A long-acting, mono-PEGylated human growth hormone analog is a potent stimulator of weight gain and bone growth in hypophysectomized rats

Endocrinology. 2007 Apr;148(4):1590-7. doi: 10.1210/en.2006-1170. Epub 2007 Jan 18.


Recombinant human GH is used to treat GH deficiency in children and adults and wasting in AIDS patients. GH has a circulating half-life of only a few hours in humans and must be administered to patients by daily injection for maximum effectiveness. Previous studies showed that longer-acting forms of GH could be created by modification of GH with multiple 5-kDa amine-reactive polyethylene glycols (PEGs). Eight of nine lysine residues and the N-terminal amino acid were modified to varying extents by amine PEGylation of GH. The amine-PEGylated GH product comprised a complex mixture of multiple PEGylated species that differed from one another in mass, in vitro bioactivity, and in vivo potency. In vitro bioactivity of GH was reduced 100- to 1000-fold by extensive amine PEGylation of the protein. Here we describe a homogeneously modified, mono-PEGylated GH protein that possesses near complete in vitro bioactivity, a long half-life, and increased potency in vivo. The mono-PEGylated GH was created by substituting cysteine for threonine-3 (T3C) of GH, followed by modification of the added cysteine residue with a single 20-kDa cysteine-reactive PEG. The PEG-T3C protein has an approximate 8-fold longer half-life than GH after sc administration to rats. Every other day or every third day administration of PEG-T3C stimulates increases in body weight and tibial epiphysis growth comparable with that produced by daily administration of GH in hypophysectomized rats. Long-acting, mono-PEGylated GH analogs such as PEG-T3C are promising candidates for future testing in humans.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bone Development / drug effects*
  • Delayed-Action Preparations
  • Drug Evaluation, Preclinical
  • Half-Life
  • Human Growth Hormone / analogs & derivatives*
  • Human Growth Hormone / chemistry
  • Human Growth Hormone / pharmacokinetics*
  • Hypophysectomy*
  • Male
  • Polyethylene Glycols / chemistry
  • Polyethylene Glycols / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Tibia / drug effects
  • Treatment Outcome
  • Weight Gain / drug effects*


  • Delayed-Action Preparations
  • Human Growth Hormone
  • Polyethylene Glycols