小柯机器人

美国贝斯以色列女执事医疗中心Dan H. Barouch团队完成HIV-1广谱中和单克隆抗体PGT121的1期临床试验。该研究于2021年10月7日在线发表于国际一流学术期刊《自然—医学》。

研究人员进行了一项单中心、随机、双盲、剂量递增、安慰剂对照的试验，对未感染HIV的成人和接受抗逆转录病毒疗法（ART）的HIV感染成人进行了一次3、10和30mg kg^-1的HIV-1 V3-聚糖特异性抗体PGT121输液，还进行了一项多中心、开放标签的试验，对未接受ART的病毒感染成人进行了一次30mg kg^-1的PGT121输液（编号NCT02960581) 主要终点是安全性和耐受性、药代动力学（PK）和未接受抗逆转录病毒疗法的成年艾滋病毒感染者的抗病毒活性。次要终点是抗PGT121抗体滴度和CD4⁺ T细胞数的变化，以及与PGT121抗性相关的HIV-1序列变异进展。

在48名入组的参与者中，没有报告与治疗相关的严重不良事件、潜在的免疫介导疾病或3级或以上的不良事件。PGT121接受者中最常见的反应是静脉内/注射部位触痛、疼痛和头痛。在HIV感染者输注PGT121后，绝对和相对的CD4⁺ T细胞计数没有变化。中和性抗药性抗体没有被激发出来。PGT121使病毒感染者的血浆HIV RNA水平中位数降低了1.77 log，病毒载量中位数为8.5天时达到最低点。两个基线病毒载量低的人在输注抗体后经历了≥168天的无抗逆转录病毒抑制，这些人的反弹病毒显示了对PGT121的完全或部分敏感性。该试验达到了预设的终点。

这些数据表明，需要进一步研究基于抗体的治疗策略在长期抑制HIV方面的潜力，包括在停止抗逆转录病毒疗法和低病毒负荷的个体中。

据介绍，HIV-1特异性广谱中和单克隆抗体目前正在开发中，被用于治疗和预防HIV-1感染。

附：英文原文

Title: Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial

Author: Stephenson, Kathryn E., Julg, Boris, Tan, C. Sabrina, Zash, Rebecca, Walsh, Stephen R., Rolle, Charlotte-Paige, Monczor, Ana N., Lupo, Sofia, Gelderblom, Huub C., Ansel, Jessica L., Kanjilal, Diane G., Maxfield, Lori F., Nkolola, Joseph, Borducchi, Erica N., Abbink, Peter, Liu, Jinyan, Peter, Lauren, Chandrashekar, Abishek, Nityanandam, Ramya, Lin, Zijin, Setaro, Alessandra, Sapiente, Joseph, Chen, Zhilin, Sunner, Lisa, Cassidy, Tyler, Bennett, Chelsey, Sato, Alicia, Mayer, Bryan, Perelson, Alan S., deCamp, Allan, Priddy, Frances H., Wagh, Kshitij, Giorgi, Elena E., Yates, Nicole L., Arduino, Roberto C., DeJesus, Edwin, Tomaras, Georgia D., Seaman, Michael S., Korber, Bette, Barouch, Dan H.

Issue&Volume: 2021-10-07

Abstract: Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30mgkg–1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30mgkg–1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77log in viremic participants, with a viral load nadir at a median of 8.5days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load.

DOI: 10.1038/s41591-021-01509-0

Source: https://www.nature.com/articles/s41591-021-01509-0

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
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