Structure-guided antibody cocktail for prevention and treatment of COVID-19

Abstract

Development of effective therapeutics for mitigating the COVID-19 pandemic is a pressing global need. Neutralizing antibodies are known to be effective antivirals, as they can be rapidly deployed to prevent disease progression and can accelerate patient recovery without the need for fully developed host immunity. Here, we report the generation and characterization of a series of chimeric antibodies against the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Some of these antibodies exhibit exceptionally potent neutralization activities in vitro and in vivo, and the most potent of our antibodies target three distinct non-overlapping epitopes within the RBD. Cryo-electron microscopy analyses of two highly potent antibodies in complex with the SARS-CoV-2 spike protein suggested they may be particularly useful when combined in a cocktail therapy. The efficacy of this antibody cocktail was confirmed in SARS-CoV-2-infected mouse and hamster models as prophylactic and post-infection treatments. With the emergence of more contagious variants of SARS-CoV-2, cocktail antibody therapies hold great promise to control disease and prevent drug resistance. Author summary Effective approaches to mitigate the COVID-19 pandemic are a pressing global need. One promising strategy is to combine neutralizing antibodies that can reduce viral load to prevent disease progression and accelerate patient recovery. However, the current supply of therapeutic antibodies for COVID-19 is insufficient to fill the enormous demand, and escape mutants may compromise the utility of existing drugs. Thus, there is an urgent worldwide need to develop highly potent neutralizing antibody cocktails. We generated a series of chimeric antibodies against the receptor-binding domain (RBD) of SARS-CoV-2 spike protein, which potently neutralize authentic SARS-CoV-2 infection according to the plaque reduction neutralization test (PRNT) and pseudovirus-based inhibition assay. These antibodies can be classified into three distinct groups based on their targets within the receptor-binding motif. Cryo-electron microscopy structural analyses of two representative receptor-binding domain-chimeric antibodies in complex with the SARS-CoV-2 spike protein further revealed two sets of non-overlapping epitopes, suggesting the potential for their combination in a therapeutic antibody cocktail. The prophylactic and therapeutic effects of these antibodies and their combination were demonstrated in SARS-CoV-2-infected mouse and hamster models. Thus, our potent neutralizing antibody cocktail has strong potential for development as an effective therapeutic drug to prevent and treat SARS-CoV-2 infection.