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Patients with multiple sclerosis who develop immunogenicity to interferon-beta have distinct transcriptomic and proteomic signatures prior to treatment which are associated with disease severity

L. Coelewij, M. Adriani, P. Dönnes, KE. Waddington, C. Ciurtin, EK. Havrdova, ABIRISK Consortium, R. Farrell, P. Nytrova, I. Pineda-Torra, EC. Jury

. 2024 ; 267 (-) : 110339. [pub] 20240811

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc24018764

Anti-drug antibodies (ADA) reduce the efficacy of immunotherapies in multiple sclerosis (MS) and are associated with increased disease progression risk. Blood biomarkers predicting immunogenicity to biopharmaceuticals represent an unmet clinical need. Patients with relapsing remitting (RR)MS were recruited before (baseline), three, and 12 (M12) months after commencing interferon-beta treatment. Neutralising ADA-status was determined at M12, and patients were stratified at baseline according to their M12 ADA-status (ADA-positive/ADA-negative). Patients stratified as ADA-positive were characterised by an early dampened response to interferon-beta (prior to serum ADA detection) and distinct proinflammatory transcriptomic/proteomic peripheral blood signatures enriched for 'immune response activation' including phosphoinositide 3-kinase-γ and NFκB-signalling pathways both at baseline and throughout the treatment course, compared to ADA-negative patients. These immunogenicity-associated proinflammatory signatures significantly overlapped with signatures of MS disease severity. Thus, whole blood molecular profiling is a promising tool for prediction of ADA-development in RRMS and could provide insight into mechanisms of immunogenicity.

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$a Anti-drug antibodies (ADA) reduce the efficacy of immunotherapies in multiple sclerosis (MS) and are associated with increased disease progression risk. Blood biomarkers predicting immunogenicity to biopharmaceuticals represent an unmet clinical need. Patients with relapsing remitting (RR)MS were recruited before (baseline), three, and 12 (M12) months after commencing interferon-beta treatment. Neutralising ADA-status was determined at M12, and patients were stratified at baseline according to their M12 ADA-status (ADA-positive/ADA-negative). Patients stratified as ADA-positive were characterised by an early dampened response to interferon-beta (prior to serum ADA detection) and distinct proinflammatory transcriptomic/proteomic peripheral blood signatures enriched for 'immune response activation' including phosphoinositide 3-kinase-γ and NFκB-signalling pathways both at baseline and throughout the treatment course, compared to ADA-negative patients. These immunogenicity-associated proinflammatory signatures significantly overlapped with signatures of MS disease severity. Thus, whole blood molecular profiling is a promising tool for prediction of ADA-development in RRMS and could provide insight into mechanisms of immunogenicity.
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$a Adriani, Marsilio $u Division of Medicine, University College London, London WC1E 6JF, United Kingdom
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$a Dönnes, Pierre $u Division of Medicine, University College London, London WC1E 6JF, United Kingdom; SciCross AB, Skövde, Sweden
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$a Waddington, Kirsty E $u Division of Medicine, University College London, London WC1E 6JF, United Kingdom
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$a Ciurtin, Coziana $u Division of Medicine, University College London, London WC1E 6JF, United Kingdom
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$a Havrdova, Eva Kubala $u Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, General University Hospital and First Faculty of Medicine, Charles University in Prague, 120 00, Czech Republic
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$a Farrell, Rachel $u Department of Neuroinflammation, University College London, Institute of Neurology and National Hospital of Neurology and Neurosurgery, London WC1N 3BG, United Kingdom
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$a Nytrova, Petra $u Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, General University Hospital and First Faculty of Medicine, Charles University in Prague, 120 00, Czech Republic
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$a Pineda-Torra, Inés $u Division of Medicine, University College London, London WC1E 6JF, United Kingdom; Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Parque Científico y Tecnológico Cartuja 93 Avda. Américo Vespucio, 24 41092 Sevilla, Spain
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$a Jury, Elizabeth C $u Division of Medicine, University College London, London WC1E 6JF, United Kingdom. Electronic address: e.jury@ucl.ac.uk
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