A novel long-acting human growth hormone fusion protein (VRS-317): enhanced in vivo potency and half-life.
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 1.4 mg/kg VRS-317 (equivalent to 0.26 mg/kg rhGH) caused a sustained pharmacodynamic response for 1 month equivalent to 0.05 mg/kg/day rhGH (1.4 mg/kg rhGH total over 28 days). In monkeys, VRS-317, having a terminal elimination half-life of approximately 110 h, 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 observations in these animal studies.
Versartis, Inc., Redwood City, California, USA. jcleland@versartis.com
Jeffrey L
JL
Cleland
Nathan C
NC
Geething
Jerome A
JA
Moore
Brian C
BC
Rogers
Benjamin J
BJ
Spink
Chai-Wei
CW
Wang
Susan E
SE
Alters
Willem P C
WP
Stemmer
Volker
V
Schellenberger
D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D005260:Female; D015870:Gene Expression; D006207:Half-Life; D000882:Haplorhini; D019382:Human Growth Hormone / Q000009:adverse effects / Q000235:genetics / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051381:Rats; D011986:Receptors, Somatotropin / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology; D013552:Swine
D011986:Receptors, Somatotropin; D011993:Recombinant Fusion Proteins; D019382:Human Growth Hormone