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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 GH¹

Division of Endocrinology and Metabolism (M.O.T., M.S., S.S.P.), Department of Medicine, and National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908; Med Klinik Innenstadt (C.S., Z.W., M.B.), Ludwig-Maximilians University, 80336 Munich, Germany; and Sensus Corporation (K.Z., J.C.S., W.F.B.), Austin, Texas 78701

Address all correspondence and requests for reprints to: Dr. Michael O. Thorner, Department of Medicine, Box 466, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. E-mail: mot{at}virginia.edu

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 sc 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.

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