Clinical testing for neutralizing antibodies to interferon-β in multiple sclerosis

Biopharmaceuticals are drugs which are based on naturally occurring proteins (antibodies, receptors, cytokines, enzymes, toxins), nucleic acids (DNA, RNA) or attenuated microorganisms. Immunogenicity of these agents has been commonly described and refers to a specific antidrug antibody response. Such immunogenicity represents a major factor impairing the efficacy of biopharmaceuticals due to biopharmaceutical neutralization. Indeed, clinical experience has shown that induction of antidrug antibodies is associated with a loss of response to biopharmaceuticals and also with hypersensitivity reactions. The first disease-specific agent licensed to treat multiple sclerosis (MS) was interferon-β (IFNβ). In its various preparations, it remains the most commonly used first-line agent. The occurrence of antidrug antibodies has been extensively researched in MS, particularly in relation to IFNβ. However, much controversy remains regarding the significance of these antibodies and incorporation of testing into clinical practice. Between 2% and 45% of people treated with IFNβ will develop neutralizing antibodies, and this is dependent on the specific drug and dosing regimen. The aim of this review is to discuss the use of IFNβ in MS, the biological and clinical relevance of anti-IFNβ antibodies (binding and neutralizing antibodies), the incorporation of testing in clinical practice and ongoing research in the field

Cross-reactivity of antibodies against interferon beta in multiple sclerosis patients and interference of the JAK-STAT signaling pathway

Abstract Interferon beta (IFNβ) therapy has immunogenic properties and induces the development of neutralizing antibodies (NAbs). From the extensive literature focused in the development of NAbs in multiple sclerosis (MS) patients, their ability to cross-react has been deficiently evaluated, despite having important consequences in the clinical practice. Here, the relation between the cross-reactivity and the NAbs titers has been evaluated in MS patients, by inhibition of the antiviral activity of IFNβ by bioassay and through the interference with the activation of the IFNß pathway (JAK-STAT), by phosphoflow. Thus, patients with intermediate-high titers of NAbs, determined by bioassay, had a 79-fold increased risk of cross-reactivity compared to patients with low titers. The cross-reactivity is also demonstrated because NAbs positive sera were able to decrease significantly the activation of pSTAT1 achieved by other different IFNβ molecules in the cells patients. Besides, a linear relationship between the STAT1 phosphorylation and NAbs titers was found. The study demonstrates that cross-reactivity increases with the titer of antibodies, which has important implications in clinical practice when switching the treatment. The direct relationship between the NAbs titer and the activation of STAT1 suggest that its determination could be an indirect method to identify the presence of NAbs