Fc effector function in bNAbs

bNAb 中的 Fc 效应子功能

• 批准号: 9002884
• 负责人: JEFFREY Victor RAVETCH
• 金额: $ 126.34万
• 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/9002884
• 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; base; defined contribution; global health; humanized mouse; 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.

最近的研究已经强调了Fc-FcR相互作用对于实现对免疫缺陷病毒的体内保护的重要性。 通过包括ADCC在内的机制中和HIV和其他病毒或细菌毒素的抗体， ADCV 1.我们已经定义了IgG Fc与Fcγ R结合所需的氨基酸和聚糖， 开发了基于FcγR人源化小鼠新品系的动物模型，以确定氨基 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介导的效应子功能对抗体介导的病毒载体的体内效力的重要性 由于bNAb对HIV的中和作用，尚未进行系统性研究来确定最佳Fc 这将导致这些活动。我们将描述Fc结构和效应子的贡献 功能的bNAb的活性，并产生修饰的bNAb优化， Fc效应子功能。将在体外测试这些重新工程化的bNAb的中和、ADCC和免疫原性。 ADCVBI，并与Nussenzweig合作，在一种新的体内中和试验中，基于TZM-bl 在携带人FcγR的小鼠中进行的测定。通过与Bjorkman的合作，我们将获得以下结构信息： 这些修饰的抗体Fc，单独的和与特异性Fcγ R复合的，这些数据将指导产生 以进一步增强Fc-FcγR功能。这些研究将产生 新型bNAb针对中和和效应子功能进行了优化，并提供了开发 免疫策略，这将导致具有最佳效应子特性的bNAb。