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Improved biological and transcriptional activity of monopegylated interferon-α-2a isomers

The Pharmacogenomics Journal volume 3, pages 312–319 (2003)Cite this article

ABSTRACT

The addition of polyethyleneglycol (PEG) side chains to interferon α-2a improves the serum stability and clinical efficacy. Current commercial PEG-INF formulations such as PEGASYS® are heterogeneous and contain multiple monopegylated isomers. We have analyzed the activity of nine, purified monopegylated variants in antiproliferative, antiviral and binding assays, together with a global transcriptional analysis using DNA oligonucleotide microarrays. We show a direct correlation between biological and transcriptional activity for all isomers and an inversed correlation between IFN-receptor 2a affinity and signal transduction. Two out of nine positional isomers have a higher specific biological and transcriptional activity than the mixture, which can be explained by unique structural features of interferon signaling, which involves two distinct receptors. The possible clinical implications are discussed, which might guide the development of pegylated interferons with improved pharmacological properties.

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References

  1. Isaacs A, Lindenmann J . Virus interference. I. The interferon. J Interferon Res 1987; 7: 429–438.

    Article  CAS  Google Scholar 

  2. Allen G, Diaz MO . Nomenclature of the human interferon proteins. J Interferon Cytokine Res 1996; 16: 181–184.

    Article  CAS  Google Scholar 

  3. Spiegel RJ . Alpha interferons: a clinical overview. Urology 1989; 34: 75–79.

    Article  CAS  Google Scholar 

  4. Baron S, Tyring S, Fleischmann Jr WR, Coppenhaver DH, Niesel DW, Klimpel GR et al. The interferons. Mechanisms of action and clinical applications. J Am Med Assoc 1991; 266: 1375–1383.

    Article  CAS  Google Scholar 

  5. Zeuzem S, Heathcote J, Martin N, Nieforth K, Modi M . Peginterferon alfa-2a (40 kDa) monotherapy: a novel agent for chronic hepatitis C therapy. Exp Opin Investig Drugs 2001; 10: 2201–2213.

    Article  CAS  Google Scholar 

  6. Reddy KR, Modi MW, Pedder S . Use of peginterferon alfa-2a (40 KD) (Pegasys®) for the treatment of hepatitis C. Adv Drug Deliv Rev 2002; 54: 571–586.

    Article  Google Scholar 

  7. Harris JM, Martin NE, Modi M . Pegylation: a novel process for modifying pharmacokinetics. Clin Pharmacokinet 2001; 40: 539–551.

    Article  CAS  Google Scholar 

  8. Bailon P, Palleroni A, Schaffer CA, Spence C, Wen-Jian F, Porter JE et al. 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 Chem 2001; 12: 195–202.

    Article  CAS  Google Scholar 

  9. Veronese FM . Peptide and protein PEGylation: a review of problems and solutions. Biomaterials 2001; 22: 405–417.

    Article  CAS  Google Scholar 

  10. Bailon P, Berthold W . Polyethylene glycol-conjugated pharmaceutical proteins. Pharm Sci Technol Today 1998; 1: 352–356.

    Article  CAS  Google Scholar 

  11. Perry MC, Jarvis B . Peginterferon-α-2a (40 kD): a review of its use in the management of chronic hepatitis C. Drugs 2001; 15: 2263–2288.

    Article  Google Scholar 

  12. Lamb MW, Martin EN . Weight-based versus fixed dosing of peginterferon (40 kDa) alfa-2a. Ann Pharmacother 2002; 36: 933–938.

    Article  Google Scholar 

  13. Foser S, Schacher A, Weyer KA, Brugger D, Dietel E, Marti S et al. Isolation, structural characterization and antiviral activity of positional isomers of monopegylated interferon alpha-2a (PEGASYS®). Protein Express Purification 2003; 30: 78–87.

    Article  CAS  Google Scholar 

  14. Bailon PS, Palleroni AV European Patent No. 809996, 1997.

  15. Certa U, Seiler M, Padovan E, Spagnoli GC . High density oligonucleotide array analysis of interferon-alpha2a sensitivity and transcriptional response in melanoma cells. Br J Cancer 2001; 85: 107–114.

    Article  CAS  Google Scholar 

  16. Uzé G, Lutfalla G, Mogensen KE . α and β interferons and their receptor and their friends and relations. J Interferon Res 1995; 15: 3–26.

    Article  Google Scholar 

  17. Domanski P, Witte M, Kellum M, Rubinstein M, Hackett R, Pitha P et al. Cloning and expression of a long form of the beta subunit of the interferon alpha beta receptor that is required for signaling. J Biol Chem 1995; 270: 21606–21611.

    Article  CAS  Google Scholar 

  18. Novick D, Cohen B, Rubinstein M . The human interferon alpha/beta receptor: characterization and molecular cloning. Cell 1994; 77: 391–400.

    Article  CAS  Google Scholar 

  19. Kim SH, Cohen B, Novick D, Rubinstein M . Mammalian type1 interferon receptors consists of two subunits: IFNaR1 and IFNaR2. Gene 1997; 196: 279–286.

    Article  CAS  Google Scholar 

  20. Platanias LC, Fish EN . Signaling pathways activated by interferons. Exp Hematol 1999; 27: 1583–1592.

    Article  CAS  Google Scholar 

  21. Hardy MP, Owczarek CM, Trajanovka S, Liu X, Kola I, Hertzog PJ . The soluble murine type I interferon receptor Ifnar-2 is present in serum, is independently regulated, and has both agonistic and antagonistic properties. Blood 2001; 97: 473–482.

    Article  CAS  Google Scholar 

  22. Piehler J, Roisman LC, Schreiber G . New structural and functional aspect of the type I interferon–receptor interaction revealed by comprehensive mutational analysis of the binding interface. J Biol Chem 2001; 51: 40425–40433.

    Google Scholar 

  23. Chang C-CJ, Chen TT, Cox BW, Dawes GN, Stemmer WPC, Punnonen J et al. Evolution of a cytokine using DNA family shuffling. Nat Biotechnol 1999; 17: 793–797.

    Article  CAS  Google Scholar 

  24. Cohen B, Novick D, Barak S, Rubinstein M . Ligand-induced association of the type I interferon receptor components. Mol Cell Biol 1995; 15: 4208–4214.

    Article  CAS  Google Scholar 

  25. Klaus W, Gsell B, Labhardt AM, Wipf B, Senn H . The three-dimensional high resolution structure of human interferon alpha-2a determined by heteronuclear NMR spectroscopy in solution. J Mol Biol 1997; 274: 661–675.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr Stefan Marti and Joelle Bisch for performing the antiviral bioassay and Josiane Kohler for running the BIAcore analysis. We are grateful to Dr Salima Matthews for critical reading of this manuscript and to Dr Hagen Pfundner and Professor Klaus Lindpaintner for continuous support to the project.

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Authors and Affiliations

  1. Department of Pharma Technical Operations Biotechnology, F Hoffmann La Roche Ltd, Basel, Switzerland

    S Foser & K Weyer

  2. Pharma Research Discovery, F Hoffmann La Roche Ltd, Basel, Switzerland

    W Huber

  3. Roche Center for Medical Genomics, F Hoffmann La Roche Ltd, Basel, Switzerland

    U Certa

Authors
  1. S Foser
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  2. K Weyer
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  3. W Huber
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  4. U Certa
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Correspondence to U Certa.

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Foser, S., Weyer, K., Huber, W. et al. Improved biological and transcriptional activity of monopegylated interferon-α-2a isomers. Pharmacogenomics J 3, 312–319 (2003). https://doi.org/10.1038/sj.tpj.6500204

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