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

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.Project Narrative Several coronavirus outbreaks have been a great threat to global health and economy, in particular the recent SARS-CoV-2 that has caused the detrimental COVID-19 pandemic. Unfortunately, there are still no approved therapies or vaccines for this devastating disease. This proposal aims to discover broad-spectrum, cross-neutralizing bispecific antibody molecules using a high throughput functional screening approach, which can be used as a therapy and/or vaccine against multiple coronavirus strains including SARS-CoV-2.