Fc effector function in bNAbs

最近的研究强调了Fc-FCR相互作用对实现体内保护的重要性 通过ADCC和ADCC等机制中和HIV和其他病毒或细菌毒素的抗体 ADCVL.我们已经定义了免疫球蛋白Fc与FcyRs结合所需的氨基酸和糖链 基于新品系的FcyR人源化小鼠建立动物模型以确定氨基的影响 人免疫球蛋白的酸和多糖修饰对其体内功能的影响。尽管越来越多的人对 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bNAbs对HIV的中和，还没有进行系统的研究来确定最佳的Fc 将导致这些活动的结构。我们将表征Fc结构和效应器的贡献 对Nussenzweig分离的bNAbs的活性的影响，并产生优化的修饰bNAbs FC效应器函数。这些重新设计的bNAbs将在体外进行中和、ADCC和 ADCVBI和与Nussenzweig合作，在一种基于TZM-bl的新的体内中和试验中 在携带人FcyR的小鼠身上进行检测。在与比约克曼的合作中，我们将获得 这些修饰的抗体Fc单独或与特定的FcyRs复合，这些数据将指导产生 进一步增强Fc-FcyR功能。这些研究将导致产生 新颖的bNAbs，针对中和和效应器功能进行了优化，并提供了开发框架 免疫策略将导致bNAbs具有最佳的效应器特性。 相关性(请参阅说明)： 产生有效的抗艾滋病毒免疫仍然是对全球卫生的一项艰巨挑战。通过 在这个子项目中提出的研究，我们将探讨潜在的增强免疫原性的机制 靶抗原以产生中和抗体并设计中和抗体以增强其 活体活动。

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 FcyRs and developed animal models based on novel strains of FcyR 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 FcyR. In collaboration with Bjorkman we will obtain structural information for these modified antibody Fc's, alone and in complex to specific FcyRs, These data will direct the generation of additional variants to further enhance Fc-FcyR 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. RELEVANCE (See instructions): The generation of effective anti-HIV immunity remains a formidable challenge to global health. Through the studies proposed in this subproject we will investigate mechanisms to enhance immunogenicity of potential target antigens to generate neutralizing antibodies and to engineer neutralizing antibodies to augment their in vivo activity.