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Abstract Details

Establishing a Role for the Bruton’s Tyrosine Kinase Inhibitor Tolebrutinib in Modulating Neuroinflammation and Disease Progression in MS
Multiple Sclerosis
S25 - MS and CNS Inflammatory Disease: Emerging Therapeutics and Biomarkers (4:24 PM-4:32 PM)
003
To characterize the pharmacokinetic properties of the central nervous system (CNS)–penetrant Bruton’s tyrosine kinase (BTK) inhibitor tolebrutinib, its effects on microglia, and its potential to modulate disease progression in MS.
Neuroinflammation in the brain and spinal cord, driven largely by CNS-resident microglia, has been proposed as a significant contributor to disability accumulation in patients with MS. BTK is expressed in microglia, as well as in B lymphocytes and monocytes/macrophages found in the periphery. BTK inhibition may provide therapeutic benefit within the CNS by targeting innate immunity associated with disease progression in MS.

Immunohistochemistry, Western immunoblotting, RNA sequencing, and monitoring of BTK or phosphorylated BTK were performed in microglial cell lines, mouse brains, and postmortem MS brains.

Transcriptome analysis was used to generate a BTK-dependent transcriptional signature in microglia. Immunohistochemistry studies and single-nucleus RNA sequencing (snRNAseq) in autopsy-derived tissues demonstrated that BTK was expressed in B cells and microglia, with increased levels in MS lesion samples. New snRNAseq data illustrated a clear shift of microglial cell gene expression to a reactive and/or inflammatory signature in progressive disease. Using a CNS-penetrant BTK tool inhibitor, the role of BTK inhibition in modulating neuroinflammation was assessed in vivo. Tolebrutinib demonstrated potent BTK binding in Ramos and microglial cell lines and potent inhibitory activity in biochemical and cellular assays. Cerebrospinal fluid (CSF) exposure analysis demonstrated that CSF concentration exceeded the cell-based in vitro 90% inhibitory concentration (IC90).
We extended our previous findings on the role of BTK in microglia to show that BTK-dependent inflammatory signaling in these cells was modulated using CNS-penetrant BTK inhibitors in vitro and in vivo, and demonstrated how microglia were altered in progressive MS. We further demonstrated the properties that render tolebrutinib uniquely able to abrogate microglia-driven neuroinflammation implicated in MS disease progression.
Authors/Disclosures
Ross C. Gruber, PhD (Takeda)
PRESENTER 		Dr. Gruber has received personal compensation for serving as an employee of Sanofi. Dr. Gruber has received stock or an ownership interest from Sanofi.
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
Evis Havari, Msc (Sanofi) Ms. Havari has received personal compensation for serving as an employee of sanofi.
Timothy J. Turner Timothy J. Turner has received personal compensation for serving as an employee of Sanofi. Timothy J. Turner has stock in Sanofi. Timothy J. Turner has received intellectual property interests from a discovery or technology relating to health care.
No disclosure on file
No disclosure on file
Bruce D. Trapp, PhD (Cleveland Clinic) Dr. Trapp has received personal compensation for serving as an employee of Renovo Neural Inc.. The institution of Dr. Trapp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Therini Bio, Inc.. Dr. Trapp has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi Genzyme. Dr. Trapp has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Disarm Therapeutics. Dr. Trapp has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Kantonsspital Aarau AG. Dr. Trapp has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for triMS.online. The institution of Dr. Trapp has received research support from Genzyme Corporation. The institution of Dr. Trapp has received research support from ALS Association. The institution of Dr. Trapp has received research support from National Institute of Neurological Disorders and Stroke.
No disclosure on file