Abstract
Recombinant human growth hormone (hGH) is a well characterized molecule with broad acceptance as a treatment for growth hormone deficiencies (GHD). However, treatment with hGH requires daily injections due to the drug’s short duration of action. Many groups have focused on PEGylation of hGH as a means to extend its half-life and generate less frequent dosage forms. This chapter provides a review of the preclinical and clinical results obtained from the many approaches directed towards modification of hGH with PEG. The chapter will describe a historical progression of PEGylation strategies and results. The first half of the chapter will discuss initial studies that utilized multiple 5 kDa PEG attachments for extension of hGH half-life and the subsequent development of a PEGylated hGH receptor antagonist, pegvisomant, a successful therapy for acromegaly. The latter half of the chapter will summarize more recent and current work focusing on site selective mono-PEGylation of hGH.
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References
Ascoli M, Segaloff S (1996) Adenohypophyseal hormones and their hypothalamic releasing factors. In: al He (ed.): Goodman and Gilman’s The Pharmacological Basis of Therapeutics McGraw-Hill, New York, 1363–1382
Kupfer SR, Underwood L, Baxter RC, Clemmons DR (1993) Enhancement of the anabolic effects of growth hormone and insulin-like growth factor I by use of both agents simultaneously. Journal of Clinical Investigation 91:391–396
Matthews LS, Norsted G, Palmiter RD (1986) Regulation of insulin-like growth factor gene expression by growth hormone. Proceedings of the National Academy of Sciences of the United States of America 83:9343–9347
Lee HJ, Riley G, Johnson O, Cleland JL, Kim N, Charnis M, Bailey L et al. (1997) In vivo characterization of sustained-release formulations of human growth hormone. Growth Hormone and IGF Research 11:41–48
Reslow M, Lonsson M, Laakso T (2003) Sustained-release of human growth hormone from PLG-coated starch microspheres. DDS&S 2:103–109
Reiter EO, Attie KM, Moshang T Jr, Silverman BL, Kemp SF, Neuwirth RB, Ford KM et al. (2001) A multicenter study of the efficacy and safety of sustained release GH in the treatment of naive pediatric patients with GH deficiency. J Clin Endocrinol MeTab. 86:4700–4706
Govardhan CK, Jung CW, Simeone B, Higbie A, Qu S, Chemmalil L, Pechenov S et al. (2005) Novel long-acting crystal formulation of human growth hormone. Pharmaceutical Research 22:1461–1470
Cleland JL, Duenas E, Daugherty A, Marian M, Yang J, Wilson M, Celniker AC et al. (1997) Recombinant human growth hormone poly(lactic-co-glycolic acid) (PLGA) microspheres provide a long lasting effect. Journal of Controlled Release 49:193–205
Osborn BL, Sekut L, Corcoran M, Poortman C, Sturm B, Chen G, Mather D et al. (2002) Albutropin: a growth hormone-albumin fusion with improved pharmacokinetics and pharmacodynamics in rats and monkeys. European Journal of Pharmacology 456:149–158
Veronese FM, Pasut G (2005) PEGylation, successful approach to drug delivery. Drug Discovery Today 10:1451–1458
Zalipsky S, Lee C (1992) Use of functionalized poly(ethylene glycol)s for modification of polypeptides. Poly(Ethylene Glycol) Chem 347–370
Fu CH, Sakamoto KM (2007) PEG-asparaginase. Expert Opinion on Pharmacotherapy 8:1977–1984
Chan B, Wara D, Bastian J, Hershfield MS, Bohnsack J, Azen CG, Parkman R et al. (2005) Long-term efficacy of enzyme replacement therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID). Clinical Immunology 117:133–143
Bailon PP, Schaffer CA, Spence CL, Fung WJ, Porter JE, Ehrlich GK, Pan W et al. (2001) Rational design of a potent, long-lasting form of interferon: A 40 kDa branched polyethylene glycol-conjugated interferon-2a for the treatment of hepatitis C. Bioconjugate Chemistry 12:195–202
Wang Y-S, Youngster S, Grace M, Bausch J, Bordens R, Wyss DF (2002) Structural and biological characterization of pegylated recombinant interferon alpha-2b and its therapeutic implications. Advanced Drug Delivery Reviews 54:547–570
Molineux G (2004) The design and development of Pegfilgrastim (PEG-rmetHuG-CSF, Neulasta®. Current Pharmaceutical Design 10:1235–1244
Behncken SN, Waters MJ (1999) Molecular recognition events involved in the activation of the growth hormone receptor. J Molecular Recognition 12:255–362
Waters MJ, Hoang HN, Fairlie DP, Pelekanos RA, Wan Y, McKinstry WJ, Paleothorpe K et al. (2006) New insights into growth hormone action. J Mol Endocrinology 36:1–7
Ross RJ, Leung KC, Maamra M, Bennett W, Doyle N, Waters MJ, Ho KKY (2001) Binding and functional studies with the growth hormone receptor antagonist, B2036-PEG (pegvisomant), reveal effects of PEGylation and evidence that it binds to a receptor dimer. Journal of Clinical Endocrinology and Metabolism 86:1716–1723
Clark R, Olson K, Fuh G, Marian M, Mortensen D, Teshima G, Chang S et al. (1996) Long-acting growth hormones produced by conjugation with polyethylene glycol. The Journal of Biological Chemistry 271:21969–21977
Wells JA, Cunnigham BC, Fuh G, Lowman HB, Bass SH, Mulkerrin MG, Ultsch M et al. (1993) The molecular basis for growth hormone-receptor interactions. Recent Progress in Hormone Research 48:253–275
Morpurgo M, Veronese F (2004) Conjugates of peptides and proteins to polyethylene glycols. In: Niemeyer CM (ed.): Methods in Molecular Biology, vol Bioconjugation Protocols. Humana Press, Totowa, New Jersey, United States, 45–69
Chen WY, Wight DC, Wagner TE, Kopchick JJ (1990) Expression of a mutated bovine growth hormone gene suppresses growth of transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 87:5061–5065
Chen WY, Chen NY, Yun J, Wagner TE, Kopchick JJ (1994) In vitro and in vivo studies of antagonistic effects of human growth hormone analogs [published erratum appears in J Biol Chem (1994) 269(32):20806] J Biol Chem 269:15892–15897
Maamra MK, Kopchick JJ, Strasburger CJ, Ross, RJM (2004) Pegvisomant, a growth hormone-specific antagonist, undergoes cellular internalization. Journal of Clinical Endocrinology and Metabolism 89:4532–4537
Fuh GC, Brian C, Fukunaga R, Nagata S, Goeddel DV, Wells JA (1992) Rational design of potent antagonists to the human growth hormone receptor. Science (Washington, DC, United States) 256:1677–1680
Olson K, Gehant R, Mukku V, O’Connell K, Tomlinson B, Totpal K, Winkler M (1997) Preparation and characterization of poly(ethylene glycol)ylated human growth hormone antagonist. In: Harris M J, Zalipski, S (ed.): Poly(ethylene glycol) Chemistry and Biological Applications Oxford University Press, New York, United States 170–181
Pradhananga S, Wilkinson I, Ross RJM (2002) Pegvisomant: structure and function. Journal of Molecular Endocrinology 29:11–14
Rodvold KA, Bennet WF, Zib KA (1997) Single-dose safety and pharmacokinetics of B2036-PEG (Somavert) after subcutaneous administration in healthy volunteers. J Clinical Pharmacology 37:869
Rodvold KA, van der Lely AJ (1999) Pharmacokinetics and pharmacodynamics of B2036-PEG, a novel growth hormone receptor antagonist, in acromegalic subjects. Proceedings 81st Annual Meeting of the Endocrine Society 1–49
Wilson ME (1998) Effects of estradiol and exogenous insulin-like growth factor I (IGF-I) on the IGF-I axis during growth hormone inhibition and antagonism. Journal of Clinical Endocrinology and Metabolism 83:4013–4021
Ben-Shlomo A, Melmed S (2008) Acromegaly. Endocrinology & Metabolism Clinics of North America 37:101–122
Roelfsema F, Biermasz NR, Pereira AM, Romijn J (2006) Nanomedicines in the treatment of acromegaly: focus on pegvisomant. International Journal of Nanomedicine 1:385–398
Colao A, Ferone D, Marzullo P (2004) Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocrine Rev 25:102–152
Freda PU, Wardlaw SL, Post KD (1998) Long-term endocrinological follow-up evaluation in 115 patients who underwent transsphenoidal surgery for acromegaly. Journal of Neurosurgery 89:353–358
Biermasz NR, Dulken HV, Roelfsema F (2000) Postoperative radiotherapy in acromegaly is effective in reducing GH concentration to safe levels. Clinical Endocrinology (Oxford, United Kingdom) 53:321–327
Abs R, Verhelst J, Maiter D, Acker KV, Nobles F, Coolens J L, Mahler C, Beckers A (1998) Cabergoline in the treatment of acromegaly. J Clinical Endocrinology 83:374–378
Lancranjan I, Atkinson AB (1999) The Sandostatin LAR group results of a European multicentre study with sandostatin LAR in acromegalic patients. Pituitary 1:105–114
van der Lely AJ, Kopchick JJ (2006) Growth hormone receptor antagonists. Neuroendocrinology 83:264–268
Roelfsema F, Biermasz NR, Pereira AM, Romijn J A (2008) The role of pegvisomant in the treatment of acromegaly. Expert Opinion on Biological Therapy 8:691–704
Thorner MO, Strasburger CJ, Wu Z, Straume M, Bidlingmaier M, Pezzoli S, Zib K et al. (1999) 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. Journal of Clinical Endocrinology and Metabolism 84:2098–2103
Parkinson C, Trainer PJ (2001) The place of pegvisomant in the management of acromegaly. Expert Opinion on Investigational Drugs 10:1725–1735
Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der Lely AJ, Dimaraki V et al. (2000) Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. New England Journal of Medicine 342:1171–1177
van der Lely AJ, Hutson RK, Trainer PJ, Besser G M, Barkan AL, Katznelson L, Klibanski A et al. (2001) Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet 358:1754–1759
Lindberg-Larsen R, Moeller N, Schmitz O, Nielsen S, Andersen M, Oerskov H, Joergensen JOL (2007) The impact of pegvisomant treatment on substrate metabolism and insulin sensitivity in patients with acromegaly. Journal of Clinical Endocrinology and Metabolism 92:1724–1728
Parkinson C, Drake WM, Roberts ME, Meeran K, Besser G M, Trainer PJ (2002) A comparison of the effects of pegvisomant and octreotide on glucose, insulin, gastrin, cholecystokinin, and pancreatic polypeptide responses to oral glucose and a standard mixed meal. Journal of Clinical Endocrinology and Metabolism 87:1797–1804
Colao A, Pivonello R, Auriemma RS, De Martino MC, Bidlingmaier M, Briganti F, Tortora F et al. (2006) Efficacy of 12-month treatment with the GH receptor antagonist pegvisomant in patients with acromegaly resistant to long-term, high-dose somatostatin analog treatment: effect on IGF-I levels, tumor mass, hypertension and glucose tolerance. European Journal of Endocrinology 154:467–477
Feenstra J, deHerder WW, ten Have SMTH, van den Beld AW, Feelders R, Janssen J, van der Lely AJ (2005) Combined therapy with somatostatin analogues and weekly pegvisomant in active acromegaly. Lancet 365:1644–1646
Schreiber I, Buchfelder M, Droste M, Forssmann K, Mann K, Sailer B, Strasburger CJ (2007) Treatment of acromegaly with the GH receptor antagonist pegvisomant in clinical practice: safety and efficacy evaluation from the German pegvisomant observational stud. European Journal of Endocrinology 156:75–82
Buckley JJ, Finn R F, Mo J, Bass LA, Ho SV (2008) PEGylation of biological macromolecules. In: Gadamasetti KB, Tamim (ed.): Process Chemistry in the Pharmaceutical Industry, vol Challenges in an Ever Changing Climate. CRC Press Taylor & Francis Group, Boca Raton, FL, United States 383–402
Rajender Reddy K, Modi MW, Pedder S (2002) Use of peginterferon alfa-2a (40 KD) (Pegasys®) for the treatment of hepatitis C. Advanced Drug Delivery Reviews 54:571–586
Kinstler O, Mollineux G, Treuheit M, Ladd D, Gegg C (2002) Mono-N-terminal polyfethylene glycol)-protein conjugates. Advanced Drug Delivery Reviews 54:477–485
Finnessy J, Girard T, Finn R, Zheng J, Kindle J, Siegel N (2004) PEGylated human growth hormone: effect of PEG size on the biology of PEG-hGH. In: 31st Annual Meeting and Exposition of the Controlled Release Society, vol 2004 Transactions. Controlled Release Society, Honolulu, Hawaii, United States p. 94
Finn R, Thiele B, Finnessy J, Liao W, Hall T, Nicastro P, Martin S et al. (2004) PEGylated growth hormone: biochemical properties of a series of conjugates. In: 31st Annual Meeting and Exposition of the Controlled Release Society, vol 2004 Transactions Controlled Release Society, Honolulu, Hawaii, United States p. 468
Webster R, Xie R, Didier E, Finn R, Finnessy J, Edgington A, Walker D (2008) PEGylation of somatropin (recombinant human growth hormone): impact on the clearance in humans. Xenobiotica 38(10): 1340–1351
Clemmons DR (2007) Long-acting forms of growth hormone-releasing hormone and growth hormone: effects in normal volunteers and adults with growth hormone deficiency. Hormone Research 68:178–181
Harris PE, Didier E, Kantaridis C, Boonen A, Weissberger G (2006) First in human study of PEGylated human growth hormone. Hormone Res 65:30
Xie R, Didier E, Harris PE, Milligan PA, Karlsson MO (2006) Population pharmacokinetic/pharmacodynamic analysis for PEGylated recombinant human growth hormone (PHA 794428) in healthy male volunteers. Annual Meeting of the Endocrine Society Program and Astracts
Abs R, Didier EA, Boonen A, Kantaridis CG, Weissberger G, Harris PE (2006) The pharmacokinetics, pharmacodynamics, and safety of PEGylated recombinant human growth hormone after single subcutaneous injections in adult male patients with growth hormone deficiency. Hormone Research 2006:Suppl 4
Cox GN, Rosendahl MS, Chlipala EA, Smith DJ, Carlson SJ, Doherty DH (2007) A long-acting, mono-PEGylated human growth hormone analog is a potent stimulator of weight gain and bone growth in hypophysectomized rats. Endocrinology 148:1590–1597
Peschke B, Zundel M, Bak S, Clausen TR, Blume N, Pedersen A, Zaragoza F et al. (2007) C-terminally PEGylated hGH-derivatives. Bioorganic & Medicinal Chemistry 15:4382–4395
Dorwald FZ (2007) New protein conjugates and methods for their preparation. International Patent Application PCT/EP2007/056819, filed 5 July 2007
Dorwald FZ, Johansen NL, Iversen LF (2006) Transglutaminase mediated conjugation of growth hormone. International Patent Application PCT/EP2006/063246, filed 15 June 2006
Wang L, Brock A, Herberich B, Schultz PG (2001) Expanding the genetic code of Escherichia coli. Science 292:498–500
Wang L, Zhang Z, Brock A, Schultz PG (2003) Addition of the keto functional group to the genetic code of Escherichia coli. Proceedings of the National Academy of Sciences 100:56–61
Cho HS, Buechler Y, Bussell S, Djavahishvili T, Hays A-M, Kraynov V, Litzinger D et al. (2005) Engineering the next generation of therapeutic proteins. Abstracts of Papers, 229th ACS National Meeting, San Diego, CA, United States
Tsubery H, Mironchik M, Fridkin M, Shechter Y (2004) Prolonging the action of protein and peptide drugs by a novel approach of reversible polyethylene glycol modification. Journal of Biological Chemistry 279:38118–38124
Pasut G, Caboi F, Schrepfer R, Tonin G, Schiavon O, Veronese FM (2007) New active poly (ethylene glycol) derivative for amino coupling. Reactive and Functional polymers 67:529–539
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Finn, R.F. (2009). PEGylation of human growth hormone: strategies and properties. In: Veronese, F.M. (eds) PEGylated Protein Drugs: Basic Science and Clinical Applications. Milestones in Drug Therapy. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-8679-5_11
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DOI: https://doi.org/10.1007/978-3-7643-8679-5_11
Publisher Name: Birkhäuser Basel
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