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Remibrutinib (LOU064) inhibits neuroinflammation driven by B cells and myeloid cells in preclinical models of Multiple Sclerosis

Nuesslein-Hildesheim, Barbara, Ferrero, Enrico, Schmid, Cindy, Huck, Catherine, Smith, Paul, Tisserand, Sarah, Rubert, Joelle, Bornancin, Frederic, Eichlisberger, Denis and Cenni, Bruno (2023) Remibrutinib (LOU064) inhibits neuroinflammation driven by B cells and myeloid cells in preclinical models of Multiple Sclerosis. Journal of neuroinflammation, 20. p. 194. ISSN 1742-2094

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Bruton’s tyrosine kinase (BTK) is a key signaling node in B cell receptor (BCR) and Fc receptor
(FcR) signaling. BTK inhibitors (BTKi) are an emerging oral treatment option for patients suffering from multiple sclerosis (MS). Remibrutinib (LOU064) is a potent, highly selective covalent BTKi with a promising preclinical and clinical profile for MS and other autoimmune or autoallergic indications.
The efficacy and mechanism of action of remibrutinib was assessed in two different experimental autoimmune encephalomyelitis (EAE) mouse models for MS. The impact of remibrutinib on B cell driven EAE pathology was determined after immunization with human myelin oligodendrocyte glycoprotein (HuMOG). The efficacy on myeloid cell and microglia driven neuroinflammation was determined in the RatMOG EAE. In addition, we assessed the relationship of efficacy to BTK occupancy in tissue, ex vivo T cell response, serum biomarkers such as total and antigen-specific immunoglobulins (Ig) and neurofilament light chain (NfL), as well as single cell RNA sequencing (scRNA-seq) in EAE brain and spinal cord tissue.
Remibrutinib inhibited B cell dependent HuMOG EAE in dose-dependent manner and strongly reduced neurological symptoms. At the efficacious oral dose of 30 mg/kg, remibrutinib showed strong BTK occupancy in the peripheral immune organs and in the brain of EAE mice. Ex vivo MOG-specific Th17 T cell recall response was reduced, but not polyclonal T cell response, indicating absence of general T cell inhibition. Remibrutinib also inhibited RatMOG EAE, suggesting that myeloid cell and microglia inhibition contribute to its efficacy in EAE. Remibrutinib did not reduce total IgG or IgM levels nor MOG-specific antibody response. In EAE brain and spinal cord tissue a clear anti-inflammatory effect in microglia was detected by scRNA-seq. Finally, remibrutinib showed potent inhibition of in vitro immune complex-driven inflammatory response in human microglia.
Remibrutinib inhibited EAE models by a two-pronged mechanism based on inhibition of pathogenic B cell autoreactivity, as well as direct anti-inflammatory effects on microglia. Remibrutinib showed efficacy in both models in absence of direct B cell depletion, broad T cell inhibition or reduction of total Ig levels. These findings support the view that remibrutinib may represent a novel treatment option for patients with MS.

Item Type: Article
Keywords: Multiple sclerosis, BTK, remibrutinib, LOU064, autoimmunity, neuroinflammation
Date Deposited: 07 Oct 2023 00:45
Last Modified: 07 Oct 2023 00:45


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