Goess Christian, Harris Christopher M, Murdock Sara, McCarthy Richard W, Sampson Erik, Twomey Rachel, Mathieu Suzanne, Mario Regina, Perham Matthew, Goedken Eric R, Long Andrew J
a AbbVie Bioresearch Center , Worcester , MA , USA.
Mod Rheumatol. 2019 May;29(3):510-522. doi: 10.1080/14397595.2018.1484269. Epub 2018 Jul 23.
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.
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.
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 IFNα-accelerated lupus nephritis model. BTK occupancy in disease models correlated with in vivo efficacy.
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.
布鲁顿酪氨酸激酶（BTK）是多种免疫受体下游细胞内信号传导所需的非受体酪氨酸激酶。我们使用体外和体内试验评估了共价BTK抑制剂ABBV-105，以确定其效力、选择性和疗效，从而验证ABBV-105在炎症性疾病中的治疗潜力。
在酶促和细胞试验中评估ABBV-105的效力和选择性。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在慢性炎症性疾病中的疗效。采用测量BTK占有率作为靶点结合生物标志物。
ABBV-105不可逆地抑制BTK，显示出卓越的激酶组选择性，并且在B细胞受体、Fc受体和TLR-9依赖性细胞试验中具有效力。口服给药导致血浆中药物快速清除，但脾脏中BTK占有率维持不变。ABBV-105抑制对非胸腺依赖性和胸腺依赖性抗原的抗体反应、大鼠胶原诱导性关节炎中的爪肿胀和骨破坏，并在IFNα加速的狼疮性肾炎模型中减轻疾病。疾病模型中的BTK占有率与体内疗效相关。
选择性BTK抑制剂ABBV-105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显示出令人信服的疗效。
