Rapid antibody screening systems to identify and engineer antiviral protection

用于识别和设计抗病毒保护的快速抗体筛选系统

• 批准号: 10353350
• 负责人: Brandon James DeKosky
• 金额: $ 26.51万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-25 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10353350
• 关键词: 2019-nCoV; Address; Antibodies; Antibody Response; Antibody-Dependent Enhancement; Antibody-mediated protection; Antigens; Area; B-Lymphocytes; Binding; Biological Assay; Biological Models; CD209 gene; COVID-19 pandemic; COVID-19 patient; Cells; Cellular Assay; Clinical; Clinical Research; Collaborations; Communicable Diseases; Consumption; Custom; Data Collection; Dengue Vaccine; Development; Directed Molecular Evolution; Disease Outbreaks; Engineering; Ensure; Epitopes; Failure; Flavivirus; Flow Cytometry; Future; Genes; Human; Immune; Immune response; Immunity; Immunologic Memory; Immunology; In Vitro; Infection; Intervention; Light; Link; Maps; Medical; Methods; Modeling; Molecular; Mutation; Nature; Patients; Pharmaceutical Preparations; Pharmacotherapy; Population; Property; Proxy; Recombinants; Recording of previous events; Recovery; Resistance; SARS-CoV-2 antibody; SARS-CoV-2 variant; Sampling; System; Techniques; Technology; Therapeutic antibodies; Time; Vaccination; Vaccine Design; Vaccine Therapy; Vaccinee; Vaccines; Variant; Viral; Viral Antibodies; Virulence; Virus; Virus Diseases; Work; Writing; Yellow fever virus; adaptive immune response; antibody engineering; antibody libraries; antigen binding; antiviral drug development; base; betacoronavirus; combat; cross reactivity; design; drug development; high throughput screening; improved; innovation; insight; medical countermeasure; multidisciplinary; neutralizing antibody; neutralizing monoclonal antibodies; next generation sequencing; pandemic disease; particle; pressure; rapid technique; screening; success; vaccine development; vaccine-induced antibodies

PROJECT SUMMARY A detailed understanding of molecular and cellular adaptive immune responses is critical to accelerate progress in human immunology and drug development. However, available technologies for analyzing antiviral neutralizing antibody responses are slow and impractical for large-scale clinical sample analysis, and can provide limited information on the scope of neutralizing antibody features in human immunity. Importantly, current methods are also unable to engineer antibody molecules to directly improve neutralization potency, which is a major limitation to the discovery of potent and broadly reactive antibody-based interventions for viral diseases. Current methods also cannot engineer broad antibody neutralization against related viruses, which is critical for drug and vaccine development against diverse viral lineages. Important examples include the diverse viral lineages of betacoronaviruses and flaviviruses, where protection against evolved and expanded viral lineages is essential for effective clinical use. This project will develop a new in vitro platform for rapid analysis and engineering of antibody neutralization. We will establish methods to directly select antibodies desired antiviral properties at high throughput, including for neutralization breadth and potency. We will apply a custom platform for natively paired antibody heavy and light chain gene capture from human immune responses to map the neutralization capacity of antiviral antibodies elicited by natural infection or vaccination, and to select for broad antibody protection against related viruses. Aim 1 will establish our new assay techniques for antiviral antibody discovery and engineering against SARS- CoV-2, which is continuously evolving after its recent emergence into human populations. This project will identify antibody variants with high potency and breadth from the immune responses of convalescent COVID-19 patients. We will also engineer promising antibodies for enhanced neutralization breadth and potency against diverse SARS-CoV-2 strains. Aim 2 will establish antiviral antibody discovery and engineering strategies against flaviviruses, using yellow fever virus as a key model system. Antibody-dependent enhancement in flaviviruses makes potent antibody neutralization a critical feature for any antibody-based clinical interventions. We will identify potent neutralizing antibodies from patients vaccinated against yellow fever virus, and engineer improved neutralizing antibodies for high potency against multiple yellow fever virus strains This work will establish a new platform approach for potent antiviral discovery and antibody engineering. Our long-term objectives are to develop robust and rapid antiviral antibody discovery platforms that can accelerate progress in the development of medical interventions for viral diseases.

项目摘要 对分子和细胞自适应免疫反应的详细理解对于加速至关重要 人类免疫学和药物开发的进展。但是，可用于分析抗病毒的技术 中和抗体反应缓慢且不切实际，用于大规模的临床样本分析，可以提供 关于人类免疫中中和抗体特征范围的信息有限。重要的是，目前 方法还无法设计抗体分子以直接提高中和效力，这是 发现对病毒疾病的有效且基于反应性抗体的干预措施的主要局限性。 当前方法还不能设计针对相关病毒的广泛抗体中和，这对于 药物和疫苗开发针对多种病毒谱系。重要的例子包括多种病毒 Betacoronaviruses和Flaviviruses的谱系，防止进化和扩展的病毒谱系的谱系是 对于有效的临床使用至关重要。 该项目将开发一个新的体外平台，用于快速分析和工程抗体中和。 我们将建立在高吞吐量（包括 用于中和广度和效力。我们将应用一个定制平台，以使本机配对的抗体沉重和 轻链基因从人免疫反应中捕获到绘制抗病毒抗体的中和能力 自然感染或疫苗接种引起，并选择针对相关病毒的广泛抗体保护。 AIM 1将建立我们针对SARS的抗病毒药抗体发现和工程技术的新测定技术 - COV-2，该公司最近出现在人类人群中后不断发展。这个项目将确定 康复感199名患者的免疫反应具有较高效力和广度的抗体变异。 我们还将设计有望抗体的抗体，以增强中和宽度和效力 SARS-COV-2菌株。 AIM 2将使用黄色建立针对黄病毒的抗病毒抗体发现和工程策略 发烧病毒作为关键模型系统。黄病毒的抗体依赖性增强使有效的抗体 中和对任何基于抗体的临床干预措施的关键特征。我们将确定有效的中和 来自疫苗接种黄热病病毒的患者的抗体，工程师改善了中和抗体的抗体 对多种黄热病病毒菌株的高效力 这项工作将为有效的抗病毒发现和抗体工程建立一种新的平台方法。我们的 长期目标是开发可加速的强大和快速的抗病毒抗体发现平台 发展病毒疾病的医疗干预措施的进展。