Background/Purpose: Bruton’s Tyrosine Kinase (BTK) is a non-receptor tyrosine kinase required for intracellular signaling pathways downstream of several key immunoreceptors, including the B cell receptor, Fc receptors, and the GPVI collagen receptor.  Due to its involvement in multiple mechanisms of inflammatory disease pathogenesis, targeting BTK may be a useful strategy for indications like rheumatoid arthritis and lupus.  ABBV-105 is a covalent, irreversible inhibitor that alkylates Cys481 specifically, resulting in durable BTK inhibition in vitro and in vivo.  Only 10 other kinases have a cysteine at this position and ABBV-105 has greater than 30-fold selectivity versus these kinases.

Methods: To evaluate the effects and specificity of BTK inhibition in vitro we evaluated ABBV-105 in BTK dependent cell assays including FCεR-mediated basophil degranulation, FCγR-mediated monocyte activation, and TLR9 agonist-mediated activation of PBMC.  As a consequence of the covalent nature of the binding, target engagement can be assessed both in vitro and in vivo by measuring the amount of unbound BTK associated with a biotinylated probe derived from a related covalent Btk inhibitor.   BTK occupancy can be calculated by comparing the free BTK levels in a sample with or without ABBV-105 treatment.  To understand the effects of BTK inhibition on inflammatory processes in vivo, we evaluated ABBV-105 in a rat collagen-induced arthritis (CIA) model and in an IFNα-accelerated lupus nephritis model in NZB/W mice.

Results: ABBV-105 potently and selectively inhibits the BTK enzyme and multiple BTK dependent cell-based assays including FCεR-mediated basophil degranulation, FCγR-mediated monocyte activation, and TLR9 agonist-mediated activation of PBMCs.  Following oral administration of ABBV-105 in vivo, there is a rapid clearance of ABBV-105 in plasma while BTK occupancy of ABBV-105 in both spleen and peripheral blood leukocytes remains.  In rat CIA, ABBV-105 fully inhibits paw swelling and bone destruction comparable to prednisolone.  ABBV-105 also significantly reduces proteinuria, prolongs survival, and reduces anti-dsDNA autoantibody titers in an IFNα-accelerated lupus nephritis model.  Efficacy in both models correlates with BTK splenic occupancy in a dose- and exposure-dependent manner.

Conclusion: Taken together, our data confirm that selective and covalent inhibition of BTK is effective in ameliorating disease pathogenesis in preclinical models of rheumatoid arthritis and lupus and may provide a therapeutic benefit to patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/efficacy-of-abbv-105-a-selective-and-irreversible-inhibitor-of-brutons-tyrosine-kinase-btk-in-multiple-models-of-inflammation/