BACKGROUND Multiple broadly neutralising monoclonal antibodies (mAbs) are in development for HIV-1 prevention. The aim of this trial was to test the PGT121.414.LS and VRC07-523LS mAbs for safety and pharmacokinetics in adults. METHODS In this first-in-human phase 1 trial (HVTN 136/HPTN 092), adults without HIV were enrolled at six university-affiliated clinical research sites in the USA. Part A evaluated escalating single intravenous doses or subcutaneous infusion of PGT121.414.LS, in four groups: 3 mg/kg intravenous (treatment group 1; n=3), 10 mg/kg intravenous (treatment group 2; n=4), 30 mg/kg intravenous (treatment group 3; n=3), and 5 mg/kg subcutaneous (treatment group 4; n=3). Part B evaluated repeated sequential intravenous administrations of 20 mg/kg PGT121.414.LS plus 20 mg/kg VRC07-523LS (treatment group 5; n=10) and sequential subcutaneous administrations of 5 mg/kg PGT121.414.LS plus 5 mg/kg VRC07-523LS (treatment group 6; n=10) on days 0, 112, and 224. Participants in treatment groups 1 and 2 were enrolled sequentially, with participants enrolled and randomly assigned to treatment groups 3 and 4 after a review of safety data. Participants in treatment groups 5 and 6 were randomly assigned in blocks after a review of safety data from treatment groups 1-4. The primary endpoints were safety and tolerability of mAbs, serum concentrations and pharmacokinetics of mAbs, and serum neutralising activity, assessed in participants who received all scheduled product administrations. Serum concentrations of each mAb were measured via a multiplex assay, and neutralisation activity against multiple HIV viruses was measured via the TZM-bl assay. Serum concentrations were estimated via an open, two-compartment model with first-order elimination from the central compartment. This study was registered with ClinicalTrials.gov (NCT04212091) and has been completed. FINDINGS Between Nov 10, 2020, and Oct 5, 2021, we enrolled 33 participants without HIV: median age was 31 years (range 22-48); 19 were assigned female sex at birth and 11 were assigned male sex at birth. Three participants and four participants were sequentially assigned to treatment groups 1 and 2, respectively, and, after safety review, six participants were randomly assigned to treatment groups 3 (n=3) and 4 (n=3); after safety review, 20 participants were randomly assigned to treatment groups 5 (n=10) and 6 (n=10). Intravenous and subcutaneous infusions were safe and well tolerated, without serious adverse events or dose-limiting toxicities. Dose escalation of PGT121.414.LS from 3 mg/kg to 30 mg/kg (intravenous) resulted in a dose-proportional increase in serum concentration of PGT121.414.LS, whether administered alone or in combination with VRC07-523LS. The estimated elimination half-life of PGT121.414.LS was 71 days (95% CI 66-75), three times that of its parental form, PGT121. The estimated subcutaneous (vs intravenous) bioavailability of PGT121.414.LS was 86·1% (95% CI 64·0-95·5). Neutralisation activities were greater in the higher-dose and dual combination intravenous groups than in the subcutaneous administration groups. INTERPRETATION These findings support further evaluation of PGT121.414.LS in combination with other mAbs for HIV-1 prevention. FUNDING US National Institute of Allergy and Infectious Diseases and US National Institutes of Health.

中文翻译：

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在美国没有 HIV 的成人中单独给药和与 VRC07-523LS 联合给药的抗 HIV-1 单克隆 PGT121.414.LS 抗体的安全性、耐受性、药代动力学和中和活性 （HVTN 136/HPTN 092）：一项首次人体、开放标签、随机对照 1 期试验。


背景 多种广泛中和单克隆抗体 （mAb） 正在开发中，用于预防 HIV-1。该试验的目的是测试 PGT121.414.LS 和 VRC07-523LS mAb 在成人中的安全性和药代动力学。方法 在这项首次人体 1 期试验 （HVTN 136/HPTN 092） 中，没有 HIV 的成年人在美国的六个大学附属临床研究地点招募。A 部分评估了增加单次静脉注射剂量或皮下输注 PGT121.414.LS，分为四组：3 mg/kg 静脉注射（治疗组 1;n=3）、10 mg/kg 静脉注射（治疗组 2;n=4）、30 mg/kg 静脉注射（治疗组 3;n=3）和 5 mg/kg 皮下注射（治疗组 4;n=3）。B 部分评估了 20 mg/kg PGT121.414.LS 加 20 mg/kg VRC07-523LS 的重复序贯静脉给药（治疗组 5;n=10）和 5 mg/kg PGT121.414.LS 加 5 mg/kg VRC07-523LS 的序贯皮下给药（治疗组 6;n=10）在第 0 天、第 112 天和第 224 天。治疗组 1 和 2 的参与者按顺序入组，参与者在审查安全性数据后入组并随机分配到治疗组 3 和 4。在审查治疗组 1-4 的安全数据后，治疗组 5 和 6 的参与者被随机分配到块中。主要终点是 mAb 的安全性和耐受性、mAb 的血清浓度和药代动力学以及血清中和活性，在接受所有预定产品给药的参与者中进行评估。通过多重测定法测定每种 mAb 的血清浓度，并通过 TZM-bl 测定法测定对多种 HIV 病毒的中和活性。 通过开放的两室模型估计血清浓度，从中央室一阶消除。这项研究已在 ClinicalTrials.gov （NCT04212091） 注册并已完成。结果 在 2020 年 11 月 10 日至 2021 年 10 月 5 日期间，我们招募了 33 名没有 HIV 的参与者：中位年龄为 31 岁（范围 22-48）;19 例出生时被分配为女性，11 例在出生时被分配为男性。3 名参与者和 4 名参与者分别被依次分配到治疗组 1 和 2，经过安全性审查，6 名参与者被随机分配到治疗组 3 （n=3） 和 4 （n=3）;安全性评价后，将 20 名参与者随机分配到治疗组 5 （n=10） 和治疗组 6 （n=10）。静脉内和皮下输注安全且耐受性良好，无严重不良事件或剂量限制性毒性。PGT121.414.LS 剂量从 3 mg/kg 增加到 30 mg/kg（静脉内）导致血清浓度 PGT121.414.LS 的剂量成比例增加，无论是单独给药还是与 VRC07-523LS 联合给药。PGT121.414.LS 的估计消除半衰期为 71 天 （95% CI 66-75），是其亲本形式 PGT121 的三倍。PGT121.414.LS 的估计皮下 （vs静脉内） 生物利用度为 86·1% （95% CI 64·0-95·5）。高剂量和双重联合静脉注射组的中和活性高于皮下给药组。解释这些发现支持进一步评估 PGT121.414.LS 与其他 mAb 联合预防 HIV-1。资助 美国国家过敏和传染病研究所和美国国立卫生研究院。