UBC Theses and Dissertations
Evolution of the anti-interferon beta (IFNβ) antibody response in multiple sclerosis patients : IgG subclass distribution, affinity maturation and clinical correlates Gibbs, Ebrima
Multiple Sclerosis (MS), a chronic degenerative disease of the central nervous system, is characterized by demyelination, axonal damage, and inflammatory lesions in the white matter. Symptoms include neurological deficits, relapses and progressive disability. Three recombinant interferon beta (IFNβ) products and glatiramer acetate are licensed for treatment. They have been shown to reduce the frequency and severity of relapses and slow disease progression in about 30% of treated patients. Long-term administration of IFNβ can result in the development of anti- (IFNβ) antibodies. Binding antibodies (BAbs) bind (IFNβ) and neutralizing antibodies (NAbs) prevent interaction with its receptor, reducing IFNβ bioavailability and clinical efficacy. The detection and characterization of anti-IFNβ antibodies does not adhere to any internationally recommended standards. A comprehensive strategy is required to elucidate the antibody properties that play a role in the immune response against IFNβ. To this extent, our objectives were: first, to investigate the IgG subclass-specificities of BAbs over time; second, to ascertain the affinity maturation pattern of BAbs and NAbs; and third, to investigate the effects of NAbs on clinical efficacy. We used an enzyme-linked-immunosorbent assay (ELISA) to measure relative distribution of IgG subclass-specific BAbs and found that subclasses not only change over time, but their distribution varies between subcutaneous (SC) IFNβ-la and SC IFNβ-lb. We also found that NAb+ patients tend to have higher levels of IgG4 subclass-specific BAbs than NAb- patients. To investigate the affinity maturation of anti-IFNβ antibodies, we utilized BiacoreTM, a biosensor device based on the optical phenomenon of Surface Plasmon Resonance (SPR). Our results indicate that relative antibody affinities, as reflected by antibody dissociation rates, improve over time in NAb+ patients. Furthermore, we found a close parallel between antibody affinity and NAb levels. Our investigation showed that the effects of NAbs on clinical efficacy are delayed, with an increase in relapse rates being more evident in NAb+ patients than in NAb- patients at year 3 (IFNβ-1b), and at year 3 and 4 (IFNβ-la). We conclude that there is a need for a quantitative and qualitative framework for monitoring anti-IFNβ antibodies that could prove valuable for better management of IFNβ-treated MS patients.
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