Safety, tolerability, pharmacokinetics, and immunogenicity of the therapeutic monoclonal antibody mAb114 targeting Ebola virus glycoprotein (VRC 608): an open-label phase 1 study
Safety, tolerability, pharmacokinetics, and immunogenicity of the therapeutic monoclonal antibody mAb114 targeting Ebola virus glycoprotein (VRC 608): an open-label phase 1 study
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DOI：
10.1016/s0140-6736(19)30036-4
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发表时间：
2019-03-02
期刊：
影响因子：
168.9
通讯作者：
Ledgerwood, Julie E.
中科院分区：
文献类型：
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作者：
Gaudinski, Martin R.;Coates, Emily E.;Ledgerwood, Julie E.
背景 mAb114 是一种单克隆抗体，靶向埃博拉病毒糖蛋白的受体结合结构域，可防止经过扎伊尔埃博拉病毒致命攻击后的恒河猴死亡。在此，我们提供来自 VRC 608 的快速数据，该研究是一项评估 mAb114 安全性、耐受性、药代动力学和免疫原性的 1 期研究。 方法 在美国国立卫生研究院 (NIH) 临床中心（美国马里兰州贝塞斯达）进行的这项 1 期剂量递增研究 (VRC 608) 中，18-60 岁的健康成年人依次入组至三个 mAb114 剂量组，剂量组分别为： 5毫克/千克、25毫克/千克和50毫克/千克。该药物在 30 分钟内静脉注射给参与者，并对参与者进行了 24 周的随访。参与者仅在中期安全评估后才被纳入增加剂量组。我们的主要终点是安全性和耐受性，药代动力学和抗药物抗体评估作为次要终点。我们通过监测临床实验室数据和自我报告以及直接临床医生对输注后 3 天的预定输注部位症状和输注后 7 天的全身症状的评估，评估了所有接受研究药物的参与者的安全性和耐受性。记录了 28 天的主动不良事件。参与者完成了药代动力学和抗药物抗体评估，并获得了至少 56 天的数据。该试验已在临床试验中注册。 gov，编号 NCT03478891，正在积极招募，但不再招募。调查结果 2018 年 5 月 16 日至 9 月 27 日期间，有 19 名符合条件的个人被招募。一名 (5%) 参与者因静脉通路不充分而未输液。在剩下的 18 名参与者 (95%) 中，三名 (17%) 被分配到 5 mg/kg 组，五名 (28%) 被分配到 25 mg/kg 组，十名 (55%) 被分配到 50 mg/kg 组，每人均按指定剂量接受单次 mAb114 输注。所有输注均耐受良好，并在 30-37 分钟内完成，没有输注反应或速率调整。所有接受研究药物的参与者都完成了局部和全身反应原性的安全评估。没有参与者报告输注部位症状。全身症状都很轻微，所有剂量组的 18 名参与者中只有 4 名 (22%) 出现全身症状。没有发生与 mAb114 相关的主动不良事件，并发生了 1 起与 mAb114 无关的严重不良事件。 mAb114 具有线性药代动力学，半衰期为 24.2 天（测量标准误差为 0.2），没有抗药物抗体形成的证据。解释 mAb114 耐受性良好，显示线性药代动力学，并且可以轻松快速地输注，使其成为爆发环境中有吸引力且可部署的治疗选择。资助疫苗研究中心、美国国家过敏和传染病研究所以及 NIH。版权所有 (c) 2019 Elsevier Ltd. 保留所有权利。
Background mAb114 is a single monoclonal antibody that targets the receptor-binding domain of Ebola virus glycoprotein, which prevents mortality in rhesus macaques treated after lethal challenge with Zaire ebolavirus. Here we present expedited data from VRC 608, a phase 1 study to evaluate mAb114 safety, tolerability, pharmacokinetics, and immunogenicity.Methods In this phase 1, dose-escalation study (VRC 608), conducted at the US National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA), healthy adults aged 18-60 years were sequentially enrolled into three mAb114 dose groups of 5 mg/kg, 25 mg/kg, and 50 mg/kg. The drug was given to participants intravenously over 30 min, and participants were followed for 24 weeks. Participants were only enrolled into increased dosing groups after interim safety assessments. Our primary endpoints were safety and tolerability, with pharmacokinetic and anti-drug antibody assessments as secondary endpoints. We assessed safety and tolerability in all participants who received study drug by monitoring clinical laboratory data and self-report and direct clinician assessment of prespecified infusion-site symptoms 3 days after infusion and systemic symptoms 7 days after infusion. Unsolicited adverse events were recorded for 28 days. Pharmacokinetic and anti-drug antibody assessments were completed in participants with at least 56 days of data. This trial is registered with ClinicalTrials. gov, number NCT03478891, and is active but no longer recruiting.Findings Between May 16, and Sept 27, 2018, 19 eligible individuals were enrolled. One (5%) participant was not infused because intravenous access was not adequate. Of 18 (95%) remaining participants, three (17%) were assigned to the 5 mg/kg group, five (28%) to the 25 mg/kg group, and ten (55%) to the 50 mg/kg group, each of whom received a single infusion of mAb114 at their assigned dose. All infusions were well tolerated and completed over 30-37 min with no infusion reactions or rate adjustments. All participants who received the study drug completed the safety assessment of local and systemic reactogenicity. No participants reported infusion-site symptoms. Systemic symptoms were all mild and present only in four (22%) of 18 participants across all dosing groups. No unsolicited adverse events occurred related to mAb114 and one serious adverse event occurred that was unrelated to mAb114. mAb114 has linear pharmacokinetics and a half-life of 24.2 days (standard error of measurement 0.2) with no evidence of anti-drug antibody development.Interpretation mAb114 was well tolerated, showed linear pharmacokinetics, and was easily and rapidly infused, making it an attractive and deployable option for treatment in outbreak settings.Funding Vaccine Research Center, US National Institute of Allergy and Infectious Diseases, and NIH. Copyright (c) 2019 Elsevier Ltd. All rights reserved.