Discovery of broad-spectrum, cross-neutralizing bispecific antibodies against SARS-CoV-2 using high throughput functional screening

项目摘要 在过去的二十年里，世界目睹了包括SARS在内的几次毁灭性的冠状病毒爆发- 2002年的CoV，2012年的MERS-CoV，以及2019年导致COVID-19大流行的SARS-CoV-2。 SARS-CoV-2很可能是从蝙蝠身上进化而来，演变成一种新的有害毒株，非常适合人类传播。 在最初发现后的头四个多月里，已经分离出4,700多个SARS-CoV-2变种， 包括可导致病毒致病性高度可变性的多种突变体。开发疫苗 SARS-CoV-2是一个正在积极追求的有效和最终目标，但有充分的理由警告说， 传统疫苗的开发将需要数年时间，而且不像人们希望的那么简单。此外，全球 COVID-19在200多个国家和地区流行，加上新冠肺炎的真实的概率， 重组事件，将加速新的适应性变体的出现， 目前正在评估的疫苗或疗法。然而，生物医学领域完全没有准备好这样做。 传统疫苗和治疗方法无法保护我们免受当前或新型毒力的情况 SARS-CoV-2变种。 该提案旨在发现广谱、交叉中和的双特异性抗体， 不仅是SARS-CoV-2，还有另外两种有害的冠状病毒株（SARS-CoV和MERS-CoV）， 使用尖端的高通量功能发现技术。这样的双特异性抗体可以靶向两个 冠状病毒的关键点，从而提供了一种有效的措施，以解决大的病毒变异性和潜在的 治疗抵抗这项I期研究的主要目的是发现广谱双特异性的 同时针对三种冠状病毒的抗体候选物（目的1和2），并优化这些候选物 分子，以获得最终的两个线索，是可行的转化研究和临床开发。这 第一阶段可行性研究将提供优化的双特异性先导分子，这些分子可以授权给 制药公司，以促进后续开发作为一种高效的治疗和/或被动 针对常见SARS-CoV-2和相关突变株的疫苗，从而使 对社会和经济产生重大影响。

Project Summary In the past two decades the world has witnessed several devastating coronavirus outbreaks including SARS- CoV in 2002, MERS-CoV in 2012, and the SARS-CoV-2 in 2019 that has caused the COVID-19 pandemic. SARS-CoV-2 likely emerged from bats, evolving into a new harmful strain that is highly fit for human transmission. In the first four-plus months since its initial identification, over 4,700 SARS-CoV-2 variants have been isolated, including diverse mutants that can contribute to high variability in viral pathogenicity. Developing vaccines for SARS-CoV-2 is a valid and ultimate goal that is being actively pursued, yet there are well-founded cautions that conventional vaccine development will take years and is less straightforward than hoped. Further, the global prevalence of COVID-19 in more than 200 countries and territories, compounded with the real probability of new recombination events, will expedite the emergence of novel fit variants that may circumvent any conventional vaccines or therapeutics currently being evaluated. However, the biomedical field is utterly unprepared for such scenarios where the conventional vaccines and therapeutics cannot protect us from current or novel virulent SARS-CoV-2 variants. This proposal aims to discover broad-spectrum, cross-neutralizing bispecific antibodies simultaneously targeting not only SARS-CoV-2 but also two other detrimental coronavirus strains (SARS-CoV and MERS-CoV), in part using a cutting-edge high throughput functional discovery technology. Such bispecific antibodies can target two critical spots of a coronavirus, thereby offering an effective measure to tackle large viral variability and potential therapeutic resistance. The main objectives of this Phase I study are to discover broad-spectrum bispecific antibody candidates against the three coronaviruses concurrently (Aims 1 and 2) and to optimize these candidate molecules to obtain final two leads that are feasible for translational research and clinical development. This Phase I feasibility study will offer optimized bispecific lead molecules that can be licensed to or co-developed by pharmaceutical companies to facilitate subsequent development as a highly effective therapy and/or passive vaccine against common SARS-CoV-2 and relevant arising mutant strains, thereby making an immediate and significant impact on the society and economy.