Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults.
Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults.
复制标题
FC修饰的HIV-1人单克隆抗体VRC01LS的安全性和药代动力学：健康成年人中的1期开放标签临床试验。
DOI：
10.1371/journal.pmed.1002493
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发表时间：
2018-01
期刊：
影响因子：
15.8
通讯作者：
VRC 606 Study Team
中科院分区：
文献类型：
--
作者：
Gaudinski MR;Coates EE;Houser KV;Chen GL;Yamshchikov G;Saunders JG;Holman LA;Gordon I;Plummer S;Hendel CS;Conan-Cibotti M;Lorenzo MG;Sitar S;Carlton K;Laurencot C;Bailer RT;Narpala S;McDermott AB;Namboodiri AM;Pandey JP;Schwartz RM;Hu Z;Koup RA;Capparelli E;Graham BS;Mascola JR;Ledgerwood JE;VRC 606 Study Team
VRC01是一种针对HIV-1包膜糖蛋白（Env） cd4结合位点的人宽中和单克隆抗体（bnMAb），目前正在IIb期成人HIV-1预防疗效试验中进行评估。VRC01LS是VRC01的改良版本，旨在通过增加与新生儿Fc受体的结合亲和力来延长血清半衰期。这项VRC01LS在hiv阴性健康成人中的I期剂量递增研究由美国国立卫生研究院（NIH）临床中心（Bethesda， MD）的疫苗研究中心（VRC）进行。研究志愿者的年龄范围为21-50岁；51%的研究志愿者为男性，49%为女性。主要目标是VRC01LS的安全性和耐受性，静脉滴注剂量分别为5mg /kg、20mg /kg和40mg /kg，每隔12周给药3次，皮下滴注剂量为5mg /kg，每隔12周给药1次或3次。次要目标是药代动力学（PK），血清中和活性和抗药物抗体的发展。2015年11月16日入学，2017年8月23日入学。本报告描述了前37名接受VRC01LS治疗的志愿者的安全数据。没有严重不良事件（SAEs）或剂量限制性毒性。轻度不适和肌痛是最常见的不良事件（ae）。有6例ae被评估为可能与VRC01LS相关，所有ae的严重程度均为轻度，并在研究期间得到缓解。根据首批25名志愿者完成评估时间表的第一剂量VRC01LS，对PK数据进行建模。1次静脉给药20 mg/kg或40 mg/kg后12周的平均（±SD）血药浓度分别为180±43 μg/mL （n = 7）和326±35 μg/mL （n = 5）。1次静脉注射和5 mg/kg皮下注射后12周的平均（±SD）血清浓度分别为40±3 μg/mL （n = 2）和25±5 μg/mL （n = 9）。在5 ~ 40mg /kg IV剂量范围内（n = 16），清除率为36±8ml /d，消除半衰期为71±18天。VRC01LS在血清中保留了预期的中和活性，未检测到抗vrc01抗体反应。本研究的潜在局限性包括典型的I期试验的小样本量，以及需要进一步描述VRC01LS在多种情况下的PK特性。人bnMAb VRC01LS在静脉或皮下给药时是安全且耐受性良好的。与野生型VRC01历史数据相比，半衰期延长了4倍以上。减少的清除率和延长的半衰期可能使其在较少频率和较低剂量的给药下达到治疗水平。这将潜在地降低制造成本，并提高使用被动给药单克隆抗体（mab）预防HIV-1感染的实用性。John Mascola和他的同事研究了VRC01LS的安全性和药代动力学，VRC01LS是一种广泛中和的抗hiv -1抗体，在健康人的血清中具有较长的半衰期。尽管传统的预防战略有所改进，但新的艾滋病毒-1感染仍在继续发生。预防获得艾滋病毒-1感染的新干预措施可能有助于扭转这一全球流行病的趋势。已经发现了能够中和许多HIV-1毒株的人单克隆抗体。这些抗体被称为广泛中和抗体（bnAbs），可以作为生物药物生产，它们保护人们免受HIV-1感染的能力正在研究中。这项研究评估了一种新形式的HIV-1抗体，这种抗体比传统抗体在血液中停留的时间更长。如果抗体在血液中停留的时间更长，那么人们可能会被保护更长的时间，并且需要更少的剂量。我们修改了一种名为VRC01的抗体，使其在血液中停留的时间更长。这种改良抗体VRC01LS的工作原理是利用人体循环利用自身抗体的方式，使身体阻止VRC01LS被分解。我们首次将VRC01LS用于健康成人，以了解它的安全性，并了解与未经修饰的VRC01相比，它在体内停留的时间。本研究发现VRC01LS是安全的。虽然有些人受到轻微肌肉疼痛和疲劳的困扰，但对参与者来说，没有严重的健康后果。与VRC01的历史数据相比，VRC01LS在血液中的停留时间是VRC01的4倍多。人们血液中的VRC01LS保留了中和HIV-1病毒的能力，正如它在实验室中所显示的那样。我们的发现意味着，对VRC01进行修改以产生VRC01LS，当与其他类似的抗体结合时可能是有用的，这些抗体正在开发中，希望生产预防HIV-1感染的药物。我们的发现也意味着这些HIV-1抗体可能需要更少的剂量来保护，从而降低产品成本。
VRC01 is a human broadly neutralizing monoclonal antibody (bnMAb) against the CD4-binding site of the HIV-1 envelope glycoprotein (Env) that is currently being evaluated in a Phase IIb adult HIV-1 prevention efficacy trial. VRC01LS is a modified version of VRC01, designed for extended serum half-life by increased binding affinity to the neonatal Fc receptor. This Phase I dose-escalation study of VRC01LS in HIV-negative healthy adults was conducted by the Vaccine Research Center (VRC) at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD). The age range of the study volunteers was 21–50 years; 51% of study volunteers were male and 49% were female. Primary objectives were safety and tolerability of VRC01LS intravenous (IV) infusions at 5, 20, and 40 mg/kg infused once, 20 mg/kg given three times at 12-week intervals, and subcutaneous (SC) delivery at 5 mg/kg delivered once, or three times at 12-week intervals. Secondary objectives were pharmacokinetics (PK), serum neutralization activity, and development of antidrug antibodies. Enrollment began on November 16, 2015, and concluded on August 23, 2017. This report describes the safety data for the first 37 volunteers who received administrations of VRC01LS. There were no serious adverse events (SAEs) or dose-limiting toxicities. Mild malaise and myalgia were the most common adverse events (AEs). There were six AEs assessed as possibly related to VRC01LS administration, and all were mild in severity and resolved during the study. PK data were modeled based on the first dose of VRC01LS in the first 25 volunteers to complete their schedule of evaluations. The mean (±SD) serum concentration 12 weeks after one IV administration of 20 mg/kg or 40 mg/kg were 180 ± 43 μg/mL (n = 7) and 326 ± 35 μg/mL (n = 5), respectively. The mean (±SD) serum concentration 12 weeks after one IV and SC administration of 5 mg/kg were 40 ± 3 μg/mL (n = 2) and 25 ± 5 μg/mL (n = 9), respectively. Over the 5–40 mg/kg IV dose range (n = 16), the clearance was 36 ± 8 mL/d with an elimination half-life of 71 ± 18 days. VRC01LS retained its expected neutralizing activity in serum, and anti-VRC01 antibody responses were not detected. Potential limitations of this study include the small sample size typical of Phase I trials and the need to further describe the PK properties of VRC01LS administered on multiple occasions. The human bnMAb VRC01LS was safe and well tolerated when delivered intravenously or subcutaneously. The half-life was more than 4-fold greater when compared to wild-type VRC01 historical data. The reduced clearance and extended half-life may make it possible to achieve therapeutic levels with less frequent and lower-dose administrations. This would potentially lower the costs of manufacturing and improve the practicality of using passively administered monoclonal antibodies (mAbs) for the prevention of HIV-1 infection. ClinicalTrials.gov NCT02599896 John Mascola and colleagues study the safety and pharmacokinetics of VRC01LS, a broadly neutralizing anti-HIV-1 antibody designed to have an extended half-life in serum, in healthy people. New HIV-1 infections continue to occur despite improvements in traditional prevention strategies. Novel interventions to prevent acquisition of HIV-1 infection may help to turn the tide of the global pandemic. Human monoclonal antibodies capable of neutralizing many strains of HIV-1 have been discovered. These antibodies, referred to as broadly neutralizing antibodies (bnAbs), can be produced as biologic medications and their ability to protect people from HIV-1 infection is being investigated. This study evaluated a new form of an HIV-1 antibody with the potential to remain in the blood for a longer period of time than traditional antibodies. If the antibodies stay in the blood longer, then people may be protected for longer periods of time and require less frequent dosing. We modified a promising antibody called VRC01 so that it stays in the blood for a longer period of time. The modified antibody, VRC01LS, works by taking advantage of how the body recycles its own antibodies, so that the body prevents VRC01LS from being broken down. We gave VRC01LS to healthy adults for the first time, to see how safe it was and to understand how long it stays in the body compared to unmodified VRC01. In this study, VRC01LS was found to be safe. There were no serious health consequences for participants, although some people were bothered by mild muscle aches and feeling tired. Compared to historical data for VRC01, VRC01LS stays in the blood more than four times longer than VRC01. The VRC01LS in people’s blood retained the ability to neutralize the HIV-1 virus, as it has been shown to do in the laboratory. Our findings mean that the modifications made to VRC01 to produce VRC01LS may be useful when incorporated into other, similar antibodies that are being developed in the hope of producing medications to prevent HIV-1 infection. Our findings also mean that fewer doses of these HIV-1 antibodies may be required for protection, thus reducing product cost.
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影响因子：
8.7
作者：
Julien JP;Lee PS;Wilson IA
通讯作者：
Wilson IA
影响因子：
8.7
作者：
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影响因子：
2.2
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影响因子：
64.8
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通讯作者：
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影响因子：
5.4
作者：
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通讯作者：
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