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Pegvisomant, a Growth Hormone-Specific Antagonist, Undergoes Cellular Internalization

Division of Clinical Sciences (M.M., R.J.M.R.), Edison Biotechnology Institute (J.J.K.), and Department of Biomedical Sciences, Ohio University, Athens, Ohio 45701; and Division of Clinical Endocrinology, Department of Medicine, Charitè Campus Mitte (C.J.S.), Berlin, Germany

Address all correspondence and requests for reprints to: Dr. Richard J. M. Ross, Sheffield University, Clinical Sciences, Northern General Hospital, Sheffield, United Kingdom S5 7AU. E-mail: r.j.ross{at}sheffield.ac.uk.

GH binding to a receptor (GHR) dimer triggers signaling and internalization of the receptor/ligand complex. Pegvisomant is a specific GH antagonist developed for the treatment of acromegaly, and the basic molecule is GH with an amino acid substitution that blocks the conformational change necessary to generate functional GHR dimerization required for signal transduction. Pegvisomant has additional polyethylene glycol moieties to prolong its half-life in the circulation and improve clinical efficacy through reduced renal clearance. Pegvisomant has a long plasma half-life, and its mode of clearance has not been established. We have studied pegvisomant internalization and demonstrate that despite its size and prolonged plasma half-life, it is internalized by cells expressing the GHR. As pegvisomant does not activate intracellular signal transduction systems, our results support the concept that the conformational changes required for GHR signaling are not essential for the intracellular trafficking of the ligand and establish one potential contributing mechanism for pegvisomant clearance.

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