Evobrutinib therapeutic response is associated with an increase in the number and maturation of peripheral and central classical dendritic cells (P7-3.005)

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<h3>Objective:</h3> To assess the impact of evobrutinib on classical dendritic cells (cDCs) in the MOG_35–55-induced chronic-progressive experimental autoimmune encephalomyelitis (EAE) Multiple sclerosis (MS) model (with limited B cell contribution). <h3>Background:</h3> Evobrutinib is an oral, highly selective covalent Bruton’s tyrosine kinase (BTK) inhibitor with promising results in a Phase II trial for relapsing MS. Lately, the role of BTK in myeloid cell activity, including cDCs, has been gaining importance in MS pathogenesis. <h3>Design/Methods:</h3> Female EAE mice received individualized daily oral treatment of vehicle (EAE-Veh) or evobrutinib (EAE-Evo) for 4 days from the day of disease onset. EAE was scored clinically each day and flow cytometry analyses of spleens and spinal cords were performed. EAE-Evo mice with a clinical course indistinguishable from that of EAE-Veh were classified as non-responders (Evo-NR), whereas those with less severe disease were considered responders (Evo-R). <h3>Results:</h3> The therapeutic response in Evo-R was associated with an increase in MHC-II⁺ cDC (mature cDCs) in the spleen. Evobrutinib shifted the correlation between CD69⁺ T cells/cDCs from positive to inverse. However, Evo-NR mice showed myeloid content similar to EAE-Veh mice and Evo-R mice exhibited a lower myeloid cell infiltrate in the spinal cord, albeit enriched in mature cDCs. Evobrutinib induced specific modifications in the immunological synapse components in cDCs. Whereas both Evo-R and Evo-NR showed a decrease in MHC-II in splenic cDCs, only Evo-R exhibited a decrease in CD80. In contrast, spinal cord cDCs showed decreased CD80 with no modification of MHC-II brightness. <h3>Conclusions:</h3> In the EAE model, evobrutinib therapeutic response shows a clear relationship with the enrichment of mature cDCs at both the peripheral and central levels, with a decrease in activated T cell presence. The interpretation of the immunological alteration of cDCs by evobrutinib will be further investigated using functional <i>ex vivo</i> assays. <b>Disclosure:</b> The institution of Dr. Clemente has received research support from EMD Serono Research &amp; Development Institute, Inc.. The institution of Dr. Clemente has received research support from Bristol Myers Squibb. The institution of Dr. Clemente has received research support from Instituto de Salud Carlos III. Dr. Clemente has received personal compensation in the range of $500-$4,999 for serving as a Reviewer of Grants with Spanish National Investigation Agency. Dr. Serrano Regal has nothing to disclose. Dr. Calahorra has nothing to disclose. Miss Alonso García has nothing to disclose. Ursula Boschert has nothing to disclose. Philipp Haselmayer has received personal compensation for serving as an employee of Merck Healthcare KGaA. Dr. Ortega has nothing to disclose. Miss Díaz has nothing to disclose. Mrs. Camacho Toledano has nothing to disclose. Mrs. Arocha has nothing to disclose.