Development and characterization of engineered therapeutic antibodies against SARS-CoV-2

针对 SARS-CoV-2 的工程化治疗抗体的开发和表征

基本信息

批准号：
10458689
负责人：
Gaya K. Amarasinghe
金额：
$ 64.99万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10458689
关键词：
2019-nCoV ACE2 Address Animal Model Animals Antibodies Antibody Therapy Binding Biological Assay Biophysics COVID-19 COVID-19 pandemic Cessation of life Characteristics China Chiroptera Collaborations Development Diamond Disease Dose Drug Combinations Engineering Epitopes Geometry Glycoproteins Health Healthcare Systems Human Immunoglobulin G Immunologics In Vitro Incidence Individual Infection Infrastructure Integration Host Factors Lentivirus Lightning Lung Mammals Methods Middle East Respiratory Syndrome Coronavirus Persons Phage Display Pharmaceutical Preparations Protein Engineering Proteins RNA Viruses Race Reporting Research Research Personnel Resistance Respiratory Disease SARS coronavirus SARS-CoV-2 antibody SARS-CoV-2 inhibitor SARS-CoV-2 pathogenesis Series Speed System Technology Testing Therapeutic antibodies Time United States Vaccines Validation Vesicular stomatitis Indiana virus Viral Virion Virus Virus Diseases Work Writing antibody engineering base betacoronavirus convalescent plasma early phase clinical trial experience in vivo indexing innovation lead candidate mouse model mutant neutralizing antibody pandemic disease physical property potency testing pre-clinical receptor receptor binding resistance mutation standard of care synergism therapeutic candidate

项目摘要

Project Summary/Abstract This R01 entitled, “Development and characterization of engineered therapeutic antibodies against SARS-CoV- 2”, builds on our project infrastructure, expertise, and experience in characterizing viral-host factor interactions in negative strand RNA viruses. Since originating in China, SARS-CoV-2 has since rapidly spread and is now a global pandemic. Significant concerns are that humans are immunologically naïve, and there are no available therapies. In the US, the disease has already overwhelmed the healthcare system in some states and have a serious knock-on effect in exacerbating the standard of care for other diseases. At the time of writing, nearly 5 million cases and >160,000 deaths have been attributed to COVID-19. The virus replicates in the lungs and causes a severe respiratory disease, COVID-19, which is fatal in >2% of cases. Neutralizing antibodies (nAbs) generated by natural infection or vaccines is known to control many infections and early studies in the current COVID-19 pandemic, including studies to test convalescent plasma treatments, are promising. These studies highlight the potential significance of nAb-based therapy. While IgG format of nAbs have long been the most extensively used format, early studies, including our own suggest that additional multivalent formats of nAbs may be more effective. This provides an innovative method to develop nAbs while acquiring potential benefits from effective neutralization at lower doses and lower likelihood of the emergence of resistance mutants. SARS-CoV- 2 is a single stranded, non-segmented, enveloped RNA virus. Viral infection requires interaction of the spike glycoprotein receptor binding domain (RBD) to the host receptor ACE2. Here, we will build on newly developed and established approaches that have been optimized through our work other systems to generate antibodies targeting spike and spike RBD using phage display technology and characterize their physical properties. We will engineer antibodies with increased valency and test for potency in in vitro neutralization assays and in vivo efficacy in a mouse model. At the completion, we expect to provide innovative and unique multivalent nAb leads with unique characteristics that will rival the best in class IgG drugs.

项目概要/摘要该 R01 的标题是“针对 SARS-CoV-的工程治疗抗体的开发和表征” 2”，建立在我们的项目基础设施、专业知识和表征病毒-宿主因素相互作用的经验之上自从起源于中国以来，SARS-CoV-2 迅速传播，现已成为一种负链 RNA 病毒。全球大流行的重大担忧是人类在免疫学上是幼稚的，并且没有可用的方法。在美国，这种疾病已经让一些州的医疗系统不堪重负，并造成了严重的后果。严重的连锁反应加剧了其他疾病的护理标准。 19 亿病例和超过 16 万人死亡归因于该病毒在肺部和肺部复制。导致严重的呼吸道疾病 COVID-19，中和抗体 (nAb) 在 2% 以上的病例中是致命的。已知自然感染或疫苗产生的病毒可以控制许多感染，并且当前的早期研究 COVID-19 大流行，包括测试恢复期血浆治疗的研究，这些研究都是有希望的。强调了基于 nAb 的治疗的潜在意义，而 IgG 形式的 nAb 长期以来一直是最重要的。常用的形式，早期研究，包括我们自己的建议，其他多价形式的 nAb 可能这提供了一种开发 nAb 的创新方法，同时从中获得潜在的好处。以较低剂量有效中和，并降低出现耐药突变体的可能性。 2是单链、不分段、有包膜的RNA病毒，病毒感染需要刺突的相互作用。宿主受体 ACE2 的糖蛋白受体结合域 (RBD) 在这里，我们将在新开发的基础上进行构建。并通过我们的工作和其他系统优化的既定方法来生成抗体使用噬菌体展示技术靶向刺突和刺突 RBD 并表征其物理特性。将设计具有更高效价的抗体，并在体外中和测定和体内测试效力完成后，我们期望提供创新且独特的多价 nAb 引线。具有可与同类最佳 IgG 药物相媲美的独特特性。