Fc effector function in bNAbs

bNAb 中的 Fc 效应子功能

• 批准号: 8617123
• 负责人: JEFFREY Victor RAVETCH
• 金额: $ 94.8万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8617123
• 关键词: Amino Acids; Animal Model; Animals; Antibodies; Antigen Targeting; Bacterial Toxins; Binding; Biochemical; Biological Assay; CCR5 gene; CD34 gene; Cells; Collaborations; Complex; Data; Development; Engineering; Exhibits; Fc domain; Fetal Liver; Generations; HIV; HIV Antibodies; HIV Infections; Hepatocyte; Human; Immunity; Immunization; Immunoglobulin G; In Vitro; Influenza; Link; Luciferases; Mediating; Modeling; Modification; Mus; Pathway interactions; Polysaccharides; Property; Role; Rosa; Services; Specificity; Structure; System; Testing; Transgenic Organisms; Vaccination; Validation; Variant; Viral; Virus; adeno-associated viral vector; antibody-dependent cell cytotoxicity; base; defined contribution; global health; immunogenicity; in vitro testing; in vivo; in vivo Model; mouse model; neutralizing antibody; novel; prevent; protein expression; reconstitution

Recent studies have highlighted the significance of Fc-FcR interactions to achieve in vivo protection for neutralizing antibodies to HIV and other viruses or bacterial toxins through mechanisms including ADCC and ADCVl. We have defined both the amino acid and glycan requirements for IgG Fc binding to FcγRs and developed animal models based on novel strains of FcγR humanized mice to determine the impact of amino acid and glycan modifications of human IgGs on their in vivo function. Despite the growing appreciation for the importance of Fc mediated effector functions to the in vivo potency of antibody mediated viral neutralization for bNAbs to HIV, no systematic studies have been performed to determine the optimal Fc structure that will result in these activities. We will characterize the contributions of Fc structure and effector functions to the activities of the bNAbs isolated by Nussenzweig and generate modified bNAbs optimized for Fc effector functions. These re-engineered bNAbs will be tested in vitro for neutralization, ADCC and ADCVBI and, in collaboration with Nussenzweig, in a novel in vivo neutralization assay, based on the TZM-bl assay in mice that carry human FcγR. In collaboration with Bjorkman we will obtain structural information for these modified antibody Fc's, alone and in complex to specific FcγRs, These data will direct the generation of additional variants to further enhance Fc-FcγR function. These studies will result in the generation of novel, bNAbs optimized for both neutralization and effector function and provide the framework to develop immunization strategies that will result in bNAbs with optimal effector properties.

最近的研究强调了 Fc-FcR 相互作用对于实现体内保护的重要性 通过 ADCC 等机制中和 HIV 和其他病毒或细菌毒素的抗体 ADCVl.我们已经定义了 IgG Fc 与 FcγR 结合的氨基酸和聚糖要求，并且 开发了基于 FcγR 人源化小鼠新品系的动物模型，以确定氨基的影响 人 IgG 的酸和聚糖修饰对其体内功能的影响。尽管人们越来越欣赏 Fc 介导的效应器功能对抗体介导的病毒体内效力的重要性 对于 HIV 的 bNAb 中和，尚未进行系统研究来确定最佳 Fc 将导致这些活动的结构。我们将描述 Fc 结构和效应子的贡献 对 Nussenzweig 分离的 bNAb 的活性发挥作用，并生成优化的修饰 bNAb Fc 效应器功能。这些重新设计的 bNAb 将在体外进行中和、ADCC 和 ADCVBI 并与 Nussenzweig 合作，进行了基于 TZM-bl 的新型体内中和测定 在携带人 FcγR 的小鼠中进行测定。与 Bjorkman 合作，我们将获得以下结构信息： 这些修饰的抗体 Fc，单独或与特定 FcγR 复合，这些数据将指导生成 进一步增强 Fc-FcγR 功能的其他变体。这些研究将导致产生 新颖的 bNAb 针对中和和效应功能进行了优化，并提供了开发框架 免疫策略将产生具有最佳效应特性的 bNAb。