Modeling the clinical phenotype of BTK inhibition in the mature murine immune system

Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice autoimmune indications. However, our current knowledge of the role of BTK in immune competence has been gathered in the context of genetic inactivation of btk in both mice and man. Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice. We implicate BTK in tonic BCR signaling, demonstrate dependence of the T3 B cell subset and IgM surface expression on BTK activity, and find that B1 cells survive and function independently of BTK. While BTK inhibition does not impact humoral memory survival, antigen-driven clonal expansion of memory B cells and antibody secreting cell generation are inhibited. These data define the role of BTK in the mature immune system and mechanistically predict the clinical phenotype of BTK inhibition.

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Benson MJ, Rodriguez V, von Schack D, Keegan S, Cook TA, Edmonds J, Benoit S, Seth N, Du S, Messing D, Nickerson-Nutter CL, Dunussi-Joannopoulos K, Rankin AL, Ruzek M, Schnute ME, Douhan J 3rd