Evobrutinib therapeutic response is associated with an increase in the number and maturation of peripheral and central classical dendritic cells
Diego Clemente1, Mari Paz Serrano-Regal1, Leticia Calahorra1, Inmaculada Alonso-García1, Ursula Boschert Shafaatian2, Philipp Haselmayer3, Cristina Ortega1, Isabel Machín-Díaz1, Celia Camacho-Toledano1, Jennifer García-Arocha1
11Neuroimmuno-Repair Group. Research Unit. Hospital Nacional de Parapléjicos-SESC, 22Ares Trading SA, Eysins, Switzerland, an affiliate of Merck KGaA, 33Merck KGaA, Darmstadt, Germany
Objective:
To assess the impact of evobrutinib on classical dendritic cells (cDCs) in the MOG35-55-induced chronic-progressive experimental autoimmune encephalomyelitis (EAE) Multiple sclerosis (MS) model (with limited B cell contribution).
Background:
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.
Design/Methods:
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).
Results:
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.
Conclusions:
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 ex vivo assays.