Acalabrutinib, a highly selective Bruton's tyrosine kinase inhibitor, is associated with high overall response rates and durable remission in previously treated chronic lymphocytic leukemia (CLL); however, complete remissions were limited. To elucidate on-target and pharmacodynamic effects of acalabrutinib, we evaluated several laboratory endpoints, including proteomic changes, chemokine modulation and impact on cell migration. Pharmacological profiling of samples from acalabrutinib-treated CLL patients was used to identify strategies for achieving deeper responses, and to identify additive/synergistic combination regimens. Peripheral blood samples from 21 patients with relapsed/refractory CLL in acalabrutinib phase I (100-400 mg/day) and II (100 mg BID) clinical trials were collected prior to and on days 8 and 28 after treatment initiation and evaluated for plasma chemokines, reverse phase protein array, immunoblotting and pseudoemperipolesis. The on-target pharmacodynamic profile of acalabrutinib in CLL lymphocytes was comparable to ibrutinib in measures of acalabrutinib-mediated changes in CCL3/CCL4 chemokine production, migration assays and changes in B-cell receptor signaling pathway proteins and other downstream survival proteins. Among several CLL-targeted agents, venetoclax, when combined with acalabrutinib, showed optimal complementary activity in vitro, ex vivo and in vivo in TCL-1 adoptive transfer mouse model system of CLL. These findings support selective targeting and combinatorial potential of acalabrutinib.

中文翻译：

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acalabrutinib 疗法的药效学和蛋白质组学分析：与 ibrutinib 的靶向作用的相似性以及联合治疗的基本原理。


Acalabrutinib 是一种高选择性布鲁顿酪氨酸激酶抑制剂，对于既往治疗的慢性淋巴细胞白血病 (CLL) 具有较高的总体缓解率和持久缓解率；然而，完全缓解是有限的。为了阐明 acalabrutinib 的靶向作用和药效学作用，我们评估了几个实验室终点，包括蛋白质组变化、趋化因子调节和对细胞迁移的影响。对接受 acalabrutinib 治疗的 CLL 患者样本进行药理学分析，用于确定实现更深层次缓解的策略，并确定相加/协同联合治疗方案。在acalabrutinib I期（100-400mg/天）和II期（100mg BID）临床试验中，在治疗开始前以及治疗后第8天和28天收集21名复发/难治性CLL患者的外周血样本，并评估血浆趋化因子、反相蛋白阵列、免疫印迹和假渗入。 Acalabrutinib 在 CLL 淋巴细胞中的靶向药效学特征在 Acalabrutinib 介导的 CCL3/CCL4 趋化因子产生变化、迁移测定以及 B 细胞受体信号通路蛋白和其他下游生存蛋白变化的测量方面与依鲁替尼相当。在几种 CLL 靶向药物中，venetoclax 与 acalabrutinib 联合使用时，在 CLL 的 TCL-1 过继转移小鼠模型系统中在体外、离体和体内均显示出最佳的互补活性。这些发现支持 acalabrutinib 的选择性靶向和组合潜力。