Product related factors influencing the immunogenicity of interferon beta-1b

Abstract

Therapeutic interferon beta is the first line treatment of relapsing remitting Multiple Sclerosis. However, despite their success in improving patient wellbeing, all IFNβ products encounter a significant problem: immunogenicity. In some patients, IFNβ products induce the formation of antidrug antibodies that undermine treatment efficacy and may even lead to treatment failure. These patients not only have a substantial health risk due to failing treatment, but are being treated with expensive products that no longer work. We thus urgently need to lower immunogenicity of therapeutic interferon beta products. In this thesis, IFNβ-1b, the most immunogenic IFNβ product, was studied. The first step in lowering immunogenicity is to understand why a product is immunogenic. Here, there are two possibilities: (1) IFNβ-1b is immunogenic because of epitopes, the foreign peptide sequences that induce a classical immune response, and (2) immunogenicity is caused by aggregates present in the products, which multiple researchers have identified as a risk factor for immunogenicity (Van Beers et al., 2010a; Haji Abdolvahab et al., 2016). Research described in this thesis aims to determine which of these potential triggers is causing immunogenicity. Furthermore, this thesis also describes investigation into another possible product related factor in immunogenicity of this drug, the formulation of IFNβ-1b. Given ethical and practical restraints, I have used the tolerant mouse models described earlier to investigate human interferon beta. Further studies will be required to provide additional insight into the mechanisms underlying the immunogenicity of therapeutic interferon beta, and to develop a product with lower immunogenicity.