Interferon-beta treatment in multiple sclerosis : analysis of neutralizing antibodies
Author: Sominanda, Ajith
Date: 2008-09-26
Location: Föreläsningssal 221, ANA 21, entréplan, Alfred Nobels allé 12
Time: 09.00
Department: Institutionen för klinisk neurovetenskap / Department of Clinical Neuroscience
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Thesis (1.859Mb)
Abstract
Multiple sclerosis (MS) is a disabling chronic neurological disease with
a significant impact on patients lives. There is no cure for MS, but
recombinant interferon beta (IFN-beta) is currently the most established
disease modifying therapy. One of the major clinical problems of IFN-beta
is the development of neutralizing antibodies (NAbs) that interfere with
the clinical efficacy of the drug. Still, in the medical community, there
is some skepticism regarding the clinical use of NAb testing and its
interpretation at the individual level. The overall aim of this thesis
was to provide evidence-based knowledge which will be useful in clinical
management. To some extent, such information could help in understanding
similar scenarios for the many emerging biopharmaceuticals that are
potentially immunogenic and might induce antibodies which could interfere
with clinical efficacy.
Biological study materials were blood samples from IFN-beta treated MS patients that were referred from neurology units in Sweden, Norway and Finland to the specialized NAb laboratory in the Neurology Division at the Karolinska University Hospital in Huddinge. NAbs were measured using the MxA induction assay and in vivo IFN-beta bioactivity was measured by the in vivo MxA mRNA assay.
We observed an overall 32% of NAb positivity in MS patients who were tested for NAbs from 2003 to 2006. Weekly low-protein-dose intramuscular IFN-beta was found to be the least seroprevalent and immunogenic product compared to the weekly-high-protein-dose subcutaneous IFN-beta preparations. A titer around 150 TRU/ml marked an important IFN-beta bioactivity level for the NAb titers as a significant in vivo drug response was retained up to this level. Titers above 600 TRU/ml were associated with complete loss of IFN-beta bioactivity. Fluctuation of NAb titers was assessed across the functionally critical titer of 150 TRU/ml and showed that the majority (72%) of patients were stable, especially the two extreme ends of the titer spectrum i.e. negative (less than 10 TRU/ml) and very high titers (>600 TRU/ml). As expected, titers close to150 TRU/ml appeared more prone to fluctuation across this level, i.e. offering a greater chance ofregaining good IFN-beta bioactivity, or, reversely, a greater risk of losing bioactivity. These observations were not influenced by treatment duration or sampling interval between consecutive NAb tests. We failed to observe an increased NAb positivity when referrals indicated an impression of disease worsening.
Conclusion: Here, we studied several clinically relevant aspects of IFN-beta NAbs. We identified differences between the IFN-beta preparations regarding the frequency of NAb induction, which we refer to as seroprevalence, but also regarding titer levels of induced NAbs, which we refer to as immunogenicity. In a population-based sample of MS patients we demonstrated that these parameters vary between IFN-beta preparations. Further, we identified titer levels that are critical for retaining the in vivo bioactivity of IFN-beta, vital for the interpretation of individual NAb tests. We showed that NAb titers are commonly stable with a greater tendency of fluctuation of mid-range titers. Finally, we showed that a clinical impression of worsening is poorly predictive of NAb status, implicating the necessity of regular NAb testing. Although NAb testing and its interpretation remains a complex area, our results have provided clinically useful knowledge of relevance in the management of MS patients treated with IFN-beta.
Biological study materials were blood samples from IFN-beta treated MS patients that were referred from neurology units in Sweden, Norway and Finland to the specialized NAb laboratory in the Neurology Division at the Karolinska University Hospital in Huddinge. NAbs were measured using the MxA induction assay and in vivo IFN-beta bioactivity was measured by the in vivo MxA mRNA assay.
We observed an overall 32% of NAb positivity in MS patients who were tested for NAbs from 2003 to 2006. Weekly low-protein-dose intramuscular IFN-beta was found to be the least seroprevalent and immunogenic product compared to the weekly-high-protein-dose subcutaneous IFN-beta preparations. A titer around 150 TRU/ml marked an important IFN-beta bioactivity level for the NAb titers as a significant in vivo drug response was retained up to this level. Titers above 600 TRU/ml were associated with complete loss of IFN-beta bioactivity. Fluctuation of NAb titers was assessed across the functionally critical titer of 150 TRU/ml and showed that the majority (72%) of patients were stable, especially the two extreme ends of the titer spectrum i.e. negative (less than 10 TRU/ml) and very high titers (>600 TRU/ml). As expected, titers close to150 TRU/ml appeared more prone to fluctuation across this level, i.e. offering a greater chance ofregaining good IFN-beta bioactivity, or, reversely, a greater risk of losing bioactivity. These observations were not influenced by treatment duration or sampling interval between consecutive NAb tests. We failed to observe an increased NAb positivity when referrals indicated an impression of disease worsening.
Conclusion: Here, we studied several clinically relevant aspects of IFN-beta NAbs. We identified differences between the IFN-beta preparations regarding the frequency of NAb induction, which we refer to as seroprevalence, but also regarding titer levels of induced NAbs, which we refer to as immunogenicity. In a population-based sample of MS patients we demonstrated that these parameters vary between IFN-beta preparations. Further, we identified titer levels that are critical for retaining the in vivo bioactivity of IFN-beta, vital for the interpretation of individual NAb tests. We showed that NAb titers are commonly stable with a greater tendency of fluctuation of mid-range titers. Finally, we showed that a clinical impression of worsening is poorly predictive of NAb status, implicating the necessity of regular NAb testing. Although NAb testing and its interpretation remains a complex area, our results have provided clinically useful knowledge of relevance in the management of MS patients treated with IFN-beta.
List of papers:
I. Sominanda A, Rot U, Suoniemi M, Deisenhammer F, Hillert J, Fogdell-Hahn A (2007). Interferon beta preparations for the treatment of multiple sclerosis patients differ in neutralizing antibody seroprevalence and immunogenicity. Mult Scler. 13(2): 208-14.
Pubmed
View record in Web of Science®
II. Sominanda A, Hillert J, Fogdell-Hahn A (2008). In vivo bioactivity of interferon-beta in multiple sclerosis patients with neutralising antibodies is titre-dependent. J Neurol Neurosurg Psychiatry. 79(1): 57-62.
Pubmed
View record in Web of Science®
III. Sominanda A, Hillert J, Fogdell-Hahn A (2008). Neutralizing antibodies against interferon beta: fluctuation is modest and titre dependent. Eur J Neurol. Aug 23: Epub ahead of print.
Pubmed
View record in Web of Science®
IV. Rot U, Sominanda A, Fogdell-Hahn A, Hillert J (2008). Impression of clinical worsening fails to predict interferon beta neutralizing antibody status. Journal of International Medical Research. [Accepted]
View record in Web of Science®
Pubmed
I. Sominanda A, Rot U, Suoniemi M, Deisenhammer F, Hillert J, Fogdell-Hahn A (2007). Interferon beta preparations for the treatment of multiple sclerosis patients differ in neutralizing antibody seroprevalence and immunogenicity. Mult Scler. 13(2): 208-14.
Pubmed
View record in Web of Science®
II. Sominanda A, Hillert J, Fogdell-Hahn A (2008). In vivo bioactivity of interferon-beta in multiple sclerosis patients with neutralising antibodies is titre-dependent. J Neurol Neurosurg Psychiatry. 79(1): 57-62.
Pubmed
View record in Web of Science®
III. Sominanda A, Hillert J, Fogdell-Hahn A (2008). Neutralizing antibodies against interferon beta: fluctuation is modest and titre dependent. Eur J Neurol. Aug 23: Epub ahead of print.
Pubmed
View record in Web of Science®
IV. Rot U, Sominanda A, Fogdell-Hahn A, Hillert J (2008). Impression of clinical worsening fails to predict interferon beta neutralizing antibody status. Journal of International Medical Research. [Accepted]
View record in Web of Science®
Pubmed
Issue date: 2008-09-05
Rights:
Publication year: 2008
ISBN: 978-91-7409-140-3
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