectomized rats and fivefold more potent than daily rhGH in juvenile monkeys. In juvenile monkeys, a monthly dose of 1.4mg/kg VRS-317 (equivalent to 0.26mg/kg rhGH) caused a sustained pharmacodynamic response for 1 month equivalent to 0.05mg/kg/day rhGH (1.4mg/kg rhGH total over 28 days). In monkeys, VRS-317, having a terminal elimination half-life of approximately 110h, was rapidly and near-completely absorbed, and was well tolerated with no observed adverse effects after every alternate week subcutaneous dosing for 14 weeks. VRS-317 also did not cause lipoatrophy in pig and monkey studies. VRS-317 is currently being studied in GH-deficient patients to confirm the observa- tions in these animal studies. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:2744-2754, 2012 |
| Databáze: | OpenAIRE |
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