A mass cytometry receptor occupancy study of natalizumab therapy in multiple sclerosis
Gerd Haga Bringeland presented her dissertation for the Ph.D. degree with the thesis “A mass cytometry receptor occupancy study of natalizumab therapy in multiple sclerosis” on June 5 2020. This thesis contributes to the understanding of the wearing-off phenomenon experienced by many MS-patients treated with natalizumab (Tysabri®). It also provides a new method for using mass cytometry to measure receptor occupancy on leukocytes.
Multiple Sclerosis (MS) is an inflammatory disease of the central nervous system that mainly affects young adults. Natalizumab (Tysabri®, Biogen, Cambridge, MA) is a therapeutic monoclonal antibody used to treat patients with relapsing-remitting MS (RRMS). The antibody prevents leukocyte migration across the blood-brain barrier into the central nervous system, and is today an effective treatment for MS. Although highly efficacious in preventing disease activity, many patients report the so-called wearing-off symptoms at the end of the 4-week dosing interval. Although wearing-off symptoms are often reported, only a few previous studies have described the phenomenon, and little is known about the underlying causes of these symptoms.
In this thesis, Gerd H. Bringeland investigated whether wearing-off symptoms at the end of the natalizumab dosing interval were associated with clinical and demographic patient characteristics or natalizumab receptor occupancy (RO) on leukocytes. She found that patients who regularly had wearing-off symptoms had lower natalizumab RO than patients who reported having such symptoms sometimes or never. The former group also had higher BMI and higher frequency of sick leave. High BMI was associated with low RO. No other demographic or disease characteristics were associated with the phenomenon.
Bringeland also developed a method for measuring the RO on leukocytes using mass cytometry. This method can be used in research on RO and personalized treatment with other antibodies as well, and not just in the treatment of multiple sclerosis.
The main supervisor for this thesis was Ph.D. Sonia Gavasso; co-supervisors were prof. Kjell-Morten Myhr and prof. Christian Vedeler.