HIV-1 dynamics and evolution during trispecific broadly neutralizing antibody therapy

三特异性广泛中和抗体治疗期间的 HIV-1 动力学和进化

基本信息

批准号：
10258850
负责人：
Daniel R. Kuritzkes
金额：
$ 82.16万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-08 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10258850
关键词：
AIDS clinical trial group Acquired Immunodeficiency Syndrome Affect Antibodies Antibody Therapy Antiviral Agents Binding Binding Sites Biological Biology Blood Cells Clear Cell Clinical Cloning Data Dose Drug Kinetics Engineering Evolution Genes Genome Glycoproteins Goals HIV HIV Envelope Protein gp120 HIV-1 HIV-1 vaccine Human Immune Immune response Individual Infection Infusion procedures Kinetics Length Link Macaca Maps Membrane Methods Modeling Molecular Virology Participant Peripheral Blood Mononuclear Cell Phase Phylogenetic Analysis Plasma Polysaccharides Population Predisposition Proteins RNA Resistance Role Safety Sampling Satellite Viruses Sequence Analysis Site Specificity Structure Surface Techniques Testing Therapeutic Time Translating Vaccine Research Variant Viral Viral load measurement Viremia Virus antigen binding antiretroviral therapy arm first-in-human follow-up glycosylation human study humanized mouse in vivo innovation laboratory experiment mathematical methods neutralizing antibody next generation sequencing nonhuman primate novel pressure response simian human immunodeficiency virus single molecule synthetic antibodies trial design

项目摘要

Abstract After years of infection, a small subset of people with HIV can develop broadly neutralizing antibodies (bnAbs), defined as antibodies that neutralize a diverse range of HIV isolates. While eliciting bnAbs is a central focus of HIV-1 vaccine research, bnAbs may have additional roles as long-acting biologic antiretroviral therapy or as an immune effector arm in virus eradication studies. Broadly neutralizing antibodies target the HIV-1 envelope glycoproteins, heterotrimers of surface gp120 and transmembrane gp41 molecules, that are 50% glycan by mass. The cloning of antibody genes from individuals with HIV identified new bnAbs with increasing potency and breadth of neutralization that have been studied clinically as HIV-1 treatment. Whereas single infusions of bnAbs can reduce plasma virus loads in people with HIV, virus variants resistant to the individual bnAb emerge quickly and limit the activity and therapeutic potential of bnAb monotherapy. Classically, an antibody molecule contains an Fc region linked to two Fab regions with identical antigen binding sites. Recently, an antibody was engineered that combined three distinct Fab regions into a single molecule. SAR441236 is a tri-specific bnAb that combines the CD4bs specificity of VRC01-LS, the V1/V2 glycan-directed binding of PGDM1400, and the gp41 MPER binding of 10E8v4 into one antibody molecule. ACTG A5377 is a phase I first-in-human study of SAR441236 that investigates the safety, pharmacokinetics (PK), and anti-HIV-1 activity of this novel trispecific bnAb. A maximum of thirty viremic participants will be studied in a single infusion dose de-escalation trial design with 24 weeks of follow-up. The goal of this proposal is to leverage samples from A5377 to determine if HIV-1 decay in response to “triple” biologic ART differs from conventional combination ART and to define the mechanisms of virus escape from a trispecific bnAb. The purpose of this proposal is to combine innovative experimental and mathematical approaches with classic molecular virology to characterize the decay of viremia and define the mechanisms of HIV-1 escape from this first-in-class trispecific bnAb. We hypothesize that the trispecific bnAb, SAR441236, clears cell-free and cell-associated virus from blood, induces large and dynamic population shifts in the HIV-1 env quasispecies, and selects for virus escape variants at the protein and glycan level to maintain infectivity in the presence of bnAb. Specific Aims of this proposal are to determine the kinetics of SAR441236-induced HIV- 1 decay, understand the effects of SAR441236 on HIV-1 env quasispecies, and define the HIV-1 env and glycan shield determinants of SAR441236 resistance. Our approaches test hypotheses that are central to understand the dynamics and evolution of HIV-1 under a trispecific bnAb selection pressure.

抽象的经过多年的感染，一小部分艾滋病毒感染者可以产生广泛的中和抗体 (bnAbs)，定义为中和多种 HIV 分离株的抗体，而引发 bnAbs 是一个核心。作为 HIV-1 疫苗研究的焦点，bnAb 可能具有作为长效生物抗逆转录病毒疗法的额外作用或作为病毒根除研究中的免疫效应臂。广泛中和抗体靶向 HIV-1 包膜糖蛋白、表面 gp120 的异三聚体和跨膜 gp41 分子，其质量百分比为 50% 抗体基因的克隆。 HIV 感染者发现了新的 bnAb，其中和效力和中和广度不断增强。作为 HIV-1 治疗进行了临床研究，而单次输注 bnAb 可以减少人体内的血浆病毒载量。对于 HIV，对单个 bnAb 具有抗性的病毒变体很快出现，并限制了其活性和治疗 bnAb 单一疗法的潜力。传统上，抗体分子包含一个 Fc 区，与两个具有相同抗原的 Fab 区相连最近，一种抗体被设计成将三个不同的 Fab 区域组合成一个单一的。 SAR441236 是一种三特异性 bnAb，结合了 VRC01-LS（V1/V2）的 CD4bs 特异性。 PGDM1400 的聚糖定向结合，以及 10E8v4 的 gp41 MPER 结合到一个抗体分子中。 ACTG A5377 是 SAR441236 的 I 期首次人体研究，研究安全性、药代动力学（PK），以及这种新型三特异性 bnAb 的抗 HIV-1 活性。最多 30 名病毒血症参与者。在单次输注剂量降阶梯试验设计中进行研究，并进行 24 周的随访。该提案的目标是利用 A5377 的样本来确定 HIV-1 是否会因响应而衰减 “三重”生物ART不同于传统的组合ART并定义病毒逃逸机制该提案的目的是将创新的实验和数学结合起来。使用经典分子病毒学方法来表征病毒血症的衰变并定义病毒血症的机制 HIV-1 从这种一流的三特异性 bnAb 中逃脱我们捕获了三特异性 bnAb，SAR441236，清除血液中的无细胞和细胞相关病毒，诱导 HIV-1 发生大规模动态群体变化 env 准种，并在蛋白质和聚糖水平上选择病毒逃逸变体以维持感染性该提案的具体目的是确定 SAR441236 诱导的 HIV-的动力学。 1 衰减，了解 SAR441236 对 HIV-1 env 准种的影响，并定义 HIV-1 env 和 SAR441236 耐药性的聚糖屏蔽决定因素我们的方法测试了至关重要的假设。了解 HIV-1 在三特异性 bnAb 选择压力下的动态和进化。