Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10162786 | Journal of Pharmaceutical Sciences | 2012 | 11 Pages |
Abstract
A novel recombinant human growth hormone (rhGH) fusion protein (VRS-317) was designed to minimize receptor-mediated clearance through a reduction in receptor binding 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 threefold 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 1.4Â mg/kg VRS-317 (equivalent to 0.26Â mg/kg rhGH) caused a sustained pharmacodynamic response for 1Â month equivalent to 0.05Â mg/kg/day rhGH (1.4Â mg/kg rhGH total over 28Â days). In monkeys, VRS-317, having a terminal elimination half-life of approximately 110Â h, was rapidly and near-completely absorbed, and was well tolerated with no observed adverse effects after every alternate week subcutaneous dosing for 14Â 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 observations in these animal studies. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association
Keywords
Related Topics
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Pharmacology, Toxicology and Pharmaceutical Science
Drug Discovery
Authors
Jeffrey L. Cleland, Nathan C. Geething, Jerome A. Moore, Brian C. Rogers, Benjamin J. Spink, Chai-Wei Wang, Susan E. Alters, Willem P.C. Stemmer, Volker Schellenberger,