Broadly neutralizing antibody combinations with single virions in HIV+ plasma

HIV血浆中单一病毒粒子的广泛中和抗体组合

• 批准号: 10699469
• 负责人: Krishanu Ray
• 金额: $ 16.09万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-23 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699469
• 关键词: AIDS prevention; Animal Model; Anti-Retroviral Agents; Antibodies; Antibody Therapy; Antiviral Agents; Apical; Binding; Binding Sites; Biological Assay; Classification; Clinical; Clinical Trials; Data; Detection; Development; Disease; Engineering; Epitopes; Exhibits; Fluorescence; Fluorescence Resonance Energy Transfer; Future; Goals; HIV; HIV Infections; HIV envelope protein; HIV therapy; HIV/AIDS; In Situ; In Vitro; Individual; Infection; Intervention; Lead; Mannose; Measures; Mediating; Methods; Modeling; Outcome; Pattern; Persons; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Play; Population; Prevention; Prevention trial; Process; Resistance; Role; Sampling; Specificity; Spectrum Analysis; Standardization; Surface; System; Techniques; Testing; Therapy trial; Variant; Viremia; Virion; Virus; clinical development; detection method; exosome; experience; experimental study; immunoreactivity; in vivo; indexing; innovation; member; neutralizing antibody; novel; particle; pre-clinical; preclinical study; prevent; screening; single molecule; tool; transmission process; viral rebound

Certain broadly HIV-neutralizing antibodies (bnAbs) are being actively investigated as agents for HIV/AIDS treatment, functional cure and/or prevention. These bnAbs are classified according to cognate epitopes clusters on the HIV envelope (Env). Rigorous preclinical studies evince several potential advantages of bnAbs over currently used antiretroviral drugs (ARVs) in various settings. Currently, optimization of breadth, potency, and virus escape resistance are primary goals for clinical development. A major issue is that all single bnAbs exhibit limited coverage of epitope variability/mutability among HIV strains, allowing virus escape. A lead mitigation strategy proposes triple combinations of bnAb classes for clinical intervention under the premise that polyspecific reactivity will boost potency and breadth. However, the identification of promising combinations is challenging. Screening through all possible triple combinations; bnAb class members; and engineered class members via clinical trials or animal models is an expensive and lengthy process. Therefore, the advancement of bnAb combinations requires a rational, preclinical selection process based on in vitro analytical systems that inform prospects for efficacy. Standardized neutralization assays will continue to play an important role; however, the data can overestimate in vivo potency and escape resistance, fail to capture important determinants of combination bnAb action, and appear incongruous with clinical outcomes in bnAb prevention or therapy trials. Past trials of mono or dual bnAb therapy did not achieve sustained virus suppression of viremia; in some cases, viral rebound occurred via resistance to only one bnAb. This experience reinforces the need for new analytical techniques that capture additional determinants of potency and escape resistance more thoroughly. Such efforts should focus on bnAb interactions with wild type virus swarms in plasma, as these are targets for infused bnAbs and mediate transmission and disease. The development of combination ARV therapies points to instantaneous inhibition and concurrent bnAb class action as highly relevant measures of potency, breadth, and escape resistance. The goal of this project is to introduce new capacities to take these measures for various bnAb combination and test settings, including wild type virus populations in plasma. In ongoing studies, we developed novel quantitative single molecule and fluorescence correlation spectroscopy (FCS) detection methods that can directly measure qualitative and quantitative aspects of triple bnAb class binding to virus populations in plasma. We hypothesize that our goals will be met by innovative applications of these techniques toward analyses of bnAb combinations and plasma viruses. Two Specific Aims are: 1) Establish and interpret the interactions of bnAb combinations with single virions or Env trimers measured by FCS techniques. 2) Characterize interactions of bnAbs and bnAb combinations with single virions in HIV+ plasma. This project will yield innovative new tools for evaluating the potency, breadth, and escape resistance of bnAb combination in highly relevant settings of wild type viruses in plasma that are not efficiently explored by current methods.

某些广泛的HIV中和抗体（bnAb）正在积极研究作为HIV/AIDS的试剂 治疗、功能性治愈和/或预防。这些bnAb根据同源表位簇进行分类 HIV信封（Env）严格的临床前研究表明，bnAbs相比于 目前在各种情况下使用抗逆转录病毒药物。目前，优化的广度，效力， 病毒逃逸抗性是临床开发的主要目标。一个主要的问题是，所有单个bnAb都表现出 HIV毒株中表位可变性/突变性的有限覆盖，允许病毒逃逸。电极导线缓解措施 该策略提出了在多特异性的前提下，用于临床干预的bnAb类别的三重组合， 反应性将提高效力和广度。然而，确定有希望的组合是具有挑战性的。 通过所有可能的三重组合筛选; bnAb类成员;和工程改造的类成员， 临床试验或动物模型是昂贵且漫长的过程。因此，bnAb的进展 联合用药需要基于体外分析系统的合理临床前选择过程， 功效的前景。标准化的中和试验将继续发挥重要作用;然而， 数据可能高估了体内效力和逃逸抗性，未能捕获重要的决定因素， 联合bnAb作用，并且似乎与bnAb预防或治疗试验中的临床结果不一致。 过去的单一或双重bnAb治疗试验没有实现对病毒血症的持续病毒抑制;在某些情况下， 病毒反弹通过仅对一种bnAb的抗性而发生。这一经验加强了对新的分析的需要， 这些技术捕获了额外的效力决定因素，并更彻底地摆脱了阻力。这种努力 应重点关注bnAb与血浆中野生型病毒群的相互作用，因为这些是输注bnAb的靶点 并介导传播和疾病。联合抗逆转录病毒疗法的发展表明， 抑制和同时bnAb集体诉讼作为效力、广度和逃逸的高度相关指标 阻力该项目的目标是引入新的能力，为各种bnAb采取这些措施， 组合和测试设置，包括血浆中的野生型病毒群体。在正在进行的研究中，我们开发了 新的定量单分子和荧光相关光谱（FCS）检测方法， 直接测量三重bnAb类与血浆中病毒群体结合的定性和定量方面。 我们假设，我们的目标将通过这些技术的创新应用来实现， bnAb组合和血浆病毒。两个具体目标是：1）建立和解释的相互作用， 通过FCS技术测量的具有单个病毒体或Env三聚体的bnAb组合。2)描述交互作用 HIV+血浆中bnAb和bnAb与单个病毒粒子的组合。该项目将产生创新的新工具 用于评价bnAb组合在以下高度相关环境中的效力、广度和耐逃逸性： 血浆中的野生型病毒不能通过当前方法有效地探索。