安全性、耐受性、药物动力学和治疗性单克隆抗体的免疫原性mAb114针对埃博拉病毒糖蛋白(VRC 608):一个开放的第一阶段研究。

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Gaudinski先生、科茨EE Novik L, Widge,豪斯KV,伯奇E,霍尔曼洛杉矶,戈登IJ,陈GL,卡特C内M,锡塔尔琴,Yamshchikov G, Berkowitz N,安德鲁斯C,巴斯克斯,Laurencot C, Misasi J,阿诺德F,卡尔顿K, Lawlor H, Gall J,水斗RT,麦克德莫特,Capparelli E, Koup RA, Mascola JR,格雷厄姆BS,沙利文新泽西,Ledgerwood我

安全性、耐受性、药物动力学和治疗性单克隆抗体的免疫原性mAb114针对埃博拉病毒糖蛋白(VRC 608):一个开放的第一阶段研究。

柳叶刀》。2019年3月2;393 (10174):889 - 898。doi: 10.1016 / s0140 - 6736 (19) 30036 - 4。Epub 2019年1月24日。

PubMed ID
30686586 (在PubMed
]
文摘

背景:mAb114是一个目标的单克隆抗体埃博拉病毒糖蛋白受体结合域,从而防止在恒河猴治疗死亡率与扎伊尔ebolavirus致命的挑战。VRC 608,这里我们提出加快数据从第一阶段的研究来评估mAb114安全,耐受性,药物动力学和免疫原性。方法:在这一阶段1中,剂量递增研究(VRC 608),由美国国家卫生研究院(NIH)临床中心(贝塞斯达,医学博士,美国),年龄在18 - 60岁之间的健康成人年顺序登记为三个mAb114剂量组5毫克/公斤,25毫克/公斤和50毫克/公斤。静脉注射毒品给参与者超过30分钟,和参与者随访24周。参与者只登记分为增加剂量组后临时安全评估。我们主要的端点的安全性和耐受性,药代动力学和禁毒抗体评估作为次要的端点。我们评估在所有参与者接受研究药物安全性和耐受性通过监测临床实验室数据和自我报告和直接指定临床医生评估infusion-site症状3天后灌注和系统性症状输液后7天。不请自来的不良事件记录为28天。药代动力学和禁毒抗体评估完成后在参与者至少56天的数据。这个试验是在ClinicalTrials.gov注册,NCT03478891数量,但不再招聘很活跃。 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.

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