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）正在积极研究为HIV/AIDS的药物 治疗，功能治愈和/或预防。这些BNAB根据同名表位簇进行分类 在艾滋病毒信封（Env）上。严格的临床前研究证明了BNAB的几个潜在优势 目前在各种情况下使用抗逆转录病毒药物（ARV）。目前，优化广度，效能和 病毒逃生性是临床发育的主要目标。一个主要问题是所有单一bnabs展示 艾滋病毒菌株中表位变异性/可变性的覆盖率有限，从而使病毒逃脱。铅缓解 策略提出了BNAB类的三重组合，用于临床干预的前提下 反应性将提高效力和广度。但是，识别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班成员；和通过 临床试验或动物模型是一个昂贵且漫长的过程。因此，BNAB的进步 组合需要基于体外分析系统的理性，临床前选择过程 疗效的前景。标准化的中和测定将继续发挥重要作用。但是， 数据可以高估体内效力和逃脱抵抗力，无法捕获重要的决定因素 BNAB的组合作用，与BNAB预防或治疗试验中的临床结果不一致。 过去对单一或双BNAB疗法的试验无法实现病毒血症的持续病毒抑制。在某些情况下， 病毒反弹是通过仅对一个BNAB的阻力而发生的。这种经验增强了对新分析的需求 更彻底地捕获效力和逃避阻力的额外决定因素的技术。这样的努力 应该专注于与血浆中的野生型病毒群的BNAB相互作用，因为这些是注入BNAB的靶标 以及中介传播和疾病。组合疗法的发展指向瞬时 抑制和并发的BNAB类诉讼，作为高度相关的效力，宽度和逃脱的措施 反抗。该项目的目的是引入新的能力，以采取各种bnab的措施 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）检测方法可以 直接测量三重BNAB类与血浆病毒群结合的定性和定量方面。 我们假设这些技术的创新应用将实现我们的目标 BNAB组合和血浆病毒。两个具体的目的是：1）建立和解释 通过FCS技术测量的单个病毒粒子或ENV三聚体的BNAB组合。 2）表征相互作用 HIV+等离子体中与单个病毒体的BNAB和BNAB组合的组合。该项目将产生创新的新工具 用于评估BNAB组合在高度相关的环境中的效力，广度和逃避阻力 血浆中未通过当前方法有效探索的野生型病毒。