Julg Boris, Walker-Sperling Victoria E K, Wagh Kshitij, Aid Malika, Stephenson Kathryn E, Zash Rebecca, Liu Jinyan, Nkolola Joseph P, Hoyt Amelia, Castro Mike, Serebryannyy Leonid, Yanosick Katherine, Speidel Tessa, Borducchi Erica N, Murzda Tetyana, Maxfield Lori, Arduino Roberto, McDermott Adrian B, Gama Lucio, Giorgi Elena E, Koup Richard A, Seaman Michael S, Rolle Charlotte-Paige, DeJesus Edwin, Li Wenjun, Korber Bette, Barouch Dan H
Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA.
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Nat Med. 2024 Dec;30(12):3534-3543. doi: 10.1038/s41591-024-03247-5. Epub 2024 Sep 12.
Human immunodeficiency virus type 1 (HIV-1)-specific broadly neutralizing monoclonal antibodies (bNAbs) have to date shown transient viral suppression when administered as monotherapy or as a cocktail of two antibodies. A combination of three bNAbs provides improved neutralization coverage of global viruses, which may more potently suppress viral escape and rebound. Here we performed an open-label, two-part study evaluating a single intravenous dose of HIV-1 bNAbs, PGT121, PGDM1400 and VRC07-523LS, in six adults without HIV in part 1 and a multicenter trial of up to six monthly infusions of these three bNAbs in 12 people living with HIV with an antiretroviral therapy (ART) interruption in part 2. The primary endpoints were safety, tolerability and pharmacokinetics, and the secondary endpoints in part 2 were antiviral activity following ART discontinuation, changes in CD4 T cell counts and development of HIV-1 sequence mutations associated with bNAb resistance. The trial met its prespecified endpoints. The bNAb treatment was generally safe and well tolerated. In part 2, 83% of participants (10 of 12) maintained virologic suppression for the duration of antibody therapy for at least 28 weeks, and 42% of participants (5 of 12) showed virologic suppression for at least 38-44 weeks, despite the decline of serum bNAb concentrations to low or undetectable levels. In exploratory analyses, early viral rebound in two individuals correlated with baseline resistance to PGT121 and PGDM1400, whereas long-term virologic control in five individuals correlated with reduced immune activation, T cell exhaustion and proinflammatory signaling following bNAb therapy. Our data show the potential of a triple bNAb cocktail to suppress HIV-1 in the absence of ART. ClinicalTrials.gov registration: NCT03721510 .
1型人类免疫缺陷病毒（HIV-1）特异性广谱中和单克隆抗体（bNAbs），迄今为止，在作为单一疗法或两种抗体的鸡尾酒疗法给药时，已显示出短暂的病毒抑制作用。三种bNAb的组合可提高对全球病毒的中和覆盖范围，这可能更有效地抑制病毒逃逸和反弹。在此，我们进行了一项开放标签、两部分的研究，在第1部分中评估了单剂量静脉注射HIV-1 bNAbs（PGT121、PGDM1400和VRC07-523LS）对6名未感染HIV的成年人的影响，在第2部分中进行了一项多中心试验，对12名接受抗逆转录病毒疗法（ART）中断治疗的HIV感染者进行了长达6个月的这三种bNAb的输注。主要终点是安全性、耐受性和药代动力学，第2部分的次要终点是ART停药后的抗病毒活性、CD4 T细胞计数的变化以及与bNAb耐药相关的HIV-1序列突变的发生情况。该试验达到了预先设定的终点。bNAb治疗总体上是安全的且耐受性良好。在第2部分中，83%的参与者（12名中的10名）在抗体治疗期间至少28周维持了病毒学抑制，42%的参与者（12名中的5名）尽管血清bNAb浓度降至低水平或检测不到水平，但仍显示出至少38 - 44周的病毒学抑制。在探索性分析中，两名个体的早期病毒反弹与对PGT121和PGDM1400的基线耐药相关，而五名个体的长期病毒学控制与bNAb治疗后免疫激活降低、T细胞耗竭和促炎信号传导减少相关。我们的数据显示了三联bNAb鸡尾酒疗法在无ART情况下抑制HIV-1的潜力。ClinicalTrials.gov注册号：NCT03721510 。
