Growth hormone (gh) receptor blockade with a peg-modified GH (B2036-PEG) lowers serum insulin-like growth factor-I but does not acutely stimulate serum GH

• Published in: The journal of clinical endocrinology and metabolism 1999-06, Vol.84 (6), p.2098-2103
• Main Authors: THORNER, M. O, STRASBURGER, C. J, WU, Z, STRAUME, M, BIDLINGMAIER, M, PEZZOLI, S. S, ZIB, K, SCARLETT, J. C, BENNETT, W. F
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Antibodies, Monoclonal; Biological and medical sciences; Hormones. Endocrine system; Human Growth Hormone - analogs & derivatives; Human Growth Hormone - antagonists & inhibitors; Human Growth Hormone - metabolism; Humans; Immunoassay; Insulin-Like Growth Factor I - metabolism; Iodine Radioisotopes; Luminescent Measurements; Male; Medical sciences; Pharmacology. Drug treatments; Stimulation, Chemical
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.84.6.2098

B2036-PEG, a GH receptor (GH-R) antagonist, is an analog of GH that is PEG-modified to prolong its action. Nine mutations alter the binding properties of this molecule, preventing GH-R dimerization and GH action. A potential therapeutic role of B2036-PEG is to block GH action, e.g. in refractory acromegaly. A phase I, placebo-controlled, single rising-dose study was performed in 36 normal young men (ages, 18-37 yr; within 15% ideal body weight). Four groups received a single s.c. injection of either placebo (n = 3 in each group, total n = 12) or B2036-PEG (0.03, 0.1, 0.3, or 1.0 mg/kg; n = 6 each dose). B2036-PEG and GH concentrations were measured 0, 0.25, 0.5, 1, 3, 6, 9, 12, 24, 36, 48, 72, 96, 120, and 144 h after dosing. Serum insulin-like growth factor-I was measured before and 1-7 days after dosing. All doses were well tolerated, with no serious or severe adverse reactions. B2036-PEG, at 1.0 mg/kg, reduced insulin-like growth factor-I by 49 +/- 6% on day 5 (P < 0.001 vs. placebo). GH was measured by two independent methods: 1) modified Nichols chemiluminescence assay (empirically corrected for B2036-PEG cross-reactivity); and 2) direct GH two-site immunoassay, using monoclonal antibodies that did not react with B2036-PEG. There was good agreement between the two methods. GH did not change substantially at any B2036-PEG dose, suggesting that B2036-PEG does not interact with hypothalamic GH-Rs to block short-loop feedback. B2036-PEG may thus block peripheral GH action without enhancing its secretion.