Review: Neutralizing antibodies against interferon-beta

Abstract

The development of neutralizing antibodies (NAbs) is a major problem in multiple sclerosis (MS) patients treated with interferon-beta (IFN-). Whereas binding antibodies (BAbs) can be demonstrated in the vast majority of patients, only a smaller proportion of patients develop NAbs. The principle in NAb in vitro assays is the utilization of cultured cell lines that are responsive to IFN-. The cytopathic effect (CPE) assay measures the capacity of NAbs to neutralize IFN-'s protective effect on cells challenged with virus and the MxA induction assay measures the ability of NAbs to reduce the IFN--induced expression of MxA, either at the mRNA or the protein level. A titer of !20 neutralizing units/ml traditionally defines NAb positivity. NAbs in high titers completely abrogate the in vivo response to IFN-, whereas the effect of low and intermediate titers is unpredictable. As clinically important NAbs appear only after 9-18 months IFN-therapy, short-term studies of two years or less are unsuitable for evaluation of clinical NAb effects. All long-term trials of three years or more concordantly show evidence of a detrimental effect of NAbs on relapses, disease activity on MRI, or on disease progression. Persistent high titers of NAbs indicate an abrogation of the biological response and, hence, absence of therapeutic efficacy, and this observation should lead to a change of therapy. As low and medium titers are ambiguous treatment decisions in patients with low NAb titres should be guided by determination of in vivo mRNA MxA induction and clinical disease activity.

Oxidized and Aggregated Recombinant Human Interferon Beta is Immunogenic in Human Interferon Beta Transgenic Mice

“…Multiple sclerosis patients treated with recombinant human interferon beta (rhIFNβ) may experience reduced efficacy of the drug during chronic treatment (2). The therapeutic effect of rhIFNβ is influenced by the formation of binding antibodies (BABs) and neutralizing antibodies (NABs).…”

Aggregated Recombinant Human Interferon Beta Induces Antibodies but No Memory in Immune-Tolerant Transgenic Mice

“…A substantial proportion of relapsing-remitting multiple sclerosis (RR-MS) patients shows a decline in response over time, which can be attributed to the formation of neutralizing antibodies (NABs). This immunological response generally starts with the appearance of BABs after approximately 9 to 18 months of treatment, followed by NABs (5). Neutralizing antibodies against rhIFNβ are tested in assays based on the inhibition of a cellular response to human interferon beta.…”

A comparative placebo-controlled clinical study on the efficacy and safety of interferon beta-1a for subcutaneous injections in patients with remitting multiple sclerosis: results of the first year of observations

“…С учетом потенциальной иммуногенности препаратов ИФН, которая во многих случаях связана со снижением иммунного ответа [6,10], особый интерес представля-ло определение в крови пациентов связывающих и нейтрализующих антител (САТ и НАТ), а также концентрации Myxovirus resistance protein 1 (далее в тексте -МхАбелка), как наиболее чувствительного показателя при исследовании НАТ [10].…”

“…Интерферон бета-1а (ИФН β-1а) -препарат, синтезируемый из ДНК клеток яичника китайского хомячка и идентичный по своей структуре натуральному белку человека. ИФН β-1а является гликозилированным белком, что во многом определяет такие его свойства, как меньшая иммуногенность по сравнению с ИФН β-1b [5,6] и высокая биологическая активность [7]. Это делает возможным применение ИФН β-1а у пациентов как с умеренной, так и с достаточно высокой активностью демиелинизирующего процесса.…”

“…Н.И. Пирогова», Москва, Россия; 2 Коммунальное Учреждение Киевского областного совета «Киевская областная клиническая больница», Киев, Украина; 3 ГУ «Институт неврологии, психиатрии и наркологии НАМН Украины», Харьков, Украина; 4 ГБУЗ Свердловской области «Свердловская областная клиническая больница №1», Екатеринбург, Россия; 5 ФГБНУ «Научный центр неврологии» РАН, Москва, Россия; 6 ГБУЗ Московской области «Московский областной научно-исследовательский клинический институт им. М.Ф.…”