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

项目概要/摘要 该R 01题为“针对SARS-CoV的工程化治疗性抗体的开发和表征- 2”，建立在我们的项目基础设施，专业知识和经验，在表征病毒-宿主因子相互作用 在负链RNA病毒中。自从起源于中国以来，SARS-CoV-2迅速传播，现在是一个 全球大流行值得关注的是，人类在免疫学上是幼稚的， 治疗在美国，这种疾病已经使一些州的医疗保健系统不堪重负， 严重的连锁反应，使其他疾病的护理标准恶化。截至发稿时，近5 2019冠状病毒病已导致超过100万例病例和超过16万例死亡。病毒在肺部复制， 导致严重的呼吸道疾病，COVID-19，在>2%的病例中是致命的。中和抗体（nAb） 已知由自然感染或疫苗产生的抗体可以控制许多感染， COVID-19大流行，包括测试恢复期血浆治疗的研究，是有希望的。这些研究 强调了基于nAb的治疗的潜在意义。虽然nAb的IgG形式长期以来是最常见的， 广泛使用的形式，早期的研究，包括我们自己的研究表明，额外的多价形式的nAb可能 更有效。这提供了一种创新的方法来开发nAb，同时从 在较低剂量下有效中和和出现抗性突变体的可能性较低。SARS冠状病毒 2是单链、非节段、有包膜RNA病毒。病毒感染需要加标物的相互作用 糖蛋白受体结合结构域（RBD）与宿主受体ACE 2结合。在这里，我们将建立在新开发的 并建立了通过我们的工作进行优化的方法， 使用噬菌体展示技术靶向刺突和刺突RBD并表征它们的物理性质。我们 将工程抗体与增加的化合价和测试的效力在体外中和试验和体内 在小鼠模型中的功效。在完成时，我们希望提供创新和独特的多价nAb线索 具有可与IgG类药物中最好的药物相媲美的独特特性。

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.