PEGylation of human growth hormone: strategies and properties

  • Rory F. Finn
Part of the Milestones in Drug Therapy book series (MDT)


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.


Growth Hormone Growth Hormone Deficiency Human Growth Hormone Growth Hormone Receptor Recombinant Human Growth Hormone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    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, 1363–1382Google Scholar
  2. 2.
    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 91:391–396CrossRefPubMedGoogle Scholar
  3. 3.
    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 83:9343–9347CrossRefGoogle Scholar
  4. 4.
    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 11:41–48Google Scholar
  5. 5.
    Reslow M, Lonsson M, Laakso T (2003) Sustained-release of human growth hormone from PLG-coated starch microspheres. DDS&S 2:103–109Google Scholar
  6. 6.
    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. 86:4700–4706CrossRefPubMedGoogle Scholar
  7. 7.
    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 22:1461–1470CrossRefPubMedGoogle Scholar
  8. 8.
    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 49:193–205CrossRefGoogle Scholar
  9. 9.
    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 456:149–158CrossRefPubMedGoogle Scholar
  10. 10.
    Veronese FM, Pasut G (2005) PEGylation, successful approach to drug delivery. Drug Discovery Today 10:1451–1458CrossRefPubMedGoogle Scholar
  11. 11.
    Zalipsky S, Lee C (1992) Use of functionalized poly(ethylene glycol)s for modification of polypeptides. Poly(Ethylene Glycol) Chem 347–370Google Scholar
  12. 12.
    Fu CH, Sakamoto KM (2007) PEG-asparaginase. Expert Opinion on Pharmacotherapy 8:1977–1984CrossRefPubMedGoogle Scholar
  13. 13.
    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 117:133–143CrossRefPubMedGoogle Scholar
  14. 14.
    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 12:195–202CrossRefPubMedGoogle Scholar
  15. 15.
    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 54:547–570CrossRefPubMedGoogle Scholar
  16. 16.
    Molineux G (2004) The design and development of Pegfilgrastim (PEG-rmetHuG-CSF, Neulasta®. Current Pharmaceutical Design 10:1235–1244CrossRefPubMedGoogle Scholar
  17. 17.
    Behncken SN, Waters MJ (1999) Molecular recognition events involved in the activation of the growth hormone receptor. J Molecular Recognition 12:255–362Google Scholar
  18. 18.
    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 36:1–7CrossRefGoogle Scholar
  19. 19.
    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 86:1716–1723CrossRefPubMedGoogle Scholar
  20. 20.
    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 271:21969–21977CrossRefPubMedGoogle Scholar
  21. 21.
    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 48:253–275PubMedGoogle Scholar
  22. 22.
    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, 45–69CrossRefGoogle Scholar
  23. 23.
    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 87:5061–5065CrossRefPubMedGoogle Scholar
  24. 24.
    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 269:15892–15897PubMedGoogle Scholar
  25. 25.
    Maamra MK, Kopchick JJ, Strasburger CJ, Ross, RJM (2004) Pegvisomant, a growth hormone-specific antagonist, undergoes cellular internalization. Journal of Clinical Endocrinology and Metabolism 89:4532–4537CrossRefPubMedGoogle Scholar
  26. 26.
    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) 256:1677–1680Google Scholar
  27. 27.
    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 170–181CrossRefGoogle Scholar
  28. 28.
    Pradhananga S, Wilkinson I, Ross RJM (2002) Pegvisomant: structure and function. Journal of Molecular Endocrinology 29:11–14CrossRefPubMedGoogle Scholar
  29. 29.
    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 37:869Google Scholar
  30. 30.
    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 1–49Google Scholar
  31. 31.
    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 83:4013–4021CrossRefPubMedGoogle Scholar
  32. 32.
    Ben-Shlomo A, Melmed S (2008) Acromegaly. Endocrinology & Metabolism Clinics of North America 37:101–122CrossRefGoogle Scholar
  33. 33.
    Roelfsema F, Biermasz NR, Pereira AM, Romijn J (2006) Nanomedicines in the treatment of acromegaly: focus on pegvisomant. International Journal of Nanomedicine 1:385–398CrossRefPubMedGoogle Scholar
  34. 34.
    Colao A, Ferone D, Marzullo P (2004) Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocrine Rev 25:102–152CrossRefGoogle Scholar
  35. 35.
    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 89:353–358CrossRefPubMedGoogle Scholar
  36. 36.
    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) 53:321–327Google Scholar
  37. 37.
    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 83:374–378CrossRefGoogle Scholar
  38. 38.
    Lancranjan I, Atkinson AB (1999) The Sandostatin LAR group results of a European multicentre study with sandostatin LAR in acromegalic patients. Pituitary 1:105–114CrossRefPubMedGoogle Scholar
  39. 39.
    van der Lely AJ, Kopchick JJ (2006) Growth hormone receptor antagonists. Neuroendocrinology 83:264–268CrossRefPubMedGoogle Scholar
  40. 40.
    Roelfsema F, Biermasz NR, Pereira AM, Romijn J A (2008) The role of pegvisomant in the treatment of acromegaly. Expert Opinion on Biological Therapy 8:691–704CrossRefPubMedGoogle Scholar
  41. 41.
    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 84:2098–2103CrossRefPubMedGoogle Scholar
  42. 42.
    Parkinson C, Trainer PJ (2001) The place of pegvisomant in the management of acromegaly. Expert Opinion on Investigational Drugs 10:1725–1735CrossRefPubMedGoogle Scholar
  43. 43.
    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 342:1171–1177CrossRefPubMedGoogle Scholar
  44. 44.
    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 358:1754–1759CrossRefPubMedGoogle Scholar
  45. 45.
    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 92:1724–1728CrossRefPubMedGoogle Scholar
  46. 46.
    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 87:1797–1804CrossRefPubMedGoogle Scholar
  47. 47.
    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 154:467–477CrossRefPubMedGoogle Scholar
  48. 48.
    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 365:1644–1646CrossRefPubMedGoogle Scholar
  49. 49.
    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 156:75–82CrossRefPubMedGoogle Scholar
  50. 50.
    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 383–402Google Scholar
  51. 51.
    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 54:571–586CrossRefGoogle Scholar
  52. 52.
    Kinstler O, Mollineux G, Treuheit M, Ladd D, Gegg C (2002) Mono-N-terminal polyfethylene glycol)-protein conjugates. Advanced Drug Delivery Reviews 54:477–485CrossRefPubMedGoogle Scholar
  53. 53.
    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. 94Google Scholar
  54. 54.
    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. 468Google Scholar
  55. 55.
    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): 1340–1351CrossRefPubMedGoogle Scholar
  56. 56.
    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 68:178–181CrossRefPubMedGoogle Scholar
  57. 57.
    Harris PE, Didier E, Kantaridis C, Boonen A, Weissberger G (2006) First in human study of PEGylated human growth hormone. Hormone Res 65:30Google Scholar
  58. 58.
    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 Google Scholar
  59. 59.
    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 4Google Scholar
  60. 60.
    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 148:1590–1597CrossRefPubMedGoogle Scholar
  61. 61.
    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 15:4382–4395CrossRefGoogle Scholar
  62. 62.
    Dorwald FZ (2007) New protein conjugates and methods for their preparation. International Patent Application PCT/EP2007/056819, filed 5 July 2007Google Scholar
  63. 63.
    Dorwald FZ, Johansen NL, Iversen LF (2006) Transglutaminase mediated conjugation of growth hormone. International Patent Application PCT/EP2006/063246, filed 15 June 2006Google Scholar
  64. 64.
    Wang L, Brock A, Herberich B, Schultz PG (2001) Expanding the genetic code of Escherichia coli. Science 292:498–500CrossRefPubMedGoogle Scholar
  65. 65.
    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 100:56–61CrossRefGoogle Scholar
  66. 66.
    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 Google Scholar
  67. 67.
    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 279:38118–38124CrossRefPubMedGoogle Scholar
  68. 68.
    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 67:529–539CrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2009

Authors and Affiliations

  • Rory F. Finn
    • 1
  1. 1.Pfizer IncChesterfieldUSA

Personalised recommendations