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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
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
- MeSH
- biologické markery krev MeSH
- dospělí MeSH
- interferon beta * terapeutické užití imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- proteomika * MeSH
- relabující-remitující roztroušená skleróza * farmakoterapie imunologie krev MeSH
- roztroušená skleróza farmakoterapie imunologie krev MeSH
- stupeň závažnosti nemoci MeSH
- transkriptom * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
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.
Citace poskytuje Crossref.org
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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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