McBride Jacqueline M, Jiang Jenny, Abbas Alexander R, Morimoto Alyssa, Li Jing, Maciuca Romeo, Townsend Michael, Wallace Daniel J, Kennedy William P, Drappa Jorn
Genentech, South San Francisco, California, USA.
Arthritis Rheum. 2012 Nov;64(11):3666-76. doi: 10.1002/art.34632.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies and inflammation in multiple organ systems. Elevation of messenger RNA levels of interferon (IFN)-regulated genes (IRGs) has been described in the peripheral blood of SLE patients and has been associated with disease activity. The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of rontalizumab, a humanized IgG1 monoclonal antibody that neutralizes IFNα, were assessed in a phase I dose-escalation study of single and repeat doses of rontalizumab in adults with mildly active SLE. The present report describes the safety results and the impact of rontalizumab on expression of IRGs, IFN-inducible proteins, and autoantibodies.
Patients were enrolled into dose groups ranging from 0.3 to 10 mg/kg, administered via intravenous (IV) or subcutaneous routes. Expression levels of 7 IRGs and IFN-inducible serum proteins were monitored as potential biomarkers for the PD activity of rontalizumab.
An acceptable safety profile was demonstrated for rontalizumab in patients with SLE. Prespecified criteria for dose-limiting toxicity were not met. The incidence of serious adverse events was comparable across cohorts. The PK properties were as expected for an IgG1 monoclonal antibody and were proportional to dose. Following administration of rontalizumab, a rapid decline in the expression of IRGs was observed in the 3 mg/kg and 10 mg/kg IV cohorts, and this effect could be sustained with repeat dosing. There was no apparent decline in the levels of IFN-inducible proteins or levels of anti-double-stranded DNA and anti-extractable nuclear antigen autoantibodies following treatment with rontalizumab.
The preliminary safety, PK profile, and observed PD effects of rontalizumab support further evaluation of its safety and efficacy in SLE.
系统性红斑狼疮（SLE）是一种慢性自身免疫性疾病，其特征为存在自身抗体以及多器官系统炎症。干扰素（IFN）调节基因（IRG）的信使核糖核酸水平在SLE患者外周血中升高，且与疾病活动相关。在一项针对轻度活动性SLE成人患者的I期剂量递增研究中，评估了中和IFNα的人源化IgG1单克隆抗体rontalizumab的安全性、耐受性、药代动力学（PK）和药效动力学（PD）。本报告描述了rontalizumab的安全性结果以及其对IRG表达、IFN诱导蛋白和自身抗体的影响。
患者被纳入剂量范围为0.3至10 mg/kg的剂量组，通过静脉内（IV）或皮下途径给药。监测7种IRG和IFN诱导血清蛋白的表达水平，作为rontalizumab PD活性的潜在生物标志物。
rontalizumab在SLE患者中显示出可接受的安全性。未达到预先设定的剂量限制毒性标准。各队列中严重不良事件的发生率相当。PK特性与IgG1单克隆抗体预期相符，且与剂量成比例。给予rontalizumab后，在3 mg/kg和10 mg/kg IV队列中观察到IRG表达迅速下降，且这种效应在重复给药时可持续。rontalizumab治疗后，IFN诱导蛋白水平或抗双链DNA和抗可提取核抗原自身抗体水平没有明显下降。
rontalizumab的初步安全性、PK概况及观察到的PD效应支持进一步评估其在SLE中的安全性和疗效。
