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：
10388267
负责人：
Daniel R. Kuritzkes
金额：
$ 81.16万
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/10388267
关键词：
AIDS clinical trial group Acquired Immunodeficiency Syndrome Affect Antibodies Antibody Therapy 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 Persons 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，一小部分艾滋病毒的人会形成广泛中和抗体（bnabs），定义为中和潜水员艾滋病毒分离株的抗体。而引起bnabs是中心 HIV-1疫苗研究的重点，BNAB可能具有长效生物抗逆转录病毒疗法的其他作用或作为病毒辐射研究中的免疫效应组。广泛中和抗体的靶向HIV-1包膜糖蛋白，表面GP120的异构体和跨膜GP41分子，质量为50％糖。抗体基因的克隆患有艾滋病毒的个体鉴定出具有效力和神经性越来越广度的新bnabs 在临床上以HIV-1治疗进行研究。而单一的bnabs输注可以减少人们的血浆病毒负荷使用HIV，病毒变体具有耐对个体BNAB的抗性，并限制了活动和治疗 BNAB单一疗法的潜力。从经典上讲，抗体分子包含一个与两个具有相同抗原的Fab区域相关的FC区域绑定位点。最近，设计了一种抗体，将三个不同的Fab区域组合成一个单一的抗体分子。 SAR441236是一种结合VRC01-LS的CD4BS特异性的TRI特异性BNAB，V1/V2 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是对SAR441236的第一阶段人类研究，该研究研究了安全，药代动力学（PK）和这种新型Tristific BNAB的抗HIV-1活性。最多三十个病毒参与者将是在单个输注剂量降级试验设计中，研究了24周的随访。该提案的目的是利用A5377的样本来确定HIV-1是否响应于 “三重”生物艺术与常规组合艺术不同，并定义病毒逃生的机制来自Tristific BNAB。该建议的目的是结合创新的实验和数学经典分子病毒学的方法来表征病毒血症的衰减并定义 HIV-1逃离了这一一流的三阶段BNAB。我们假设Trispific BNAB，SAR441236，从血液中清除无细胞和与细胞相关的病毒，引起HIV-1的大量和动态种群变化 env quasispecies，并选择病毒在蛋白质和聚糖水平上逃脱变体以保持感染 BNAB的存在。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 Quasispecies的影响，并定义HIV-1 Env和 Glycan屏蔽确定SAR441236电阻。我们的方法测试假设是了解在特异性BNAB选择压力下HIV-1的动力学和演变。