Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development

Hegen, Harald; Millonig, Alban; Bertolotto, Antonio; Comabella, Manuel; Giovanonni, Gavin; Guger, Michael; Hoelzl, Martina; Khalil, Michael; Killestein, Joep; Lindberg, Raija L. P.; Malucchi, Simona; Mehling, Matthias; Montalbán, Xavier; Polman, CH; Rudzki, Dagmar; Schautzer, Franz; Sellebjerg, Finn; Sørensen, P. Soelberg; Deisenhammer, Florian

doi:10.1177/1352458513503597

Cited by 43 publications

(36 citation statements)

References 35 publications

(64 reference statements)

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“…In some cases, BAbs have been shown to cause a loss of bioactivity, but not neutralizing activity in the CPE assay, thus these antibodies are not classed as NAbs (Gilli et al., 2007). However, it has been proposed that BAb titres may be a predictive tool for future NAb development (Hegen et al., 2014). …”

Section: Discussionmentioning

confidence: 99%

MxA mRNA decrease preceding NAb detection in IFNβ‐treated MS patients

et al. 2017

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BackgroundMultiple sclerosis (MS) patients treated with interferon beta (IFNβ) are at risk of a declining response to treatment because of the production of IFNβ‐neutralizing antibodies (NAbs). The expression of Myxovirus resistance protein A (MxA) mRNA is regarded as a marker of IFNβ bioactivity.AimsThe aim of this study was to analyze the kinetics of MxA mRNA expression during long‐term IFNβ treatment and assess its relationship to NAb production.MethodsA prospective, observational, open‐label, non‐randomized study was designed in multiple sclerosis patients starting IFNβ treatment. NAbs and MxA mRNA were monitored every six months.Results119 patients were consecutively enrolled and 107 were included in the final analysis. Both the presence of NAbs and a decrease in MxA mRNA below the cut off were revealed in 15 patients, however, in six patients (40%) positivity for NAbs was preceded by the decrease in MxA mRNA. In addition, a further six patients showing a decline in MxA mRNA did not have detectable NAbs.ConclusionOur data indicate that quantification of MxA mRNA is a more sensitive identifier of loss of IFNβ efficacy than the NAb positivity.

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Section: Discussionmentioning

confidence: 99%

MxA mRNA decrease preceding NAb detection in IFNβ‐treated MS patients

et al. 2017

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“…Whereas IFNb serum levels peak early after administration (within minutes after IV [26][27][28] and several hours after SC or IM injection [25][26][27][28][29][32][33][34][35][36][37]), the classical PD markers (see above) peak after approximately 24 h [26][27][28][29]35] up to 48 h [34,36,37]. With continuous therapy, there are also late IFNb effects, as for example MMP-9 concentrations are significantly decreased (as compared to baseline) not before a treatment period of several months [49,85]. Apart from PD markers at the mRNA or protein level, there are changes on a cellular level.…”

Section: Correlation Between Pharmacokinetic and Pharmacodynamic Markersmentioning

confidence: 98%

Pharmacokinetic considerations in the treatment of multiple sclerosis with interferon-β

Hegen

Auer

Deisenhammer

2015

Expert Opinion on Drug Metabolism & Toxicology

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IFNβ has a bioavailability of ∼ 30% after subcutaneous or intramuscular administration, shows peak serum concentrations within several hours, has a half-life of < 1 day and is eliminated by a renal and hepatic pathway. PK parameters do not substantially differ between the types of IFNβ and routes of administration; only pegylation of IFNβ results in substantially increased and prolonged PK. Although no clinical dose-effect relationship could be established, there is an association of IFNβ dose with magnetic resonance imaging outcome parameters. Furthermore, there is an association of IFNβ serum levels with the occurrence of adverse events and anti-drug antibodies.

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“…BAbs can be detected in the serum of IFNβ-treated patients after 3--6 months and NAbs after 6-12 months of continuous treatment [54]. The production of NAbs, appearing 6-12 months after the beginning of the treatment, is delayed in comparison to the classical immunological induction of antibodies against a new antigen which requires 2-4 weeks [55].…”

Section: Clinical Relevance Of Nabsmentioning

confidence: 99%