Linking Antibody Cooperativity and Effector Cell Engagement

将抗体协同性和效应细胞参与联系起来

• 批准号: 10475288
• 负责人: Guido Ferrari
• 金额: $ 95.74万
• 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/10475288
• 关键词: Address; Antibodies; Antibody Response; Antibody Specificity; Autologous; Biophysics; Cell physiology; Cells; Clinical Trials; Collaborations; Complement; Data; Effector Cell; Epitopes; Fc Receptor; Foundations; Genetic; Genetic Variation; Genotype; Goals; HIV-1; HIV-1 vaccine; Heterogeneity; Human; IgG Receptors; IgG1; IgG3; Immune response; Immunoglobulin A; Immunoglobulin Allotypes; Immunoglobulin G; In Situ; Incubated; Individual; Infection; Inflammatory; Knowledge; Link; Lymphoid Tissue; Macaca mulatta; Mediating; Membrane; Modeling; Monoclonal Antibodies; Mucous Membrane; NK Cell Activation; Natural Killer Cells; Nature; Phagocytosis; Phenotype; Plasma; Preparation; Prevention; Prevention strategy; Property; Reporting; Research Personnel; Serum; Specificity; Testing; Therapeutic; Tissues; Translating; Translations; Vaccine Design; Vaccines; Virion; Virus Replication; Work; base; cytokine; defined contribution; design; genetic variant; immunoprophylaxis; improved; in vivo; infection risk; monocyte; neutralizing antibody; neutralizing monoclonal antibodies; nonhuman primate; novel vaccines; polyclonal antibody; preclinical study; programs; recruit; response; transcriptomics; vaccine candidate; vaccine strategy; vaccine trial; vaccine-induced antibodies

ABSTRACT_Project 2 A key goal for HIV-1 vaccine design is the induction of broadly neutralizing responses. Although this goal has not been achieved, preclinical studies in non-human primates have identified several vaccine strategies that achieved some level of protection without inducing broadly neutralizing antibodies. These findings and emerging data from the field indicate that an achievable path forward is to leverage a polyclonal response comprised of multiple antibody responses that work together to eliminate virus replication. A critical gap in knowledge is the nature of vaccine-elicited polyclonal antibody responses that can achieve protection against infection within mucosal tissues in the non-human primates in order to translate into protection in human clinical trials. Moreover, there is a lack of information on how best to design polyclonal combinations of non- neutralizing and neutralizing antibodies to recruit Fc-Receptor bearing cells at the mucosal compartment to leverage different antibody combinations for improved protection. Our central hypothesis is that the composition of polyclonal Ab responses significantly impacts recruitment of monocytes and NK cells and their cooperation for Fc-mediated functions. To test our primary hypothesis, we will evaluate combinations of monoclonal antibody and polyclonal vaccine-induced plasma antibodies for their ability to more efficiently kill infected cells by examining antibody-dependent cellular mediated killing and/or phagocytosis of infected cells. We will define the transcriptomic profile of Fc-receptor bearing cells recruited by effective polyclonal preparations to understand the optimal FcR-bearing cells that should be recruited by effective vaccine-induced antibodies. These signatures will enable to understand how species-specific FcR and cellular diversity impact translation from rhesus macaques to humans. Lastly, we will determine differences in the interaction between FcR-bearing cells recruited by optimal mAb combinations for their ability to eliminate infected cells and secrete antiviral cytokines with limited pro-inflammatory profile. These questions will be addressed in the following Aims: Aim 1. Define contribution of IgG1, IgG3, and IgA for recognition of infected cells and virus particles. Aim 2. Identify the functional properties of effector cell subsets recruited by IgG1, IgG3, and polyclonal Ab combinations. Aim 3. Determine whether monocytes and NK cells are serially recruited to eliminate infected cells.

摘要_项目2 HIV-1疫苗设计的一个关键目标是诱导广泛的中和反应。尽管这个目标已经 在非人类灵长类动物上的临床前研究已经确定了几种疫苗策略， 在不诱导广泛中和抗体的情况下获得了一定程度的保护。这些调查结果和 来自该领域的新数据表明，一条可实现的前进道路是利用多克隆反应 由多种抗体反应组成，它们共同作用以消除病毒复制。在…方面的严重差距 知识是疫苗引发的多克隆抗体反应的性质，可以实现对 非人灵长类动物黏膜组织内的感染，以便转化为对人类的保护 临床试验。此外，缺乏关于如何最好地设计非克隆的多克隆组合的信息。 中和和中和抗体在粘膜间隔招募Fc受体阳性细胞以 利用不同的抗体组合来加强保护。我们的中心假设是 多克隆抗体应答的组成显著影响单核细胞和NK细胞的募集及其 FC中介功能的协作。为了测试我们的主要假设，我们将评估以下组合 单抗和多克隆疫苗诱导的血浆抗体更有效地杀伤 通过检测抗体依赖的细胞介导的杀伤和/或对感染细胞的吞噬作用来检测感染细胞。 我们将确定有效的多克隆招募的Fc受体承载细胞的转录图谱 了解有效疫苗诱导应招募的最佳FCR承载细胞的准备 抗体。这些签名将使我们能够了解特定物种的FCR和细胞多样性如何影响 从恒河猴到人类的翻译。最后，我们将确定两者之间的交互差异 最佳单抗组合对FCR携带细胞清除感染细胞和分泌细胞能力的影响 具有有限促炎特征的抗病毒细胞因子。这些问题将在以下几个方面得到解决 目标： 目的1.明确IgG1、IgG3和IgA对识别感染细胞和病毒颗粒的贡献。 目的2.鉴定由IgG1、IgG3和多克隆募集的效应细胞亚群的功能特性 AB组合。 目的3.确定单核细胞和NK细胞是否被串联募集以清除感染细胞。