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Development of Pegylated Interferons for the Treatment of Chronic Hepatitis C

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Abstract

The chemical attachment of poly(ethylene glycol) [PEG] to therapeutic proteins produces several benefits, including enhanced plasma half-life, lower toxicity, and increased drug stability and solubility. In certain instances, pegylation of a protein can increase its therapeutic efficacy by reducing the ability of the immune system to detect and mount an attack on the compound.

A PEG-protein conjugate is formed by first activating the PEG moiety so that it will react with, and couple to, the protein. PEG moieties vary considerably in molecular weight and conformation, with the early moieties (monofunctional PEGs; mPEGs) being linear with molecular weights of 12kD or less, and later moieties being of increased molecular weights. PEG2, a recent innovation in PEG technology, involves the coupling of a 30kD (or less) mPEG to lysine that is further reacted to form a branched structure that behaves like a linear mPEG of much larger molecular weight. These compounds are pH and temperature stable, and this factor along with the large molecular weight may account for the restricted volume of distribution seen with drugs utilising these reagents.

Three PEG-protein conjugates are currently approved for clinical use in the US, with more under clinical development. Pegademase is used in the treatment of severe combined immunodeficiency disease, pegaspargase for the treatment of various leukaemias, and pegylated interferon-α for chronic hepatitis C virus infections. As illustrated in the case of the 2 pegylated interferon-αs, all pegylated proteins are not equal. The choice of PEG reagent and coupling chemistry is critical to the properties of the PEG-protein conjugate, with the molecular weight of the moiety affecting its rate and route of clearance from the body, and coupling chemistry affecting the strength of the covalent attachment of PEG to therapeutic protein.

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  1. Use of tradenames is for product identification only and does not imply endorsement.

References

  1. Abuchowski A, vanEs T, Palczuk NC, et al. Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol. J Biol Chem 1977; 252: 3578–81

    CAS  PubMed  Google Scholar 

  2. Harris JM, Zalipsky S, editors. Poly(ethylene glycol): chemistry and biological applications. Washington, DC: American Chemical Society, 1997

    Google Scholar 

  3. Harris JM. Polyethylene glycol chemistry. Biotechnical and biomedical applications. New York: Plenum, 1992

  4. Working PK, Newman MS, Johnson J, et al. Safety of poly(ethylene glycol) and poly(ethylene glycol) derivatives. In: Harris JM, Zalipsky S, editors. Poly(ethylene glycol): chemistry and biological applications. Washington, DC: American Chemical Society, 1997: 45–59

    Chapter  Google Scholar 

  5. Cheng TL, Wu PY, Wu MF, et al. Accelerated clearance of polyethylene glycol-modified proteins by anti-polyethylene glycol IgM. Bioconjug Chem 1999; 10: 520–8

    Article  CAS  PubMed  Google Scholar 

  6. Yamaoka T, Tabata Y, Ikada Y Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J Pharm sci 1994; 83: 601–6

    Article  CAS  PubMed  Google Scholar 

  7. Katre NV. Immunogenicity of recombinant IL-2 modified by covalent attachment of polyethylene glycol. J Immunol 1990; 144: 209–13

    CAS  PubMed  Google Scholar 

  8. Monfardini C, Schiavon O, Caliceti P, et al. A branched monomethoxypoly(ethylene glycol) for protein modification. Bioconjug Chem 1995; 6: 62–9

    Article  CAS  PubMed  Google Scholar 

  9. Caliceti P, Schiavon O, Veronese FM. Biopharmaceutical properties of uricase conjugated to neutral and amphiphilic polymers. Bioconjug Chem 1999; 10: 638–46

    Article  CAS  PubMed  Google Scholar 

  10. Yoshinaga Y, Harris JM. Effects of coupling chemistry on activity of a polyethylene glycol-modified enzyme. J Bioact Comp Polym 1989; 4: 17–24

    Article  Google Scholar 

  11. Dust JM, Fang ZH, Harris JM. Proton NMR characterization of polyethylene glycols and derivatives. Macromolecules 1990; 23: 3742–6

    Article  CAS  Google Scholar 

  12. Abuchowski A, Kazo GM, Verhoest CR, et al. Cancer therapy with chemically modified enzymes. I. Antitumor properties of polyethylene glycol-asparaginase conjugates. Cancer Biochem Biophys 1984; 7: 175–86

    CAS  PubMed  Google Scholar 

  13. Harris JM. Synthesis of polyethylene glycol derivatives. J Macromol sci Rev Macromol Chem Phys 1985; C25: 325–73

    Article  CAS  Google Scholar 

  14. Zalipsky S, Seltzer R, Menon-Rudolph S. Evaluation of a new reagent for covalent attachment of polyethylene glycol to proteins. Biotechnol Appl Biochem 1992; 15: 100–14

    Article  CAS  PubMed  Google Scholar 

  15. Gilbert CW, Park-Cho M. Interferon polymer conjugates. US Patent 5,951,974, Sep. 14, 1999

  16. Zalipsky S. Alkyl succinimidyl carbonates undergo Lossen rearrangement in basic buffers. Chem Commun 1998; 69-70

  17. Kinstler OB, Brems DN, Lauren SL, et al. Characterization and stability of N-terminally PEGylated rhG-CSF. Pharm Res 1996; 13(7): 996–1002

    Article  CAS  PubMed  Google Scholar 

  18. Edwards CK. Pegylated recombinant human soluble tumor necrosis factor receptor type I (rHu-sTNF-RI): novel high-affinity TNF receptor designed for chronic inflammatory diseases. Ann Rheum Dis 1999; 58 Suppl. 1: 173–81

    Google Scholar 

  19. Morpurgo M, Veronese FM, Kachensky D, et al. Preparation and characterization of poly(ethylene glycol) vinylsulfone. Bioconjug Chem 1996; 7: 363–8

    Article  CAS  PubMed  Google Scholar 

  20. El Tayar N, Roberts MJ, Harris JM, et al. Polyol-IFN-beta conjugates, WO 99/55377

  21. Harris JM, Kozlowski A. Polyethylene glycol and related polymers monosubstituted with propionic or butanoic acids and functional derivatives thereof for biotechnical applications. US Patent 5,672,662, Sep 30; 1997

  22. Thorner MO, Strasburger CJ, Wu Z, et al. 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. J Clin Endocrinol Metab 1999 Jun; 84(6): 2098–103

    Article  CAS  PubMed  Google Scholar 

  23. Goffin V, Bernichtein S, Carriere O, et al. The human growth hormone antagonist B2036 does not interact with the prolactin receptor. Endocrinology 1999 Aug; 140(8): 3853–6

    Article  CAS  PubMed  Google Scholar 

  24. Ross RJ, Leung KC, Maamra M, et al. 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. J Clin Endocrinol Metab 2001 Apr; 86(4): 1716–23

    Article  CAS  PubMed  Google Scholar 

  25. Chapman, AP, Antoniw P, Spitali M, et al. Therapeutic antibody fragments with prolonged in vivo half-lives. Nat Biotechnol 1999; 17: 780–3

    Article  CAS  PubMed  Google Scholar 

  26. Bentley MD, Harris JM, Kozlowski A. Heterobifunctional poly(ethylene glycol) derivatives and methods for their preparation. PCT US99/23536: Oct 8; 1999

  27. Hershfield MS. Biochemistry and immunology of poly(ethylene glycol)-modified adenosine deaminase (PEG-ADA). In: Harris JM, Zalipsky S, editors. Poly(ethylene glycol): chemistry and biological applications. Washington, DC: American Chemical Society, 1997: 145–54

    Chapter  Google Scholar 

  28. Burnham NL. Polymers for delivering peptides and proteins. Am J Hosp Pharm 1994; 51:210–8

    CAS  PubMed  Google Scholar 

  29. Hillman BC, Sorensen RU. Management options: SCIDS with adenosine deaminase deficiency. Ann Allergy 1994; 72:395–404

    Google Scholar 

  30. Hershfield MS. PEG-ADA replacement therapy for adenosine deaminase deficiency: an update after 8.5 years. Clin Immunol Immunopathol 1995; 76: S228–32

    Article  CAS  PubMed  Google Scholar 

  31. Keating MJ, Holmes R, Lerner S, et al. L-asparaginase and PEG asparaginase — past, present, and future. Leuk Lymphoma 1993; 10 Suppl.: 153–7

    Article  PubMed  Google Scholar 

  32. Holle LM. Pegaspargase: an alternative. Ann Pharmacother 1997; 3: 616–24

    Google Scholar 

  33. Olson K, Gehant R, Mukku V, et al. Preparation and characterization of poly(ethylene glycol)ylated human growth hormone antagonist. In: Harris JM, Zalipsky S, editors. Poly (ethylene glycol): chemistry and biological applications. Washington, DC: American Chemical Society, 1997: 170–81

    Chapter  Google Scholar 

  34. Liang JT, Rehermann B, Seeff LB, et al. Pathogenesis, natural history, treatment and prevention of hepatitis C. Ann Intern Med 2000; 132: 296–305

    CAS  PubMed  Google Scholar 

  35. McHutchison JG, Gordon SC, Schiff ER, et al, and the Hepatitis Interventional Therapy Group. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998: 339; 1485–92

    Article  CAS  PubMed  Google Scholar 

  36. Poynard T, Marcellin P, Lee S, et al. Randomised trial of interferon alfa-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alfa-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998; 352: 1426–32

    Article  CAS  PubMed  Google Scholar 

  37. O’Brien C, Pockros P, Reddy R, et al. A double-blind, multicenter, randomized, parallel dose-comparison study of six regimens of 5kD, linear peginterferon alfa-2a compared with Roferon-A in patients with chronic hepatitis C. Antiviral Therapy 1999; 4 Suppl. 4: 15

    Google Scholar 

  38. Bailon P, Spence C, Schaffer CA, et al. Pharmacological properties of five polyethylene glycol conjugates of interferon alfa-2a. Antiviral Therapy 1999; 4 Suppl. 4: 27

    Google Scholar 

  39. Heathcote EJ, Shiffman ML, Cooksley GE, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000; 343: 1673–80

    Article  CAS  PubMed  Google Scholar 

  40. Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000; 343: 1666–72

    Article  CAS  PubMed  Google Scholar 

  41. Bailon P, Palleroni A, Schaffer CA, et al. Rational design of a potent, long-lasting form of interferon: a 40 kDa branched polyethylene glycol-conjugated interferon alpha-2a for the treatment of hepatitis C. Bioconjug Chem 2001 Mar-Apr; 12(2): 195–202

    Article  CAS  PubMed  Google Scholar 

  42. Algranati NE, Sy S, Modi MW. A branched methoxy 40 kDa polyethylene glycol (PEG) moiety optimizes the pharmacokinetics (PK) of peginterferon α-2a (PEG-IFN) and may explain its enhanced efficacy in chronic Hepatitis C (CHC). Hepatology 1999; 30 (4 Pt 2): 190A

    Google Scholar 

  43. Sulkowski MS, Reindollar R, Yu J. Pegylated interferon alfa-2a (PEGASYS™) and ribavirin combination therapy for chronic hepatitis C: a phase II open-label study. Gastroenterology 2000; 118 Suppl. 2: 950

    Article  Google Scholar 

  44. Glue P, Fang JW, Rouzier-Panis R, et al. Pegylated interferon-alpha2b; pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin Pharmacol Ther 2000 Nov; 68(5): 556–67

    Article  CAS  PubMed  Google Scholar 

  45. Trepo C, Lindsay K, Niederau C, et al. Pegylated interferon alfa-2b (PEG-Intron) monotherapy is superior to interferon alfa-2b (Intron A) for the treatment of chronic hepatitis C [abstract GS2/07]. J Hepatology 2000; 32: 29

    Google Scholar 

  46. Manns MP, McHutchison JG, Gordon S, et al. Peginterferon alfa-2b plus ribavirin compared to interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C: 24 week treatment analysis of a multicenter, multinational phase III randomized controlled trial. Hepatology 2000; 32(4): 297A

    Article  Google Scholar 

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Acknowledgements

The development of this manuscript was supported by Shearwater Corporation. Shearwater Corporation manufactures the PEG reagents used in much of the work described in this review.

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  1. Shearwater Corporation, 1112 Church St., Huntsville, Alabama, 35801, USA

    Antoni Kozlowski, Stephen A. Charles &  J. Milton Harris

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  1. Antoni Kozlowski
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  2. Stephen A. Charles
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Correspondence to J. Milton Harris.

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Kozlowski, A., Charles, S.A. & Harris, J.M. Development of Pegylated Interferons for the Treatment of Chronic Hepatitis C. BioDrugs 15, 419–429 (2001). https://doi.org/10.2165/00063030-200115070-00001

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