Variability in detection and quantification of interferon β-1b–induced neutralizing antibodies

Journal of Neuroinflammation

Joachim Reischl¹  Christoph Pohl¹  Jürgen Heubach¹  Stephan Lehr¹  Susanne Schwenke¹  Haruhiko Nakajima⁸  Yukiko Nakada⁸  Rupert Sandbrink¹  Brigitte Stemper¹  Timon Bogumil²  Ludwig Kappos⁶  Douglas R Jeffery⁴  Massimo Filippi³  Stuart Cook^1,10  Giancarlo Comi³  Barry GW Arnason⁹  Douglas S Goodin⁵  Bernd Kieseier⁷  Hans-Peter Hartung^1,11 

[1] Bayer Pharma AG, Sellerstr 31, Berlin, 13342, Germany;Bayer HealthCare Pharmaceuticals, P.O. Box 1000, Montville, NJ, 07045-1000, USA;Scientific Institute and University Hospital San Raffaele, Via Olgettina 60, Milan, 20132, Italy;The MS Center at Advance Neurology, Cornerstone Healthcare, 152 Kinderton Way, Suite 101, Advance, NC, 27006, USA;University of California, Rm. M794, San Francisco, CA, 94143-0114, USA;University Hospital, Petersgraben 4, Basel, CH-4031, Switzerland;Heinrich-Heine-Universität, Moorenstraße 5, Düsseldorf, 40225, Germany;Mitsubishi Chemical Medience Corporation, 3-30-1, Shimura, Itabashi-ku, Tokyo, 174-8555, Japan;Surgery Brain Research Institutes, 5812 S. Ellis Av., SBRI J209 (MC 2030), Chicago, IL, 60637, USA;UMD New Jersey Medical School, 65 Bergen Street - Suite 1435, Newark, NJ, 07101-1709, USA;Department of Neurology, Heinrich-Heine-Universität, Düsseldorf, D-40225, Germany

关键词: Round robin;    Neutralizing antibodies;    Interferon beta;    IFNB-1b;    Clinical trials randomized controlled;    Multiple sclerosis;   

Others  :  1212520
DOI  :  10.1186/1742-2094-9-129

 received in 2012-02-29, accepted in 2012-06-15,  发布年份 2012

【 摘 要 】

Background

Interferon-beta (IFNB) therapy for multiple sclerosis can lead to the induction of neutralizing antibodies (NAbs) against IFNB. Various methods are used for detection and quantification of NAbs.

Methods

Blood samples from 125 IFNB-1b–treated patients, which were tested NAb negative or NAb positive after conclusion of a clinical study, were retested three years after first being assessed in four different laboratories that offer routine NAb testing to practicing neurologists. The myxovirus protein A (MxA) induction assay, the cytopathic effect (CPE) assay (two laboratories), or the luciferase assay were used. Intra- and inter-laboratory agreement between assays with respect to NAb detection and NAb titer quantification were evaluated.

Results

High agreement for NAb detection (kappa coefficient, 0.86) and for titer levels was observed for the intra-laboratory comparison in the laboratory using the MxA induction assay performed three years ago and now. A similarly high agreement for NAb detection (kappa coefficient, 0.87) and for titer quantification was noted for the MxA assay of this laboratory with one of two laboratories using the CPE assay. All other inter-laboratory comparisons showed kappa values between 0.57 and 0.68 and remarkable differences in individual titer levels.

Conclusions

There are considerable differences in the detection and quantification of IFNB-induced NAbs among laboratories offering NAb testing for clinical practice using different assay methods. It is important that these differences are considered when interpreting NAb results for clinical decision-making and when developing general recommendations for potentially clinically meaningful NAb titer levels.

【 授权许可】

   
2012 Hartung et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Giovannoni G, Munschauer FE, Deisenhammer F: Neutralising antibodies to interferon beta during the treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry 2002, 73:465-469.
• [2]Goodin DS, Frohman EM, Hurwitz B, O'Connor PW, Oger JJ, Reder AT, Stevens JC: Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the therapeutics and technology assessment subcommittee of the American academy of neurology. Neurology 2007, 68:977-984.
• [3]Gilli F, Bertolotto A, Sala A, Hoffmann F, Capobianco M, Malucchi S, Glass T, Kappos L, Lindberg RL, Leppert D: Neutralising antibodies against IFN-beta in multiple sclerosis: antagonization of IFN-beta mediated suppression of MMPs. Brain 2004, 127:259-268.
• [4]Hesse D, Sellebjerg F, Sørensen PS: Absence of MxA induction by interferon beta in patients with MS reflects complete loss of bioactivity. Neurology 2009, 73:372-377.
• [5]Rice GP, Paszner B, Oger J, Lesaux J, Paty D, Ebers G: The evolution of neutralizing antibodies in multiple sclerosis patients treated with interferon beta-1b. Neurology 1999, 52:1277-1279.
• [6]Bellomi F, Scagnolari C, Tomassini V, Gasperini C, Paolillo A, Pozzilli C, Antonelli G: Fate of neutralizing and binding antibodies to IFN beta in MS patients treated with IFN beta for 6 years. J Neurol Sci 2003, 215:3-8.
• [7]Petkau AJ, White RA, Ebers GC, Reder AT, Sibley WA, Lublin FD, Paty DW: Longitudinal analyses of the effects of neutralising antibodies on interferon beta-1b in relapsing-remitting multiple sclerosis. Mult Scler 2004, 10:126-138.
• [8]Sørensen PS, Koch-Henriksen N, Ross C, Clemmesen KM, Bendtzen K, Danish Multiple Sclerosis Study Group: Appearance and disappearance of neutralizing antibodies during interferon-beta therapy. Neurology 2005, 65:33-39.
• [9]Reder AT, Ebers GC, Traboulsee A, Li D, Langdon D, Goodin DS, Bogumil T, Beckmann K, Konieczny A, Investigators of the 16-Year Long-Term Follow-Up Study: Cross-sectional study assessing long-term safety of interferon-β-1b for relapsing-remitting MS. Neurology 2010, 74:1877-1885.
• [10]Killestein J, Polman CH: Determinants of interferon β efficacy in patients with multiple sclerosis. Nat Rev Neurol 2011, 7:221-228.
• [11]Malucchi S, Gilli F, Caldano M, Marnetto F, Valentino P, Granieri L, Sala A, Capobianco M, Bertolotto A: Predictive markers for response to interferon therapy in patients with multiple sclerosis. Neurology 2008, 70:1119-1127.
• [12]Massart C, Gibassier J, Oger J, Le Page E, Edan G: Neutralizing antibodies to interferon beta in multiple sclerosis: analytical evaluation for validation of a cytopathic effect assay. Clin Chim Acta 2007, 377:185-191.
• [13]O'Connor P, Filippi M, Arnason B, Comi G, Cook S, Goodin D, Hartung H-P, Jeffery D, Kappos L, Boateng F, Filippov V, Groth M, Knappertz V, Kraus C, Sandbrink R, Pohl C, Bogumil T, BEYOND Study Group: 250 μg or 500 μg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomized, multicentre study. Lancet Neurol 2009, 8:889-897.
• [14]Goodin DS, Hartung HP, O'Connor P, Filippi M, Arnason B, Comi G, Cook S, Jeffery D, Kappos L, Bogumil T, Knappertz V, Sandbrink R, Beckmann K, White R, Petkau J, Pohl C, BEYOND Study Group: Neutralizing antibodies to interferon beta-1b multiple sclerosis: a clinico-radiographic paradox in the BEYOND trial. Mult Scler 2012, 18:181-195.
• [15]Files JG, Gray JL, Do LT, Foley WP, Gabe JD, Nestaas E, Pungor E: A novel sensitive and selective bioassay for human type I interferons. J Interferon Cytokine Res 1998, 18:1019-1024.
• [16]Pungor E, Files JG, Gabe JD, Do LT, Foley WP, Gray JL, Nelson JW, Nestaas E, Taylor JL, Grossberg SE: A novel bioassay for the determination of neutralizing antibodies to IFN-beta-1b. J Interferon Cytokine Res 1998, 18:1025-1030.
• [17]Grossberg SE, Taylor JD, Siebenlist RE, et al.: Biological and immunological assays of human interferons. In Manual of Clinical Immunology. 3rd edition. Edited by Rocklin R. ASM Publishing, Washington, DC; 1986:295-299.
• [18]Farrell R, Kapoor R, Leary S, Rudge P, Thompson A, Miller D, Giovannoni G: Neutralizing anti-interferon beta antibodies are associated with reduced side effects and delayed impact on efficacy of Interferon-beta. Mult Scler 2008, 14:212-218.
• [19]Lam R, Farrell R, Aziz T, Gibbs E, Giovannoni G, Grossberg S, Oger J: Validating parameters of a luciferase reporter gene assay to measure neutralizing antibodies to IFNbeta in multiple sclerosis patients. J Immunol Methods 2008, 336:113-118.
• [20]Viera AJ, Garrett JM: Understanding interobserver agreement: the kappa statistic. Fam Med 2005, 37:360-363.
• [21]Polman C, Bertolotto A, Deisenhammer F, Giovannoni G, Hartung H-P, Hemmer B, Killestein J, McFarland HF, Oger J, Pachner AR, Petkau J, Reder AT, Reingold SC, Schellekens H, Sørensen PS: Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol 2010, 9:740-750.
• [22]Deisenhammer F, Schellekens H, Bertolotto A: Measurement of neutralizing antibodies to interferon beta in patients with multiple sclerosis. J Neurol 2004, 251(suppl 2):II31-II39.
• [23]McKay F, Schibeci S, Heard R, Stewart G, Booth D: Analysis of neutralizing antibodies to therapeutic interferon-beta in multiple sclerosis patients: a comparison of three methods in a large Australasian cohort. J Immunol Methods 2006, 310:20-29.
• [24]Files JG, Hargrove D, Delute L, Cantillon M: Measured neutralizing titers of IFN-beta neutralizing antibodies (NAbs) can depend on the preparations of IFN-beta used in the assay. J Interferon Cytokine Res 2007, 27:637-642.
• [25]Hemmer B, Berthele A: Should we measure the bioavailability of interferon β in vivo in patients with multiple sclerosis? Nat Clin Pract Neurol 2009, 4:126-127.