Signatures of immune reprogramming in anti-CD52 therapy of MS: markers for risk stratification and treatment response

Laura Bierhansl, Tobias Ruck, Steffen Pfeuffer, Catharina C Gross, Heinz Wiendl, Sven G Meuth, Laura Bierhansl, Tobias Ruck, Steffen Pfeuffer, Catharina C Gross, Heinz Wiendl, Sven G Meuth

Abstract

Background: Multiple sclerosis is one of the most prevalent neurological diseases in young adults affecting over 2 million people worldwide. Alemtuzumab is a highly effective therapy in relapsing remitting MS. Alemtuzumab is a monoclonal CD52 antibody that proved its efficacy against an active comparator (interferon [IFN]-β1a) in a phase II trial and two phase III trials regarding clinical and MRI outcomes. Nevertheless, the exact mode of action is still unknown. Alemtuzumab is commonly associated with secondary autoimmune disorders significantly affecting the risk-benefit ratio. Therefore, new biomarkers predicting treatment response and adverse events are urgently needed. This study aims to further elucidate the mechanism of action of the neuroprotective potential of alemtuzumab in relapsing-remitting multiple sclerosis (RRMS).

Methods/design: This is a 3-year multicentre, explorative study including overall 150 patients comprising three different groups: (i) de novo patients prior and after alemtuzumab treatment initiation, (ii) patients under alemtuzumab treatment and (iii) patients requiring more than two alemtuzumab infusions. Peripheral blood and serum samples will be collected semi-annually for several in vitro/ex vivo assays to detect and characterize immune cells including their functional activity. Furthermore, data of MRI scans and disease-related impairment (using EDSS and MSFC), as well as the number and time of relapses, will be assessed. The clinical study is registered at clinicaltrials.gov (NCT04082260).

Perspective: Our study will provide deep insights into the underlying immunological changes in a longitudinal analysis of alemtuzumab treated RRMS patients. By combining clinical, radiological and functional immune-phenotype data, we will be able to identify biomarkers and/or immune signatures predicting treatment response and adverse events. Thereby, the understanding of the mechanisms of action of alemtuzumab will improve its efficacy and safety for present and future patients.

Keywords: Alemtuzumab; Biomarker, mechanism of action, secondary autoimmune disease; CD52; Disease-modifying therapy, risk stratification; Relapse-remitting multiple sclerosis.

Conflict of interest statement

Competing interestsLB has no competing interests. TR reports grants from German Ministry of Education, Science, Research and Technology, during the conduct of the study; grants and personal fees from Sanofi Genzyme, personal fees from Biogen, personal fees and non-financial support from Merck Serono, personal fees from Roche, personal fees from Teva, outside the submitted work. SP reports personal fees and non-financial support from Sanofi Genzyme, personal fees from Biogen, personal fees and non-financial support from Merck Serono, personal fees from Mylan, and grants from Diamed, outside the submitted work CCG reports grants from German Ministry of Education, Science, Research and Technology, grants from Collaborative Research Centre CRC TR128, during the conduct of the study; personal fees from Sanofi Genzyme, grants from Biogen, personal fees from Bayer Health Care, grants from Novartis, grants from Euroimmun, personal fees from Mylan, outside the submitted work. HW reports grants from German Ministry of Education, Science, Research and Technology, grants from Collaborative Research Centre CRC TR128, during the conduct of the study; grants and personal fees from Biogen, personal fees from Eygen, personal fees from Merck Serono, personal fees from Novartis, grants and personal fees from Roche, grants and personal fees from Sanofi Genzyme, personal fees from Teva, grants from GlaxoSmithKline, personal fees from WebMD Global, personal fees from Abbvie, personal fees from Alexion, personal fees from Acetelion, personal fees from Swiss Multiple Sclerosis Society, outside the submitted work. SGM reports grants from German Ministry of Education, Science, Research and Technology, during the conduct of the study; personal fees from Almirall, personal fees from Bayer Health Care, grants and personal fees from Biogen, grants and personal fees from Diamed, personal fees from Fresenius Medical Care, grants and personal fees from Sanofi Genzyme, grants and personal fees from Merck Serono, personal fees from Novartis, grants and personal fees from ONO Pharma, personal fees from Roche, personal fees from Teva, outside the submitted work.

© The Author(s) 2019.

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