Contributions
Abstract: 143
Type: Oral
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: B cells are increasingly recognised to play a key role in relapsing-remitting and primary progressive Multiple Sclerosis (MS), a notion which is substantiated by the recent success of anti-CD20 intervention in these disorders. One alternative strategy to pan B cell depletion may be therapeutic abrogation of pathogenic B cell differentiation and/or function. Bruton's tyrosine kinase (BTK) is critically involved in B cell receptor signaling and subsequent activation of B cells. BTK inhibition (BTKi) could thus be a promising strategy to selectively impair pathogenic function, such as antigen presentation and/or cytokine release by antigen-activated B cells. The goal of this study was to test the clinical and immunological efficacy of BTKi in an experimental autoimmune encephalomyelitis (EAE) model, in which pathogenic B cells are centrally involved.
Methods: C57Bl/6 mice were immunised with conformational MOG 1-117 protein, a model in which B cells can directly recognise the immunogen. Oral treatment with the BTK inhibitor evobrutininb (M2951) at daily doses of 1, 3 or 10 mg/kg or vehicle started 7 days prior to immunisation. Another control group of mice received 200 µg anti-CD20 or isotype control once weekly starting 3 weeks before immunization. EAE severity was assessed daily using a standard scale (0-5). Histopathology was performed at the end of the study on spinal cord sections. Extent of cellular infiltration was determined by HE and immunohistochemistry, demyelination was assessed by LFB/PAS staining.
Results: BTKi showed a significant, dose dependent amelioration of EAE severity at its acute onset as well as throughout the 60-day observation period. While the lowest dose (1mg/kg) exerted no detectable effect, the intermediate (3 mg/kg) as well as the highest dose (10 mg/kg) of the BTK inhibitor significantly ameliorated EAE severity in its extent comparable to anti-CD20 treatment. Supporting these clinical measures, BTKi furthermore reduced CNS inflammation and demyelination.
Conclusions: BTK inhibition proves to be effective in limiting CNS inflammation, demyelination and clinical severity in a B cell dependent EAE model. Ongoing mechanistic experiments aim to dissect in detail the effect of BTKi to control various pathogenic B cell properties. These experiments highlight that therapeutic silencing of harmful B cell function may be a valuable addition to the armamentarium of B cell-directed therapeutics in MS.
Disclosure:
Sebastian Torke: nothing to disclose.
Roland Grenningloh: nothing to disclose
Ursula Boschert: nothing to disclose.
Martin Weber Weber is serving as an editor for PLoS One. He received travel funding and/or speaker honoraria from Biogen-Idec, Merck Serono, Novartis, Roche and Bayer. He receives research support from the National Multiple Sclerosis Society (NMSS; PP 1660), the Deutsche Forschungsgemeinschaft (DFG; WE 3547/4-1), from Novartis, Merck Serono, TEVA, Biogen-Idec, Roche and the ProFutura Programm of the Universitätsmedizin Göttingen.
Abstract: 143
Type: Oral
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: B cells are increasingly recognised to play a key role in relapsing-remitting and primary progressive Multiple Sclerosis (MS), a notion which is substantiated by the recent success of anti-CD20 intervention in these disorders. One alternative strategy to pan B cell depletion may be therapeutic abrogation of pathogenic B cell differentiation and/or function. Bruton's tyrosine kinase (BTK) is critically involved in B cell receptor signaling and subsequent activation of B cells. BTK inhibition (BTKi) could thus be a promising strategy to selectively impair pathogenic function, such as antigen presentation and/or cytokine release by antigen-activated B cells. The goal of this study was to test the clinical and immunological efficacy of BTKi in an experimental autoimmune encephalomyelitis (EAE) model, in which pathogenic B cells are centrally involved.
Methods: C57Bl/6 mice were immunised with conformational MOG 1-117 protein, a model in which B cells can directly recognise the immunogen. Oral treatment with the BTK inhibitor evobrutininb (M2951) at daily doses of 1, 3 or 10 mg/kg or vehicle started 7 days prior to immunisation. Another control group of mice received 200 µg anti-CD20 or isotype control once weekly starting 3 weeks before immunization. EAE severity was assessed daily using a standard scale (0-5). Histopathology was performed at the end of the study on spinal cord sections. Extent of cellular infiltration was determined by HE and immunohistochemistry, demyelination was assessed by LFB/PAS staining.
Results: BTKi showed a significant, dose dependent amelioration of EAE severity at its acute onset as well as throughout the 60-day observation period. While the lowest dose (1mg/kg) exerted no detectable effect, the intermediate (3 mg/kg) as well as the highest dose (10 mg/kg) of the BTK inhibitor significantly ameliorated EAE severity in its extent comparable to anti-CD20 treatment. Supporting these clinical measures, BTKi furthermore reduced CNS inflammation and demyelination.
Conclusions: BTK inhibition proves to be effective in limiting CNS inflammation, demyelination and clinical severity in a B cell dependent EAE model. Ongoing mechanistic experiments aim to dissect in detail the effect of BTKi to control various pathogenic B cell properties. These experiments highlight that therapeutic silencing of harmful B cell function may be a valuable addition to the armamentarium of B cell-directed therapeutics in MS.
Disclosure:
Sebastian Torke: nothing to disclose.
Roland Grenningloh: nothing to disclose
Ursula Boschert: nothing to disclose.
Martin Weber Weber is serving as an editor for PLoS One. He received travel funding and/or speaker honoraria from Biogen-Idec, Merck Serono, Novartis, Roche and Bayer. He receives research support from the National Multiple Sclerosis Society (NMSS; PP 1660), the Deutsche Forschungsgemeinschaft (DFG; WE 3547/4-1), from Novartis, Merck Serono, TEVA, Biogen-Idec, Roche and the ProFutura Programm of the Universitätsmedizin Göttingen.