Contributions
Abstract: P678
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Bruton's tyrosine kinase (Btk) is a member of the TEC family of non-receptor tyrosine kinases expressed in cells of hematopoietic origin, including B cells and myeloid cells, but not T cells. In addition to its well-known effects on diverse B cell functions, BTK mediates signaling in innate immune cells downstream of various receptors including Fc, integrin, chemokine and Toll-like receptors. The goal of this study was to test the clinical efficacy of BTK inhibition in an experimental autoimmune encephalomyelitis (EAE) model not responsive to B cell inhibition, but in which pathogenic T cells and innate immune cells are centrally involved in disease.
Methods: EAE was induced in SJL/J mice by Proteolipic Protein (PLP) 139-151 peptide and Complete Freund's adjuvant (CFA) on day 0. Mice also received a pertussis toxin injection on day 0 and day 2. Disease severity was scored using a standard scale from 0 - 5. Treatment with the BTKi M2951 (0.3, 1, 3, 10 mg/kg), or vehicle was conducted in 2 separate experiments using both prophylactic and late-therapeutic regimens. The compound Fingolimod (FTY720 1 mg/kg) served as a positive, anti-CD20 AB as a negative control. Blood was collected at the end of the studies for pharmacokinetic and BTK occupancy analysis. Gene expression analysis was performed on spinal cords.
Results: Both prophylactic and therapeutic treatment with M2951 reduced clinical score in a dose dependent manner. While the lowest dose (0.3 mg/kg) exerted a minimal effect, higher doses (1, 3, 10 mg/kg) of the BTKi significantly ameliorated EAE severity when administered before disease onset or after the peak of the disease. M2951 (10 mg/kg) reached comparable efficacy to FTY720 in the therapeutic setting. After M2951 treatment a high degree of BTK occupancy was achieved in peripheral blood early in disease, while BTK occupancy in the brain was found only at later timepoints. Anti-PLP titers were not reduced by M2951 treatment, but myeloid genes in the spinal cord were affected by M2951.
Conclusions: BTK inhibition proved to be effective in limiting CNS inflammation and clinical severity in a T cell dependent EAE model. Given the fact that BTK is not expressed in T cells, further mechanistic experiments are needed to investigate the effect of BTKi on innate immune cells in the context of this disease. Our results suggest that BTK inhibition might have broader therapeutic benefit in MS than seen with B cell depletion alone.
Disclosure: All authors are employees of EMD Serono Inc.
Abstract: P678
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Bruton's tyrosine kinase (Btk) is a member of the TEC family of non-receptor tyrosine kinases expressed in cells of hematopoietic origin, including B cells and myeloid cells, but not T cells. In addition to its well-known effects on diverse B cell functions, BTK mediates signaling in innate immune cells downstream of various receptors including Fc, integrin, chemokine and Toll-like receptors. The goal of this study was to test the clinical efficacy of BTK inhibition in an experimental autoimmune encephalomyelitis (EAE) model not responsive to B cell inhibition, but in which pathogenic T cells and innate immune cells are centrally involved in disease.
Methods: EAE was induced in SJL/J mice by Proteolipic Protein (PLP) 139-151 peptide and Complete Freund's adjuvant (CFA) on day 0. Mice also received a pertussis toxin injection on day 0 and day 2. Disease severity was scored using a standard scale from 0 - 5. Treatment with the BTKi M2951 (0.3, 1, 3, 10 mg/kg), or vehicle was conducted in 2 separate experiments using both prophylactic and late-therapeutic regimens. The compound Fingolimod (FTY720 1 mg/kg) served as a positive, anti-CD20 AB as a negative control. Blood was collected at the end of the studies for pharmacokinetic and BTK occupancy analysis. Gene expression analysis was performed on spinal cords.
Results: Both prophylactic and therapeutic treatment with M2951 reduced clinical score in a dose dependent manner. While the lowest dose (0.3 mg/kg) exerted a minimal effect, higher doses (1, 3, 10 mg/kg) of the BTKi significantly ameliorated EAE severity when administered before disease onset or after the peak of the disease. M2951 (10 mg/kg) reached comparable efficacy to FTY720 in the therapeutic setting. After M2951 treatment a high degree of BTK occupancy was achieved in peripheral blood early in disease, while BTK occupancy in the brain was found only at later timepoints. Anti-PLP titers were not reduced by M2951 treatment, but myeloid genes in the spinal cord were affected by M2951.
Conclusions: BTK inhibition proved to be effective in limiting CNS inflammation and clinical severity in a T cell dependent EAE model. Given the fact that BTK is not expressed in T cells, further mechanistic experiments are needed to investigate the effect of BTKi on innate immune cells in the context of this disease. Our results suggest that BTK inhibition might have broader therapeutic benefit in MS than seen with B cell depletion alone.
Disclosure: All authors are employees of EMD Serono Inc.