Bristol Myers Squibb, Princeton, NJ, USA.
Quotient Sciences, Nottingham, UK.
Arthritis Res Ther. 2022 Aug 18;24(1):199. doi: 10.1186/s13075-022-02850-6.
Mitogen-activated protein kinase (MAPK)-activated protein kinase-2 (MK2) is activated downstream of p38 MAPK and regulates stability of mRNAs encoding inflammatory cytokines. CC-99677 is a novel, irreversible, covalent MK2 inhibitor under development for the treatment of ankylosing spondylitis (AS) and other inflammatory diseases. As part of a phase I clinical trial to assess safety and tolerability, we evaluated target engagement, pharmacokinetics, and pharmacodynamics of CC-99677.
The MK2 inhibitor CC-99677 was evaluated for its effect on cytokine expression in vitro in peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with a definitive AS diagnosis. A novel in vitro model was developed to compare the potential for tachyphylaxis of CC-99677 and p38 inhibitors in THP-1 cells. The effect of CC-99677 on tristetraprolin (TTP) and cytokine mRNA was assessed in stimulated human monocyte-derived macrophages. In a first-in-human study, thirty-seven healthy volunteers were randomly assigned to daily oral doses of CC-99677 or placebo, and blood was collected at pre-specified time points before and after dosing. CC-99677 concentrations were assessed in the plasma, and CC-99677 binding to MK2 was evaluated in PBMCs. Ex vivo stimulation of the whole blood was conducted from participants in the first-in-human study to assess the pharmacodynamic effects.
In vitro, CC-99677 inhibited tumor necrosis factor (TNF), interleukin (IL)-6, and IL-17 protein production in samples of monocytes and macrophages from AS patients and healthy volunteers via an mRNA-destabilization mechanism. In the in vitro model of tachyphylaxis, CC-99677 showed a differentiated pattern of sustained TNF protein inhibition compared with p38 inhibitors. CC-99677 reduced TTP phosphorylation and accelerated the decay of inflammatory cytokine mRNA in lipopolysaccharide-stimulated macrophages. Administration of CC-99677 to healthy volunteers was safe and well-tolerated, with linear pharmacokinetics and sustained reduction of ex vivo whole blood TNF, IL-6, and chemokine synthesis.
CC-99677 inhibition of MK2 is a promising approach for the treatment of inflammatory diseases and may overcome the limitations of p38 MAPK inhibition.
ClinicalTrials.gov NCT03554993 .
丝裂原活化蛋白激酶（MAPK）-激活的蛋白激酶-2（MK2）是 p38 MAPK 下游的一种激活蛋白，调节编码炎症细胞因子的 mRNA 的稳定性。CC-99677 是一种新型的不可逆、共价 MK2 抑制剂，目前正在开发用于治疗强直性脊柱炎（AS）和其他炎症性疾病。作为一项评估安全性和耐受性的 I 期临床试验的一部分，我们评估了 CC-99677 的靶标结合、药代动力学和药效动力学。
评估了 MK2 抑制剂 CC-99677 在体外对健康供体和确诊为 AS 的患者外周血单核细胞（PBMC）中细胞因子表达的影响。建立了一种新的体外模型，以比较 CC-99677 和 p38 抑制剂在 THP-1 细胞中潜在的脱敏作用。评估了 CC-99677 对刺激的人单核细胞衍生巨噬细胞中 tristetraprolin（TTP）和细胞因子 mRNA 的影响。在首次人体研究中，37 名健康志愿者被随机分配接受 CC-99677 或安慰剂的每日口服剂量，并在给药前和给药后规定的时间点采集血液。评估了血浆中的 CC-99677 浓度，并评估了 CC-99677 在 PBMC 中与 MK2 的结合。对首次人体研究中的参与者进行了全血的体外刺激，以评估药效学效应。
体外，CC-99677 通过一种 mRNA 降解机制抑制来自 AS 患者和健康志愿者的单核细胞和巨噬细胞样本中肿瘤坏死因子（TNF）、白细胞介素（IL）-6 和 IL-17 蛋白的产生。在脱敏的体外模型中，与 p38 抑制剂相比，CC-99677 显示出 TNF 蛋白抑制的持续分化模式。CC-99677 降低了 TTP 磷酸化并加速了脂多糖刺激的巨噬细胞中炎症细胞因子 mRNA 的衰减。CC-99677 给药于健康志愿者是安全且耐受良好的，具有线性药代动力学和持续降低体外全血 TNF、IL-6 和趋化因子合成。
CC-99677 抑制 MK2 是治疗炎症性疾病的一种很有前途的方法，可能克服 p38 MAPK 抑制的局限性。
ClinicalTrials.gov NCT03554993。
