Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study.
Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study.
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DOI：
10.1186/ar4492
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发表时间：
2014-02-24
影响因子：
4.9
通讯作者：
Yoo S
中科院分区：
文献类型：
--
作者：
Goldberg A;Geppert T;Schiopu E;Frech T;Hsu V;Simms RW;Peng SL;Yao Y;Elgeioushi N;Chang L;Wang B;Yoo S
I型干扰素(IFN)与系统性硬化症(SSC)的发病机制有关。MEDI-546是一种针对I型干扰素受体的研究中的人源性单抗。这项第一阶段研究评估了单次和多次静脉注射Medi-546对患有SSc的成年人的安全性/耐受性、药代动力学(PK)、免疫原性和药效学(PD)。患有SSc的受试者(≥18岁)参加了一项开放标签的剂量递增研究，接受单次(0.1、0.3、1.0、3.0、10.0或20.0 mg/kg)或每周4次静脉注射(0.3、1.0或5.0 mg/kg/周)的Medi-546。受试者被跟踪了12周。安全性评估包括不良事件(AEs)、实验室结果和病毒监测。采集所有受试者的血液样本，以测定PK、抗药物抗体(ADAs)的存在和I型干扰素诱导基因的表达。在34名受试者(平均年龄47.4岁)中，32人完成治疗，33人完成研究。总体而言，报告了148例紧急治疗不良反应(TEAE)(68.9%为轻度，27.7%为中度)。TEAEs包括1级输注反应(5.0 mg/kg/周多次给药)。在4种严重不良反应(皮肤溃疡、骨髓炎、眩晕和慢性粒细胞白血病)中，只有慢性粒细胞白血病(CML)(每周多次给药1.0 mg/kg)可能与治疗有关。在较低剂量下，Medi-546表现为非线性PK。5名受试者检测到ADAS，对PK无明显影响。I型干扰素在全血中的抑制在1天内达到峰值，在皮肤中的抑制在7天后达到峰值。这项研究中观察到的安全性/耐受性、PK和PD特征支持Medi-546的进一步临床开发。ClinicalTrials.gov NCT00930683
Type I interferons (IFNs) are implicated in the pathogenesis of systemic sclerosis (SSc). MEDI-546 is an investigational human monoclonal antibody directed against the type I IFN receptor. This Phase 1 study evaluated the safety/tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of single and multiple intravenous doses of MEDI-546 in adults with SSc. Subjects (≥18 years) with SSc were enrolled in an open-label, dose-escalation study to receive single (0.1, 0.3, 1.0, 3.0, 10.0, or 20.0 mg/kg), or 4 weekly intravenous doses (0.3, 1.0, or 5.0 mg/kg/week) of MEDI-546. Subjects were followed for 12 weeks. Safety assessments included adverse events (AEs), laboratory results, and viral monitoring. Blood samples were collected from all subjects for determination of PK, presence of anti-drug antibodies (ADAs), and expression of type I IFN-inducible genes. Of 34 subjects (mean age 47.4 years), 32 completed treatment and 33 completed the study. Overall, 148 treatment-emergent AEs (TEAEs) were reported (68.9% mild, 27.7% moderate). TEAEs included one grade 1 infusion reaction (5.0 mg/kg/week multiple dose). Of 4 treatment-emergent serious AEs (skin ulcer, osteomyelitis, vertigo, and chronic myelogenous leukemia (CML)), only CML (1.0 mg/kg/week multiple dose) was considered possibly treatment-related. MEDI-546 exhibited non-linear PK at lower doses. ADAs were detected in 5 subjects; no apparent impact on PK was observed. Peak inhibition of the type I IFN signature in whole blood was achieved within 1 day and in skin after 7 days. The safety/tolerability, PK, and PD profiles observed in this study support further clinical development of MEDI-546. ClinicalTrials.gov NCT00930683
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