ABBV-105, a selective and irreversible inhibitor of Bruton's tyrosine kinase, is efficacious in multiple preclinical models of inflammation
ABBV-105, a selective and irreversible inhibitor of Bruton's tyrosine kinase, is efficacious in multiple preclinical models of inflammation
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DOI：
10.1080/14397595.2018.1484269
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发表时间：
2019-05-04
影响因子：
2.2
通讯作者：
Long, Andrew J.
中科院分区：
文献类型：
--
作者：
Goess, Christian;Harris, Christopher M.;Long, Andrew J.
目的：布鲁顿酪氨酸激酶（BTK）是多种免疫受体下游的细胞内信号传导所需的非受体酪氨酸激酶。我们评估了ABBV-105，一种共价BTK抑制剂，使用体外和体内测定来确定效力、选择性和功效，以验证ABBV-105在炎性疾病中的治疗潜力。方法：ABBV-105的效力和选择性在酶和细胞测定中进行了评价。使用抗体产生的机制模型评估ABBV-105对体内B细胞功能的影响。在关节炎和狼疮的动物模型中评估ABBV-105在慢性炎性疾病中的功效。采用BTK占有率的测量作为靶接合生物标志物。结果如下：ABBV-105不可逆地抑制BTK，证明了上级激酶组选择性，并且在B细胞受体、Fc受体和TLR-9依赖性细胞测定中是有效的。经口给药导致血浆中的快速清除，但维持BTK脾脏占用。ABBV-105抑制对胸腺非依赖性和胸腺依赖性抗原的抗体应答、大鼠胶原诱导的关节炎中的爪肿胀和骨破坏，并减少IFN α加速的狼疮肾炎模型中的疾病。疾病模型中的BTK占有率与体内功效相关。结论：ABBV-105是一种选择性BTK抑制剂，在抗体产生的临床前机制模型以及类风湿性关节炎和狼疮模型中表现出令人信服的功效。
Objectives: Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase required for intracellular signaling downstream of multiple immunoreceptors. We evaluated ABBV-105, a covalent BTK inhibitor, using in vitro and in vivo assays to determine potency, selectivity, and efficacy to validate the therapeutic potential of ABBV-105 in inflammatory disease. Methods: ABBV-105 potency and selectivity were evaluated in enzymatic and cellular assays. The impact of ABBV-105 on B cell function in vivo was assessed using mechanistic models of antibody production. Efficacy of ABBV-105 in chronic inflammatory disease was evaluated in animal models of arthritis and lupus. Measurement of BTK occupancy was employed as a target engagement biomarker. Results: ABBV-105 irreversibly inhibits BTK, demonstrating superior kinome selectivity and is potent in B cell receptor, Fc receptor, and TLR-9-dependent cellular assays. Oral administration resulted in rapid clearance in plasma, but maintenance of BTK splenic occupancy. ABBV-105 inhibited antibody responses to thymus-independent and thymus-dependent antigens, paw swelling and bone destruction in rat collagen induced arthritis, and reduced disease in an IFN alpha-accelerated lupus nephritis model. BTK occupancy in disease models correlated with in vivo efficacy. Conclusion: ABBV-105, a selective BTK inhibitor, demonstrates compelling efficacy in pre-clinical mechanistic models of antibody production and in models of rheumatoid arthritis and lupus.