Safety and pharmacokinetics of broadly neutralising human monoclonal antibody VRC07-523LS in healthy adults: a phase 1 dose-escalation clinical trial
Safety and pharmacokinetics of broadly neutralising human monoclonal antibody VRC07-523LS in healthy adults: a phase 1 dose-escalation clinical trial
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DOI：
10.1016/s2352-3018(19)30181-x
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发表时间：
2019-10-01
期刊：
影响因子：
16.1
通讯作者：
Stein, Judy
中科院分区：
文献类型：
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作者：
Gaudinski, Martin R.;Houser, Katherine V.;Stein, Judy
人类单克隆抗体，有效和广泛中和HIV-1正在开发中，以预防和治疗HIV-1感染。在这个阶段1临床试验，我们的目的是确定广泛中和的单克隆抗体VRC 07 - 523 LS，VRC 01的工程变体，目标的HIV-1包膜蛋白的CD 4结合位点的安全性，耐受性和药代动力学特征。方法这个阶段1，开放标签，剂量递增的临床试验是在美国国立卫生研究院临床中心贝塞斯达，MD，美国。通过IRB批准的书面和电子媒体从大华盛顿，DC地区招募个人。我们招募了18-50岁的健康、HIV-1阴性成年人。入选标准为良好的一般健康状况，通过临床实验室检查、病史和体格检查进行测量。参与者在招募期间自行选择进入七个开放组之一，而不进行随机分配。四组接受1、5、20或40 mg/kg的VRC 07 - 523 LS单次静脉内给药，一组接受5 mg/kg单次皮下给药。两组以12周的间隔接受三次剂量的20 mg/kg静脉内VRC 07 - 523 LS或5 mg/kg皮下VRC 07 -523 LS。主要结局是VRC 07 - 523 LS的安全性和耐受性，通过剂量、途径和给药次数进行评估。这项研究注册于ClinicalTrials.gov，NCT 03015181。结果在2017年2月21日至2017年9月13日期间，我们招募了26名参与者，包括11名（42%）男性和15名（58%）女性。2例（8%）受试者提前退出研究：第1组1例受试者入组研究但从未接受过VRC 07 - 523 LS，第6组1例受试者在单次给药后选择退出。第7组中有1例（4%）受试者仅接受了3次计划给药中的1次。17名参与者接受静脉给药，8名参与者接受皮下给药。VRC 07 - 523 LS安全且耐受性良好，我们未观察到严重不良事件或剂量限制性毒性作用。所有报告的局部和全身反应原性的严重程度均为轻度至中度。静脉给药后最常报告的症状为3例（18%）受试者的不适或肌痛，2例（12%）受试者的头痛或寒战。皮下给药后最常报告的症状是疼痛和触痛，四名参与者（50%）和不适或头痛，三名（38%）participator.Interpretation安全和耐受性良好，VRC 07 - 523 LS是一个强大的和实用的候选人列入HIV-1预防和治疗策略。该试验的结果还表明，经工程改造以改善药代动力学和中和特性的HIV-1广泛中和单克隆抗体可安全用于临床。版权所有（C）2019 Elsevier Ltd.保留所有权利。
Background Human monoclonal antibodies that potently and broadly neutralise HIV-1 are under development to prevent and treat HIV-1 infection. In this phase 1 clinical trial we aimed to determine the safety, tolerability, and pharmacokinetic profile of the broadly neutralising monoclonal antibody VRC07-523LS, an engineered variant of VRC01 that targets the CD4 binding site of the HIV-1 envelope protein.Methods This phase 1, open-label, dose-escalation clinical trial was done at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Individuals were recruited from the greater Washington, DC, area by IRB-approved written and electronic media. We enrolled healthy, HIV-1-negative adults aged 18-50 years. Inclusion criteria were good general health, measured through clinical laboratory tests, medical history, and physical examination. Participants self-selected into one of seven open groups during enrolment without randomisation. Four groups received a single intravenous dose of 1, 5, 20, or 40 mg/kg of VRC07-523LS, and one group received a single 5 mg/kg subcutaneous dose. Two groups received three doses of either 20 mg/kg intravenous VRC07-523LS, or 5 mg/kg subcutaneous VRC07-523 LS at 12-week intervals. The primary outcome was the safety and tolerability of VRC07-523LS, assessed by dose, route, and number of administrations. This study is registered with ClinicalTrials.gov , NCT03015181.Findings Between Feb 21, 2017, and September 13, 2017, we enrolled 26 participants, including 11 (42%) men and 15 (58%) women. Two (8%) participants withdrew from the study early: one participant in group 1 enrolled in the study but never received VRC07-523LS, and one participant in group 6 chose to withdraw after a single administration. One (4%) participant in group 7 received only one of the three scheduled administrations. 17 participants received intravenous administrations and 8 participants received subcutaneous administrations. VRC07-523LS was safe and well tolerated, we observed no serious adverse events or dose-limiting toxic effects. All reported local and systemic reactogenicity was mild to moderate in severity. The most commonly reported symptoms following intravenous administration were malaise or myalgia in three (18%) participants and headache or chills in two (12%) participants. The most commonly reported symptoms following subcutaneous administration were pain and tenderness in four participants (50%) and malaise or headache in three (38%) participants.Interpretation Safe and well tolerated, VRC07-523LS is a strong and practical candidate for inclusion in HIV-1 prevention and therapeutic strategies. The results from this trial also indicate that an HIV-1 broadly neutralising monoclonal antibody engineered for improved pharmacokinetic and neutralisation properties can be safe for clinical use. Copyright (C) 2019 Elsevier Ltd. All rights reserved.