J Neurol (2004) 251 [Suppl 2] : II/1II/3

DOI 10.1007/s00415-004-1201-x

Hans-Peter Hartung
Huub Schellekens
Frederick E. Munschauer III

INTRODUCTION

Neutralizing antibodies to interferon beta

in patients with multiple sclerosis: scientific
background and clinical implications

Interferon beta (IFN) and glatiramer acetate are the

standard of care for the treatment of patients with relapsing MS. Three different IFN formulations are available for the treatment of MS: IFN-1b (Betaseron,
Berlex Laboratories, Montville, N. J., USA; Betaferon,
Schering, Berlin, Germany), IFN-1a-Avonex (Biogen,
Inc., Cambridge, Mass., USA), and IFN-1a-Rebif
(Serono, Inc., Rockland, Mass., USA). However, one of
the challenges associated with use of all protein therapeutics, including the use of IFN treatment in patients
with MS, is the development of neutralizing antibodies
(NAbs).
Clear evidence exists in the MS literature of the differences in immunogenicity among IFN products, with
studies showing that 28 % to 47 % of patients develop
NAbs to IFN-1b [2, 8, 19], 12 % to 28 % develop NAbs to
IFN-1a-Rebif [2, 1416, 18], and 2 % to 6 % develop
NAbs to IFN-1a-Avonex [3, 7, 10, 14, 20]. Hence, IFN1b therapy is more immunogenic than IFN-1a therapy,
Hans-Peter Hartung, MD
Heinrich-Heine University
Department of Neurology
Dsseldorf, Germany
Huub Schellekens, MD
Central Laboratory Animal Institute and Department
of Innovation Studies
Utrecht University
Utrecht, The Netherlands
Frederick E. Munschauer III, MD
The Jacobs Neurological Institute
Buffalo General Hospital
Buffalo, New York, USA

JON 1201

Professor Hans-Peter Hartung, MD (
)

Department of Neurology
Heinrich-Heine University
Moorenstrasse 5
40225 Dsseldorf, Germany
Tel.: +49-211-81-17880
Fax: +49-211-81-1869
E-Mail: hans-peter.hartung@uni-duesseldorf.de

and IFN-1a-Rebif treatment is more immunogenic

than IFN-1a-Avonex treatment. Factors that likely contribute to differences in immunogenicity among these
formulations include differences in chemical structure,
route of administration, dose, and frequency of administration [3, 11, 12, 19].
The clinical significance of NAbs to IFN has been a
controversial issue within the medical community. This
controversy likely stems from a general lack of consensus regarding how and when NAbs should be measured,
who should be tested for NAbs, and which titer levels
should be considered clinically relevant. However,
recognition is increasing that NAbs reduce the therapeutic efficacy of IFN; data from phase III studies [4, 9]
and extensions of large phase III clinical trials [16] have
shown diminished clinical efficacy of IFNs in patients
who have a positive result on NAb testing compared
with those who have a negative result. This phenomenon
is not unique to IFN in patients with MS; antibodies to
other protein-based therapies have been shown to have
adverse effects on clinical outcomes [21]. For example,
antibodies to factor VIII result in neutralization of its
clotting effects in hemophilia [13] and antibodies to
IFN-alpha are associated with a loss of efficacy in patients with hepatitis or cancer [1, 5, 6, 17, 22]. Therefore,
it is important for neurologists to consider the potential
for the development of NAbs to effectively manage patients with MS on IFN therapy.
This supplement is based on the proceedings of an
international consensus conference, which was held on
August 30, 2002, in Paris, France. At this conference,
neurologists and other experts from 11 countries who
specialize in the treatment of MS explored issues related
to the development of NAbs to IFNs. The goals of this
meeting were to [1] review the state of the art for NAb
testing, [2] reach a consensus on the clinical relevance of
NAbs to IFNs in patients with MS, and [3] establish a
framework for the development of patient management
guidelines. Topics that are addressed in the supplement

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include the following: the mechanism of action of IFN

in the treatment of MS; immunogenicity of other protein therapeutics; incidence and significance of NAbs
reported during clinical studies of IFN in MS; and
types of assays used to measure NAbs to IFN.
This supplement concludes with recommendations
for monitoring NAbs and provides neurologists with options for managing patients who develop NAbs. It is
hoped that the information provided herein will ultimately reduce the risk of development of NAbs during
IFN therapy, maximize clinical outcomes, and optimize
the choice of therapy in this patient population.
Acknowledgments The participation of the following individuals
in the consensus conference is gratefully acknowledged: Antonio

Bertolotto, MD, Centro Riferimento Regionale Sclerosi Multipla, Orbassano, Italy; Nicole Casadevall, MD, Hopital Hotel Dieu, Paris,
France; Juha-Pekka Erlinna, MD, Finnish Special Neurology Center,
Turku, Finland; Professor Hans-Peter Hartung, Heinrich-Heine University, Dsseldorf, Germany; Professor Thibault Moreau, Hopital
General, Dijon, France; Professor Alfons Billiau, Rega Institute University of Leuven, Leuven, Belgium; Professor Florian Deisenhammer,
University of Innsbruck, Innsbruck, Austria; Paolo Gallo, MD, Clinica
Neurologica Prima, Padova, Italy; Professor Reinhard Hohlfeld, MaxPlanck-Institute for Neurobiology, Martinsried, Germany; Frederick
Munschauer, MD, The Jacobs Neurological Institute, Buffalo General
Hospital, Buffalo, New York, USA; Professor George Rice, Multiple
Sclerosis Clinic, London, Ontario, Canada; Pierrette Seeldrayers, MD,
CHU Charleroi, Charleroi, Belgium; Timothy Vartanian, MD, PhD,
Harvard Institute of Medicine, Boston, Mass., USA; Huub Schellekens,
MD, Utrecht University, Utrecht, The Netherlands; Professor Per
Slberg Srensen, Rigshospitalet, Copenhagen, Denmark.

References
1. Antonelli G, Giannelli G, Currenti M,
Simeoni E, Del Vecchio S, Maggi F,
Pistello M, Roffi L, Pastore G, Chemello
L, Dianzani F (1996) Antibodies to
interferon (IFN) in hepatitis C patients
relapsing while continuing recombinant IFN-2 therapy. Clin Exp
Immunol 104:384387
2. Bertolotto A, Malucchi S, Sala A,
Orefice G, Carrieri PB, Capobianco M,
Milano E, Melis F, Giordana MT (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:
148153
3. Clanet M, Radue EW, Kappos L,
Hartung HP, Hohlfeld R, SandbergWollheim M, Kooijmans-Coutinho
MF, Tsao EC, Sandrick AW, and the
European IFN-1a (Avonex) DoseComparison Study Investigators
(2002) A randomized, double-blind,
dose-comparison study of weekly interferon -1a in relapsing MS. Neurology 59:15071517
4. European Study Group on Interferon
-1b in Secondary Progressive MS
(1998) Placebo-controlled multicentre
randomised trial of interferon -1b in
treatment of secondary progressive
multiple sclerosis. Lancet 352:
14911497
5. Freund M, von Wussow P, Diedrich H,
Eisert R, Link H, Wilke H, Buchholz F,
LeBlanc S, Fonatsch C, Deicher H, Poliwoda H (1989) Recombinant human
interferon (IFN) alpha-2 b in chronic
myelogenous leukemia: dose dependency of response and frequency of
neutralizing anti-interferon antibodies. Br J Haematol 72:350356

6. Giannelli G, Antonelli G, Fera G, Del

Vecchio S, Riva E, Broccia C, Schiraldi
O, Dianzani F (1994) Biological and
clinical significance of neutralizing
and binding antibodies to interferonalpha (IFN-) during therapy for
chronic hepatitis C. Clin Exp Immunol
97:49
7. Herndon RM, Jacobs LD, Coats ME,
Goodkin DE, Mass MK, Richert JR,
Rudick RA, Waubant EL, WeinstockGuttman B, Scaramucci JO, Burnett
BK, Jones WE, Simonian NA (1999) Results of an ongoing, open-label, safetyextension study of interferon beta-1a
(Avonex) treatment in multiple sclerosis. Int J MSCare 2:16. Available at:
http://mscare/org. Accessed November
22:2002
8. The IFNB Multiple Sclerosis Study
Group (1993) Interferon beta-1b is
effective in relapsing-remitting
multiple sclerosis. I. Clinical results
of a multicenter, randomized, doubleblind, placebo-controlled trial.
Neurology 43:655661
9. The IFNB Multiple Sclerosis Study
Group and 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:
889894
10. Jacobs LD, Beck RW, Simon JH, Kinkel
RP, Brownscheidle CM, Murray TJ,
Simonian NA, Slasor PJ, Sandrock AW,
and the CHAMPS Study Group (2000)
Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N
Engl J Med 343:898904

11. Konrad MW, Childs AL, Merigan TC,

Borden EC (1987) Assessment of the
antigenic response in humans to a
recombinant mutant interferon beta.
J Clin Immunol 7:365375
12. Larocca AP, Leung SC, Marcus SG,
Colby CB, Borden EC (1989) Evaluation of neutralizing antibodies in
patients treated with recombinant
interferon-ser. J Interferon Res
9(suppl 1)S51S60
13. Lusher JM (2000) Inhibitor antibodies
to factor VIII and factor IX: management. Sem Thromb Hemost 26:
179188
14. Panitch H, Goodin DS, Francis G,
Chang P, Coyle PK, OConnor P, Monaghan E, Li D, Weinshenker B, for the
EVIDENCE (EVidence of Interferon
Dose-response: European North American Comparative Efficacy) Study
Group and the University of British
Columbia MS/MRI Research Group
(2002) Randomized, comparative
study of interferon -1a treatment regimens in MS. The EVIDENCE Trial.
Neurology 59:14961506
15. PRISMS (Prevention of Relapses and
Disability by Interferon -1a Subcutaneously in Multiple Sclerosis) Study
Group (1998) Randomised doubleblind placebo-controlled study of interferon -1a in relapsing/remitting
multiple sclerosis. Lancet 352:
14981504
16. The PRISMS (Prevention of Relapses
and Disability by Interferon--1a Subcutaneously in Multiple Sclerosis)
Study Group and the University of
British Columbia MS/MRI Analysis
Group (2001) PRISMS-4: Long-term
efficacy of interferon--1a in relapsing
MS. Neurology 56:16281636

II/3

17. Quesada JR, Rios A, Swanson D, Trown

P, Gutterman JU (1985) Antitumor
activity of recombinant-derived
interferon alpha in metastatic renal
cell carcinoma. J Clin Oncol 3:
15221528
18. Rice GPA, Francis GS, and the PRISMS
Study Group (2001) Further evidence
of dose effect of IFN beta-1a based on
neutralizing antibody status. Poster
presented at the 11th Annual Meeting
of the European Neurological Society;
April 2125:2001; Paris, France
19. Ross C, Clemmesen KM, Svenson M,
Sorensen PS, Koch-Henriksen N, Skovgaard GL, Bendtzen K, and the Danish
Multiple Sclerosis Study Group (2000)
Immunogenicity of interferon- in
multiple sclerosis patients: influence of
preparation, dosage, dose frequency,
and route of administration. Ann
Neurol 48:706712

20. Rudick RA, Simonian NA, Alam JA,

Campion M, Scaramucci JO, Jones W,
Coats ME, Goodkin DE, WeinstockGuttman B, Herndon RM, Mass MK,
Richert JR, Salazar AM, Munschauer
FE III, Cookfair DL, Simon JH, Jacobs
LD, and the Multiple Sclerosis Collaborative Research Group (MSCRG)
(1998) Incidence and significance of
neutralizing antibodies to interferon
beta-1a in multiple sclerosis. Neurology 50:12661272

21. Schellekens H (2002) Bioequivalence

and the immunogenicity of biopharmaceuticals. Nat Rev 1:457462
22. Steis RG, Smith JW II, Urba WJ, Clark
JW, Itri LM, Evans LM, Schoenberger
C, Longo DL (1988) Resistance to recombinant interferon alfa-2a in hairycell leukemia associated with neutralizing anti-interferon antibodies.
N Engl J Med 318:14091413