Engineering a Long Lasting Tethered, Multimeric Human Growth Hormone Protein to Improve Pharmacokinetic Half-Life and Potency

Abstract

Long-acting human growth hormone (hGH) is intended to improve compliance, adherence and efficacy for patients with growth hormone deficiency or other growth disorders. There is poor patient compliance with daily dosing and novel strategies for improving pharmacokinetic half-life and potency are under development. Subcutaneously and intramuscularly administered recombinant human growth hormone (aka somatropin) has a short half-life of just a few hours. Growth hormone is cleared by glomerular filtration based on its size and through receptor mediated uptake. By engineering a multimeric hGH, the clearance via glomerular filtration may be reduced and the receptor binding improved through multiple points of contact. A synthetic form of hGH was created by linking multiple hGH proteins together through bi-functional PEG linkers. In addition a recombinant form of hGH was created by expressing three hGH proteins tethered together by a repetitive amino acid linker sequence. These engineered proteins were evaluated for structure and function. The tethered hGH proteins were potent and increased weight gain in hypophysectomized rats.