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

• 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
• 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; 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

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.

项目摘要/摘要 这种R01的标题为“针对SARS-COV-的工程治疗抗体的开发和表征 2英寸，建立在我们的项目基础设施，专业知识和经验的基础上 在负链RNA病毒中。自从中国起源以来，SARS-COV-2此后迅速传播，现在是 全球大流行。重大的担忧是人类在免疫学上是幼稚的，没有可用的 疗法。在美国，该疾病已经使某些州的医疗系统不堪重负，并且 加剧其他疾病的护理标准，严重的敲门效应。在写作时，将近5个 数百万病例和> 160,000例死亡归因于19号。病毒在肺部复制 引起严重的呼吸道疾病，即19例，在> 2％的病例中致命。中和抗体（NABS） 已知由自然感染或疫苗产生的，可以控制当前的许多感染和早期研究 有望进行Covid-19-19的大流行，包括测试康复血浆治疗的研究。这些研究 强调基于NAB的治疗的潜在意义。虽然长期以来的IgG格式一直是 广泛使用的格式，早期研究，包括我们自己的表明，NABS的其他多价格式可能 更有效。这提供了一种创新的方法来开发NAB，同时从 较低剂量的有效神经化和抗药性突变体出现的可能性较低。 sars-cov- 2是单个链，非细分的，包膜的RNA病毒。病毒感染需要尖峰的相互作用 糖蛋白受体结合结构域（RBD）与宿主受体ACE2。在这里，我们将建立在新开发的基础上 并通过我们的工作系统进行了优化的其他系统来生成抗体 使用噬菌体显示技术对尖峰和尖峰RBD定位并表征其物理特性。我们 将工程抗体具有提高的价值并测试体外神经元化测定和体内的效力 鼠标模型的功效。完成后，我们希望提供创新和独特的多价NAB潜在客户 具有独特的特征，可能会在IgG类药物中享有最佳状态。