Farrell, R.A.; (2010) Neutralising antibodies to interferon beta in multiple sclerosis. Doctoral thesis , UCL (University College London).

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Abstract

Multiple Sclerosis is the most common non-traumatic cause of neurological disability in young people. Until recently few treatments existed for Multiple Sclerosis and Interferon beta was the first and remains the most commonly prescribed. As a biological product it induces antibodies to the protein which may abrogate the efficacy of the drug (neutralising antibodies - NAbs). Testing for these antibodies has been problematic as biological assays are difficult to standardise, time consuming and expensive. In the experiments described here we sought to develop a novel cell-based reporter-gene assay to reliably test for Nabs, to explore the relationship between NAbs, treatment efficacy, biological activity and correlate NAb titres with in vivo biomarker induction to establish guidelines to interpret results. The work presented in this thesis describes the development and validation of the luciferase assay and has shown that subjects who develop NAbs experienced increased relapse rates, (which lag behind the appearance of NAbs). Evaluating the in vivo biological response to IFNβ injection it was established that in subjects with NAbs there was titre dependent loss of bioactivity with reduced myxovirus resistance protein A (MxA) level in those with titres 100 – 600 NU and absent response in those with titres > 600 NU. Opinion amongst neurologists (UK, USA, Canada and Austria) regarding NAbs was evaluated and revealed uncertainty of their significance in the clinical setting, and the reluctance of some neurologists to incorporate NAb testing into routine practice. Results were similar in the countries surveyed in that 90 – 100% were aware of NAbs and thought they abrogate clinical efficacy, yet few routinely tested for them, particularly in the UK. The validated luciferase assay has since been dissemintated to 9 countries. Since it’s launch in the UK in 2006 over 4,000 patients have been tested for NAbs. This work directly translates into clinical practice and provides a useful service to aid management of subjects with MS.

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