Recombinant human growth hormone (GH)-binding protein enhances the growth-promoting activity of human GH in the rat.
To address the role of the GH-binding protein (GHBP) in GH physiology, two forms of recombinant human GHBP (rhGHBP) were given alone or in combination with rhGH to hypophysectomized rats or GH-deficient dwarf rats. Hypophysectomized rats were given daily sc injections of excipient, hGH, rhGHBP, or rhGH plus rhGHBP (produced in Escherichia coli) for 7 days. Injections of rhGH induced dose-related body weight gain and bone growth that were increased by the coadministration of rhGHBP with rhGH; rhGHBP alone had no effect. Serum insulin-like growth factor increased 24 h later when rhGH was given together with rhGHBP (P < 0.01), but not when rhGH was given alone. E. coli-derived rhGHBP also enhanced the bioactivity of coadministered rhGH in the GH-deficient dwarf rat. In contrast, the glycosylated rhGHBP, made in human A293 cells, inhibited the growth-promoting activity of coadministered rhGH. The opposite effects of these two forms of rhGHBP could be explained by clearance studies that showed radiolabeled rhGH bound to A293 cell-derived rhGHBP to be cleared more rapidly from the blood than free rhGH. Natural rabbit GHBP and E. coli-derived rhGHBP both prolonged the presence of rhGH in blood. It is proposed that by slowing the clearance of GH, GHBP increased the bioactivity of GH. In summary, codelivery of rhGHBP and rhGH caused a dose-dependent enhancement of the activity of rhGH in two rat models of GH deficiency. This suggests that endogenous circulating GHBP may increase the activity of blood-borne GH in a similar manner.
Clark
R G
RG
Genentech, Inc., South San Francisco, California 94080-4990, USA. rossc@gene.com
Mortensen
D L
DL
Carlsson
L M
LM
Spencer
S A
SA
McKay
P
P
Mulkerrin
M
M
Moore
J
J
Cunningham
B C
BC
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004357:Drug Synergism; D004392:Dwarfism / Q000235:genetics; D004926:Escherichia coli / Q000378:metabolism; D019382:Human Growth Hormone / Q000493:pharmacokinetics / Q000494:pharmacology*; D007016:Hypophysectomy; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D011817:Rabbits; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins
D002352:Carrier Proteins; D011994:Recombinant Proteins; D019382:Human Growth Hormone; C051815:somatotropin-binding protein