Journal of Neuroimmune Pharmacology

, Volume 6, Issue 1, pp 158–162 | Cite as

n-Dodecyl-β-d-Maltoside Inhibits Aggregation of Human Interferon-β-1b and Reduces Its Immunogenicity

  • Robert A. Rifkin
  • Edward T. Maggio
  • Sonny Dike
  • Douglas A. Kerr
  • Michael Levy
ORIGINAL ARTICLE

Abstract

The development of neutralizing antibodies to the protein drug interferon-β is a significant impediment to its use in the treatment of multiple sclerosis. Neutralizing antibodies to interferon-β arise from aggregation of the peptide during manufacturing and storage. We tested the ability of dodecylmaltoside, a nontoxic alkylsaccharide surfactant, to reduce aggregation of interferon-β in vitro and to reduce its immunogenicity in vivo. Interferon-β, in solution with and without dodecylmaltoside, was periodically evaluated for aggregation by light scatter for 1 month. Interferon-β, with and without dodecylmaltoside, was given 3 days/week for 1 month to mice; the sera of these mice were analyzed for anti-interferon-β antibodies by ELISA. Dodecylmaltoside reduces the aggregation of interferon-β in vitro and its immunogenicity in vivo. Our positive findings warrant additional tests of dodecylmaltoside as a therapeutic adjuvant in rodent models of multiple sclerosis.

Keywords

multiple sclerosis interferon-beta excipients disaccharides/chemistry 

References

  1. Bayer HealthCare Pharmaceuticals Inc. (2007) Betaseron prescribing information. Bayer HealthCare Pharmaceuticals, Leverkusen, GermanyGoogle Scholar
  2. Biogen Idec Inc (2006) Avonex prescribing information. Biogen Idec, CambridgeGoogle Scholar
  3. Bohidar HB (1998) Light scattering and viscosity study of heat aggregation of insulin. Biopolymers 45:1–8CrossRefPubMedGoogle Scholar
  4. Environmental Protection Agency (2005) Alkyl (C10–C16) polyglycosides; exemptions from the requirement of a tolerance. 40 CFR Part 180. 70 (177): 54281–54286Google Scholar
  5. Fradkin AH, Carpenter JF, Randolph TW (2009) Immunogenicity of aggregates of recombinant human growth hormone in mouse models. J Pharm Sci 98:3247–3264CrossRefPubMedGoogle Scholar
  6. Higashi Y, Sokawa Y, Watanabe Y, Kawade Y, Ohno S, Takaoka C, Taniguchi T (1983) Structure and expression of a cloned cDNA for mouse interferon-β. J Biol Chem 258(15):9522–9529PubMedGoogle Scholar
  7. IFNB Multiple Sclerosis Study Group (1993) Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43:655–661Google Scholar
  8. IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group (1995) Interferon beta-lb in the treatment of multiple sclerosis. Neurology 45:1277–1285Google Scholar
  9. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, Fischer JS, Goodkin DE, Granger CV, Simon JH, Alam JJ, Bartoszak DM, Bourdette DN, Braiman J, Brownscheidle CM, Coats ME, Cohan SL, Dougherty DS, Kinkel RP, Mass MK, Munschauer FE 3rd, Priore RL, Pullicino PM, Scherokman BJ, Whitham RH (1996) Intramuscular interferon beta-la for disease progression in relapsing multiple sclerosis. Ann Neurol 39:285–294CrossRefPubMedGoogle Scholar
  10. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, Simonian NA, Slasor PJ, Sandrock AW (2000) Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 343(13):898–904CrossRefPubMedGoogle Scholar
  11. Maggio ET (2008) Stabilizing alkylglycosides compositions and methods thereof. US Patent 7,522,542, 16 Sept 2008Google Scholar
  12. Mosmann TR, Sad S (1996) The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 17(3):138–146CrossRefPubMedGoogle Scholar
  13. Panitch HS, Hirsch RL, Schindler J, Johnson KP (1987) Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune function. Neurology 37:1097–1102PubMedGoogle Scholar
  14. Panitch H, Goodin DS, Francis G, Chang P, Coyle PK, O'Connor P, Monaghan E, Li D, Weinshenker B (2002) Randomized, comparative study of interferon-β-1a treatment regimens in MS. Neurology 59(10):1496–1506PubMedGoogle Scholar
  15. Panitch H, Goodin D, Francis G, Chang P, Coyle P, O'Connor P, Li D, Weinshenker B (2005) Benefits of high-dose, high-frequency interferon beta-1a in relapsing–remitting multiple sclerosis are sustained to 16 months: final comparative results of the EVIDENCE trial. J Neurol Sci 239(1):67–74CrossRefPubMedGoogle Scholar
  16. Perini P, Calabrese M, Biasi G, Gallo P (2004) The clinical impact of interferon beta antibodies in relapsing–remitting MS. J Neurol 251(3):305–309CrossRefPubMedGoogle Scholar
  17. Pfizer (2008) Rebif prescribing information. Pfizer, New YorkGoogle Scholar
  18. Rosenberg AS (2006) Effects of protein aggregates: an immunologic perspective. AAPS J 8:E501–E507CrossRefPubMedGoogle Scholar
  19. Roy S, Jung R, Kerwin BA, Randolph TW, Carpenter JF (2005) Effects of benzyl alcohol on aggregation of recombinant human interleukin-1-receptor antagonist in reconstituted lyophilized formulations. J Pharm Sci 94(2):382–396CrossRefPubMedGoogle Scholar
  20. Schellekens H (2003) Immunogenicity of therapeutic proteins. Nephrol Dial Transplant 18:1257–1259CrossRefPubMedGoogle Scholar
  21. Sorensen PS, Ross C, Clemmesen KM, Bendtzen K, Frederiksen JL, Jensen K, Kristensen O, Petersen T, Rasmussen S, Ravnborg M, Stenager E, Koch-Henriksen N (2003) Clinical importance of neutralising antibodies against interferon beta in patients with relapsing–remitting multiple sclerosis. Lancet 362(9391):1184–1191CrossRefPubMedGoogle Scholar
  22. Stanton GJ, Weigent DA, Fleischmann WR Jr, Dianzani F, Baron S (1987) Interferon review. Invest Radiol 22:259–273CrossRefPubMedGoogle Scholar
  23. Vartanian T, Sorensen PS, Rice G (2004) Impact of neutralizing antibodies on the clinical efficacy of interferon beta in multiple sclerosis. J Neurol 251:1125–1130CrossRefGoogle Scholar
  24. Weber N, Benning H (1984) Metabolism of orally administered alkyl beta-glycosides in the mouse. J Nutr 114:247–254PubMedGoogle Scholar
  25. Yong VW (2002) Differential mechanisms of action of interferon-β and glatiramer acetate in MS. Neurology 59:802–808PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Robert A. Rifkin
    • 1
  • Edward T. Maggio
    • 2
  • Sonny Dike
    • 1
  • Douglas A. Kerr
    • 3
  • Michael Levy
    • 1
  1. 1.Department of NeurologyThe Johns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Aegis Therapeutics, LLCSan DiegoUSA
  3. 3.Biogen Idec, IncCambridgeUSA

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