Journal of Neurology

, Volume 254, Issue 7, pp 827–837 | Cite as

Neutralising antibodies to interferon β in multiple sclerosis

Expert panel report
  • H.-P. Hartung
  • C. Polman
  • A. Bertolotto
  • F. Deisenhammer
  • G. Giovannoni
  • E. Havrdova
  • B. Hemmer
  • J. Hillert
  • L. Kappos
  • B. Kieseier
  • J. Killestein
  • C. Malcus
  • M. Comabella
  • A. Pachner
  • H. Schellekens
  • F. Sellebjerg
  • K. Selmaj
  • P. S. Sorensen


Interferon beta (IFNβ) therapy for multiple sclerosis (MS) is associated with a potential for the development of neutralising antibodies (NAbs) that negatively affect therapy. Several factors influence the development of NAbs, such as lack of complete sequence homology with the endogenous IFNβ sequence, frequency of administration, level of dose and formulation of IFNβ. Taken together, the evidence that NAb status reduces clinical efficacy in MS patients is strong. Standardised assays for NAbs are lacking, and titres vary over time. NAb testing is a critical component of care for MS patients because it provides information on one of the most important factors determining clinical responsiveness to IFNβ therapy. This expert panel report attempts to move the field towards resolution of the remaining issues and considers several aspects of NAbs, including their clinical relevance, factors influencing immunogenicity, assays to quantify NAbs and the definition of clinically relevant titres.

Key words

neutralising antibodies interferon β multiple sclerosis NAb+ NAb- 


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  1. 1.
    Ross C, Clemmesen KM, Svenson M, et al. (2000) Immunogenicity of interferon-β in multiple sclerosis patients: influence of preparation, dosage, dose frequency, and route of administration. Ann Neurol 48:706–712CrossRefPubMedGoogle Scholar
  2. 2.
    Bertolotto A, Malucchi S, Sala A, et al. (2002) Differential effects of three interferon betas on neutralising antibodies in patients with multiple sclerosis: a follow up study in an independent laboratory. J Neurol Neurosurg Psychiatry 73:148–153CrossRefPubMedGoogle Scholar
  3. 3.
    Panitch H, Goodin DS, Francis G, et al. (2002) Randomized, comparative study of interferon β-1a treatment regimens in MS: the EVIDENCE trial. Neurology 59:1496–1506PubMedGoogle Scholar
  4. 4.
    Sorensen PS (2003) Antibodies to IFNbeta. The Danish National IFN-beta Project. Neurology 61(9 suppl 5):S27–S28PubMedGoogle Scholar
  5. 5.
    Sorensen PS, Koch-Hendriksen N, Ross C, et al. (2005) Appearance and disappearance of neutralizing antibodies during interferon-beta therapy. Neurology 65:33–39CrossRefPubMedGoogle Scholar
  6. 6.
    Brainin M, Barnes M, Baron J-C, et al. (2004) Guidance for the preparation of neurological management guidelines by EFNS scientific task forces - revised recommendations 2004. Eur J Neurol 11:577–581CrossRefPubMedGoogle Scholar
  7. 7.
    IFNβ Multiple Sclerosis Study Group, the University of British Columbia MS/MRI Analysis Group (1996) Neutralizing antibodies during treatment of multiple sclerosis with interferon beta- 1b: experience during the first three years. Neurology 47:889–894Google Scholar
  8. 8.
    Jacobs LD, Cookfair DL, Rudick RA, et al. (1996) Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 39:285–294CrossRefPubMedGoogle Scholar
  9. 9.
    Rudick RA, Simonian NA, Alam JA, et al. (1998) Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Neurology 50:1266–1272PubMedGoogle Scholar
  10. 10.
    Kappos L, Clanet M, Sandberg-Wollheim M, et al. (2005) Neutralizing antibodies and efficacy of interferon β-1a: a 4-year controlled study. Neurology 65:40–47CrossRefPubMedGoogle Scholar
  11. 11.
    Herndon RM, Jacobs LD, Coats ME, et al. (1999) Results of an ongoing, open-label, safety-extension study of interferon beta-1a (Avonex) treatment in multiple sclerosis. Int J MS Care 1:1–6Google Scholar
  12. 12.
    Herndon RM, Rudick RA, Munschauer FE III, et al. (2005) Eight-year immunogenicity and safety of interferon beta-1a-Avonex® treatment in patients with multiple sclerosis. Mult Scler 11:409–419CrossRefPubMedGoogle Scholar
  13. 13.
    Jacobs LD, Beck RW, Simon JH, et al. (2000) Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 343:898–904CrossRefPubMedGoogle Scholar
  14. 14.
    Clanet M, Radue EW, Kappos L, et al. (2002) A randomized, double-blind, dose-comparison study of weekly interferon β-1a in relapsing MS. Neurology 59:1507–1517PubMedGoogle Scholar
  15. 15.
    PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis) Study Group (1998) Randomised doubleblind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet 352:1498–1504CrossRefGoogle Scholar
  16. 16.
    PRISMS (Prevention of Relapses and Disability by Interferon-β-1a Subcutaneously in Multiple Sclerosis) Study Group, the University of British Columbia MS/MRI Analysis Group (2001) PRISMS-4: long-term efficacy of interferon-β-1a in relapsing MS. Neurology 56:1628–1636Google Scholar
  17. 17.
    Francis GS, Rice GPA, Alsop JC, for the PRISMS Study Group (2005) Interferon β-1a in MS. Results following development of neutralizing antibodies in PRISMS. Neurology 65:48–55CrossRefPubMedGoogle Scholar
  18. 18.
    Petkau AJ, White RA, Ebers GC, et al. (2004) Longitudinal analyses of the effects of neutralizing antibodies on interferon beta-1b in relapsing-remitting multiple sclerosis. Mult Scler 10:126–138CrossRefPubMedGoogle Scholar
  19. 19.
    Deisenhammer F, Giovannoni G (2004) Longitudinal analyses of the effects of neutralizing antibodies on interferon beta-1b in relapsing/remitting multiple sclerosis. Mult Scler 10:713–714CrossRefPubMedGoogle Scholar
  20. 20.
    European Study Group on Interferon β-1b in Secondary Progressive MS (1998) Placebo-controlled multicentre randomised trial of interferon β-1b in treatment of secondary progressive multiple sclerosis. Lancet 352:1491–1497CrossRefGoogle Scholar
  21. 21.
    Polman C, Kappos L, White R, et al. (2003) Neutralizing antibodies during treatment of secondary progressive MS with interferon β-1b. Neurology 60:37–43PubMedCrossRefGoogle Scholar
  22. 22.
    Sorensen PS, Ross C, Clemmesen KM, et al. (2003) Clinical importance of neutralising antibodies against interferon beta in patients with relapsingremitting multiple sclerosis. Lancet 362:1184–1191CrossRefPubMedGoogle Scholar
  23. 23.
    Deisenhammer F, Reindl M, Harvey J, et al. (1999) Bioavailability of interferon beta 1b in MS patients with and without neutralizing antibodies. Neurology 52:1239–1243Google Scholar
  24. 24.
    Pachner A, Narayan K, Price N, et al. (2003) MxA gene expression analysis as an IFNβ bioactivity measurement in patients with multiple sclerosis and the identification of antibody-mediated decreased bioactivity. Mol Diagn 7:17–25CrossRefPubMedGoogle Scholar
  25. 25.
    Pachner AR, Dail D, Pak E, et al. (2005) The importance of measuring IFNß bioactivity: monitoring in MS patients and the effect of anti-IFNβ antibodies. J Neuroimmunol 166:180–188CrossRefPubMedGoogle Scholar
  26. 26.
    Bertolotto A, Gilli F, Sala A, et al. (2003) Persistent neutralizing antibodies abolish the interferon β bioavailability in MS patients. Neurology 60:634–639CrossRefPubMedGoogle Scholar
  27. 27.
    Wandinger KP, Lünemann JD, Wengert O, et al. (2003) TNF-related apoptosis inducing ligand (TRAIL) as a potential response marker for interferon-beta treatment in multiple sclerosis. Lancet 361:2036–2043CrossRefPubMedGoogle Scholar
  28. 28.
    Conradt HS, Egge H, Peter-Katalinic J, et al. (1987) Structure of the carbohydrate moiety of human interferon-β secreted by a recombinant Chinese hamster ovary cell line. J Biol Chem 262:14600–4605PubMedGoogle Scholar
  29. 29.
    Patten PA, Schellekens H (2003) The immunogenicity of biopharmaceuticals. Lessons learned and consequences for protein drug development. Dev Biol 112:81–87Google Scholar
  30. 30.
    Schellekens H (2003) Relationship between biopharmaceutical immunogenicity of epoetin alfa and pure red cell aplasia. Curr Med Res Opin 19:433–434CrossRefPubMedGoogle Scholar
  31. 31.
    Casadevall N, Nataf J, Viron B, et al. (2002) Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 346:469–475CrossRefPubMedGoogle Scholar
  32. 32.
    Verhelst D, Rossert J, Casadevall N, et al. (2004) Treatment of erythropoietin- induced pure red cell aplasia: a retrospective study. Lancet 363:1768–1771CrossRefPubMedGoogle Scholar
  33. 33.
    Grossberg SE (2003) Perspectives on the neutralization of interferons by antibody. Neurology 61(9 suppl 5):S21–S23PubMedGoogle Scholar
  34. 34.
    Bendtzen K (2003) Anti-IFN BAb and NAb antibodies. A minireview. Neurology 61(9 suppl 5):S6–S10PubMedGoogle Scholar
  35. 35.
    Pachner AR, Oger J, Palace J (2003) The measurement of antibodies binding to IFNβ in MS patients treated with IFNβ. Neurology 61(9 suppl 5):S18–S20PubMedGoogle Scholar
  36. 36.
    Lawrence N, Oger J, Aziz T, et al. (2003) A sensitive radioimmunoprecipitation assay for assessing the clinical relevance of antibodies to IFNβ. J Neurol Neurosurg Psychiatry 74:1236–1239CrossRefPubMedGoogle Scholar
  37. 37.
    Pachner AR (2003) An improved ELISA for screening for neutralizing anti-IFNβ antibodies in MS patients. Neurology 61:1444–1446PubMedGoogle Scholar
  38. 38.
    WHO Expert Committee on Biological Standardization (1985) Thirty-fifth report. World Health Organization Technical Report Series 725. World Health Organization, Geneva, SwitzerlandGoogle Scholar
  39. 39.
    Meager A (2004) Seventh WHO informal consultation on standards for cytokines, growth factors and endocrinological substances. Biologicals 32:105–111CrossRefPubMedGoogle Scholar
  40. 40.
    Kawade Y (1986) Quantitation of neutralization of interferon by antibody. Meth Enzymol 119:558–573CrossRefPubMedGoogle Scholar
  41. 41.
    Grossberg SE, Kawade Y, Kohase M, et al. (2001) The neutralization of interferons by antibody. I. Quantitative and theoretical analyses of the neutralization reaction in different bioassay systems. J Interferon Cytokine Res 21:729–742CrossRefPubMedGoogle Scholar
  42. 42.
    Grossberg SE, Kawade Y, Kohase M, et al. (2001) The neutralization of interferons by antibody. II. Neutralizing antibody unitage and its relationship to bioassay sensitivity: the tenfold reduction unit. J Interferon Cytokine Res 21:743–755CrossRefPubMedGoogle Scholar
  43. 43.
    von Wussow P, Jakschies D, Hochkeppel HK, et al. (1990) The human intracellular Mx-homologous protein is specifically induced by type I interferons. Eur J Immunol 20:2015–2019CrossRefPubMedGoogle Scholar
  44. 44.
    Files JG, Gray JL, Do LT, et al. (1998) A novel sensitive and selective bioassay for human type I interferons. J Interferon Cytokine Res 18:1019–1024CrossRefPubMedGoogle Scholar
  45. 45.
    Gneiss C, Reindl M, Lutterotti A, et al. (2004) Interferon-beta: the neutralizing antibody (NAb) titre predicts reversion to NAb negativity. Mult Scler 10:507–510CrossRefPubMedGoogle Scholar
  46. 46.
    Hartung HP, Munschauer F, Schellekens H (2005) Significance of neutralizing antibodies to interferon beta during treatment of multiple sclerosis: expert opinions based on the Proceedings of an International Consensus Conference. Eur J Neurol 12:588–601CrossRefPubMedGoogle Scholar
  47. 47.
    Pachner AR, Pak E, Narayan K (2006) Multiplex analysis of expression of three IFN beta-inducible genes in antibody-positive MS patients. Neurology 66:444–446CrossRefPubMedGoogle Scholar
  48. 48.
    Kob M, Harvey J, Schautzer F, et al. (2003) A novel and rapid assay for the detection of neutralizing antibodies against interferon-beta. Mult Scler 9:32–5CrossRefPubMedGoogle Scholar
  49. 49.
    Sorensen PS, Deisenhammer F, Duda P, et al. (2005) Guidelines on use of anti- IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol 12:817–827CrossRefPubMedGoogle Scholar
  50. 50.
    Hemmer B, Stüve O, Kieseier B, Schellekens H, Hartung HP (2005) Immune response to immunotherapy: the role of neutralising antibodies to interferon beta in the treatment of multiple sclerosis. Lancet Neurol 4:403–412CrossRefPubMedGoogle Scholar
  51. 51.
    Giovannoni, G, Barbarash OL, Jaber A, et al. on behalf of the RNF Study Group (2006) Reduced immunogenicity with a new formulation of interferon-beta-1a (Rebif): 24-week results of a phase IIIb study. Mult Scler 12 (suppl 1):P675Google Scholar

Copyright information

© Steinkopff-Verlag 2007

Authors and Affiliations

  • H.-P. Hartung
    • 1
  • C. Polman
    • 2
  • A. Bertolotto
    • 3
  • F. Deisenhammer
    • 4
  • G. Giovannoni
    • 5
  • E. Havrdova
    • 6
  • B. Hemmer
    • 7
  • J. Hillert
    • 8
  • L. Kappos
    • 9
  • B. Kieseier
    • 1
  • J. Killestein
    • 2
  • C. Malcus
    • 10
  • M. Comabella
    • 11
  • A. Pachner
    • 12
  • H. Schellekens
    • 13
  • F. Sellebjerg
    • 14
  • K. Selmaj
    • 15
  • P. S. Sorensen
    • 14
  1. 1.Dept. of NeurologyHeinrich-Heine-UniversityDüsseldorfGermany
  2. 2.VU University Medical CenterAmsterdamThe Netherlands
  3. 3.A.S.O. San Luigi GonzagaRegione GonzoleTorinoItaly
  4. 4.Innsbruck Medical UniversityInnsbruckAustria
  5. 5.Institute of NeurologyLondonUnited Kingdom
  6. 6.Charles UniversityPragueCzech Republic
  7. 7.University of DüsseldorfDüsseldorfGermany
  8. 8.Karolinska University HospitalStockholmSweden
  9. 9.University Hospital BaselBaselSwitzerland
  10. 10.Hôpital Neurologique BronLyonFrance
  11. 11.Unitat de Neuroimmunologia ClinicaBarcelonaSpain
  12. 12.New Jersey Medical SchoolPrincetonUSA
  13. 13.Utrecht UniversityUtrechtThe Netherlands
  14. 14.Copenhagen University HospitalCopenhagenDenmark
  15. 15.Medical University of LódzLódzPoland

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