Fc effector function in bNAbs

bNAb 中的 Fc 效应子功能

• 批准号: 8517324
• 负责人: JEFFREY Victor RAVETCH
• 金额: $ 58.57万
• 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/8517324
• 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; Instruction; 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 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.

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