Bridging Antibody Fc-mediated Antiviral Functions Across Humans and Non-human Primates

桥接抗体 Fc 介导的人类和非人类灵长类动物的抗病毒功能

• 批准号: 9925737
• 负责人: GEORGIA Doris TOMARAS
• 金额: $ 410.48万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925737
• 关键词: Animal Model; Animals; Antibodies; Antigen-Antibody Complex; Antiviral Agents; Biology; Biophysics; Cells; Chemicals; Clinic; Clinical Trials; Collaborations; Communication; Effector Cell; Ensure; Epitopes; Expression Profiling; Fc Receptor; Fc domain; Financial Activity; Genotype; Goals; Grant; HIV; HIV vaccine; HIV-1; HIV-1 vaccine; Human; Human immunodeficiency virus test; Immune system; Immunity; Infection prevention; Institutes; Institution; Intervention; Learning; Macaca mulatta; Maps; Mediating; Memory; Modeling; Monitor; Monoclonal Antibodies; Outcome; Passive Immunization; Phenotype; Positioning Attribute; Prevention strategy; Recording of previous events; Regimen; Research Personnel; Resources; Rhesus; Risk; Role; Specificity; Structure; Supervision; Testing; Translating; Translations; Vaccine Design; Vaccines; Virion; Virus; Work; antigen binding; base; design; efficacy trial; experience; glycosylation; immunoprophylaxis; improved; insight; nonhuman primate; programs; public health relevance; receptor function; recruit; response; success; synergism; tool; translation to humans; vaccine development; vaccine trial

 DESCRIPTION (provided by applicant): HIV-1 vaccine efficacy trials and multiple animal studies, including those related to HIV-cure strategies, have shown that antibody interactions with cells - mediated by the antibody constant (Fc) region - can harness multiple aspects of the immune system to provide protection through mechanisms other than by neutralization. However, it is unknown whether candidate HIV-1 vaccine regimens that include induction of Fc-mediated antibody functions can be tested in the rhesus macaque (RM) nonhuman primate (NHP) in a way that can be translated to humans. In order to more effectively translate insights gained from RM studies to the clinic, there is a need to fully define the protective signatures of Fc-mediated antibody functions across rhesus macaques and humans. The work we propose will map antibody (Ab) and Fc-receptor (FcR) biology across humans and RMs with the goal of making observed protective responses in RMs more predictive of human responses, thus accelerating the most promising vaccine concepts to be advanced to the clinic with success. Our central hypothesis is that the RM model can be substantially improved for testing antibody-based interventions and vaccines through elucidation of key variables that impact species-specific FcγR-dependent effector functions (i.e. antibody epitope specificity, immune complex formation, isotype/subclass, glycosylation, and FcR genotype/phenotype). To test this, we propose three synergistic, inter-related scientific Projects supported by three Cores to achieve the following Overall Aims: Overall AIM 1. Characterize effective anti-HIV-1 Fc-FcR biology across RM to humans. Overall AIM 2. Define HIV-1 virion and infected cell epitopes for antibody recognition. Overall AIM 3. Determine the Fv and Fc features of antibodies yielding maximal anti-HIV-1 activity.

 描述（由适用提供）：HIV -1疫苗效率试验和多个动物研究，包括与HIV抗性策略相关的动物研究，表明抗体与细胞的相互作用 - 由抗体常数（FC）区域介导的细胞 - 可以利用免疫系统的多个方面，以通过中和化的机制提供保护。但是，尚不清楚包括诱导FC介导的抗体功能的候选HIV-1疫苗方案是否可以在恒河猕猴（RM）非人类灵长类动物（NHP）中进行测试。为了更有效地将从RM研究获得的见解转化为诊所，有必要充分定义整个恒河猴和人类中FC介导的抗体功能的受保护特征。我们提出的工作将绘制跨人和RMS的抗体（AB）和FC受体生物学（FCR）生物学，目的是使RMS中观察到的受保护反应更加预测人类反应，从而加速最有希望的疫苗概念，以使其成功地推进临床。我们的核心假设是，通过阐明影响规格特异性FcγR依赖性效应子功能的关键变量（即抗体表位特异性，免疫复合物形成，同型/同型/同型/同类型，同类药物基因型和FCRCRCRENOTYPE），可以大大改善基于抗体的干预和疫苗接种的RM模型。为了测试这一点，我们提出了三个由三个核心支持的协同，相互关联的科学项目，以实现以下整体目标：总体目标1。遍及RM的有效抗HIV-1 FC-1 FC-1 FC-FCR生物学对人类。总体目的2。定义HIV-1病毒体和感染的细胞表位，以识别抗体识别。总体目标3。确定产生最大抗HIV-1活性的抗体的FV和FC特征。

项目成果

Coming together at the hinges: Therapeutic prospects of IgG3.

• DOI: 10.1080/19420862.2021.1882028
• 发表时间: 2021-01
• 期刊: mAbs
• 影响因子: 5.3
• 作者: Chu TH;Patz EF Jr;Ackerman ME
• 通讯作者: Ackerman ME

Recent insights into Fc-mediated effector responses to HIV-1.

• DOI: 10.1097/coh.0000000000000638
• 发表时间: 2020-09
• 期刊: Current opinion in HIV and AIDS
• 影响因子: 4.1
• 作者: Carpenter MC;Ackerman ME
• 通讯作者: Ackerman ME

Adjuvanted HIV-1 vaccine promotes antibody-dependent phagocytic responses and protects against heterologous SHIV challenge.

• DOI: 10.1371/journal.ppat.1008764
• 发表时间: 2020-09
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Om K;Paquin-Proulx D;Montero M;Peachman K;Shen X;Wieczorek L;Beck Z;Weiner JA;Kim D;Li Y;Mdluli T;Shubin Z;Bryant C;Sharma V;Tokarev A;Dawson P;White Y;Appelbe O;Klatt NR;Tovanabutra S;Estes JD;Matyas GR;Ferrari G;Alving CR;Tomaras GD;Ackerman ME;Michael NL;Robb ML;Polonis V;Rolland M;Eller MA;Rao M;Bolton DL
• 通讯作者: Bolton DL