Mechanisms of Antibody Fc Mediated Protection

抗体 Fc 介导的保护机制

• 批准号: 10475284
• 负责人: GEORGIA Doris TOMARAS
• 金额: $ 59.14万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-25 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475284
• 关键词: AIDS prevention; Animal Model; Antibodies; Antibody Binding Sites; Antibody Response; Antibody titer measurement; Antibody-mediated protection; Biophysics; CD4 Positive T Lymphocytes; Cell physiology; Cells; Complement; Data; Databases; Differentiation Antigens; Effector Cell; Epitopes; Exhibits; Fc Receptor; Flow Cytometry; Goals; HIV; HIV Infections; HIV vaccine; Human; Humoral Immunities; Immune; Immune system; Immunity; Immunodeficient Mouse; Immunoprevention; In Situ; In Vitro; Infection; Knowledge; Link; Macaca mulatta; Measures; Mediating; Methods; Modeling; Mouse Strains; Natural Killer Cells; Nature; Neutralization Tests; Neutralizing antibody assay; Outcome; Pattern; Phagocytosis; Primary Infection; SIV; Surface; System; Testing; Therapeutic; Vaccination; Virus; antibody-dependent cell cytotoxicity; base; cell killing; comparative; confocal imaging; cross reactivity; efficacy testing; exhaustion; experimental study; granulocyte; humanized mouse; imaging modality; immune function; in vivo; monocyte; neutralizing antibody; nonhuman primate; novel; novel strategies; preservation; prevent; programs; protective effect; protective efficacy; rational design; reactivation from latency; reconstitution; recruit; response; simian human immunodeficiency virus

ABSTRACT_Project 1 Major efforts to develop HIV vaccines and other immunoprevention approaches are based on the premise that anti-Env antibody (Ab) responses will protect against HIV, SIV or SHIV in humans and nonhuman primates (NHP) if present before exposure. Humoral responses comprise two Ab functions that must be considered for HIV prevention: direct neutralizing activity, enabled by epitope-paratope interactions; and the recruitment of antiviral effector cells (NK cells, monocytes, granulocytes), via Fc-Fc receptor interactions. Although applications of neutralizing activity have been exhaustively studied, the utility of antibody Fc-mediated functions in HIV prevention is only partially defined. Further, how these functions allow non-neutralizing antibodies (nnAbs) to afford protective human immunity is an unresolved but significant question as many nnAbs recognize invariant epitopes, can be raised by vaccination, and recruit Fc-mediated effector functions in experimental settings. It is likely that past limitations in establishing clear links between protection and nnAb FC-mediated functions may be explained by an incomplete understanding of target epitope sensitivity, optimal applications of Abs and/or usage of animal models for efficacy testing. Accordingly, the goal of this project is to fill these information gaps and determine whether and how Fc-mediated immune functions can be most effectively employed for the rational design of HIV prevention methods. We will use recent advances in animal models and Fc-FcR dependent immunity to build new approaches that can bridge epitope presentation patterns, effector cell recruitment and target cell killing in situ, and protective efficacy in vivo. We will validate two hypothetical scenarios for Fc-mediated immunity in preventing HIV infection suggested by our data. 1) Non-neutralizing Abs will exhibit efficacy in a human immune background according to identifiable qualities of epitope targeting, isotype and Fc-mediated effector mechanism. 2) Polyclonal mixtures of bnAbs and cross- reactive nnAbs will afford more potent protection in a human immune background than either Ab type alone; thus affording protective efficacy in vivo at what would otherwise be limiting titers. These will be tested using novel in vitro systems and immunodeficient mice reconstituted to produce human backgrounds and effector mechanisms, as well as comparative experiments in RM immune backgrounds. The Specific Aims are: Aim 1. Identify windows of vulnerability to Fc-mediated activities in a primary infection system. Aim 2. Demonstrate that nnAbs and their Fc-dependent functions, alone and/or with sub-efficacious bnAb titers, protect against HIV infection in vivo.

Abstract_project 1 开发艾滋病毒疫苗和其他免疫预防方法的重大努力是基于这样的前提。 抗ENV抗体（AB）的反应将预防人类和非人类隐私中的艾滋病毒，SIV或SHIV （NHP）如果在暴露前存在。体液响应包括必须考虑的两个AB功能 艾滋病毒预防：由表位 - 围绕相互作用启用的直接中和活性；和招募 抗病毒效应细胞（NK细胞，单核细胞，粒细胞）通过FC-FC受体相互作用。虽然 中和活性的应用已详尽地研究，抗体FC介导的实用性 预防艾滋病毒的功能仅是部分定义的。此外，这些功能如何允许非中和 获得受保护的人类免疫力的抗体（NNABS）是一个尚未解决但重大的问题 可以通过疫苗接种来提高识别不变的表位的NNAB，并在FC介导的效应子功能中提出 实验设置。过去的限制可能是在保护与NNAB之间建立明确联系的局限性 FC介导的功能可以通过对目标表位灵敏度的不完全理解，最佳来解释 ABS的应用和/或动物模型用于效率测试的应用。根据该项目的目标是 填补这些信息差距，并确定FC介导的免疫功能是否最能成为 有效地用于预防HIV预防方法的合理设计。我们将利用动物的最新进展 模型和FC-FCR依赖性免疫力，以建立可以桥接发作演示的新方法 模式，效应细胞募集和靶细胞杀死原位，并保护体内有效性。我们将验证 FC介导的免疫力预防我们的数据提出的两个假设方案。 1） 非中和ABS将根据人类免疫背景表现出效率 表位靶向，同种型和FC介导的效应器机制。 2）BNAB和跨的多克隆混合物 反应性NNABs在人类免疫背景中将提供比单独的AB类型更有效的保护。 在体内提供受保护效率的这种限制效率。这些将使用 新型体外系统和免疫缺陷的小鼠重构以产生人类的背景和效应子 机理以及RM免疫背景中的比较实验。具体目的是： 目标1。确定原发性感染系统中FC介导活动的脆弱性窗户。 AIM 2。证明单独和/或具有效率的NNABS及其依赖FC的功能 BNAB滴度，预防体内艾滋病毒感染。