Abstract
Structural principles underlying the composition and synergistic mechanisms of protective monoclonal antibody cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic antibody cocktail against SARS-CoV-2. On the basis of our previously identified humanized cross-neutralizing antibody H014, we systematically analyzed a fully human naive antibody library and rationally identified a potent neutralizing antibody partner, P17, which confers effective protection in animal model. Cryo-EM studies dissected the nature of the P17 epitope, which is SARS-CoV-2 specific and distinctly different from that of H014. High-resolution structure of the SARS-CoV-2 spike in complex with H014 and P17, together with functional investigations revealed that in a two-antibody cocktail, synergistic neutralization was achieved by S1 shielding and conformational locking, thereby blocking receptor attachment and viral membrane fusion, conferring high potency as well as robustness against viral mutation escape. Furthermore, cluster analysis identified a hypothetical 3rd antibody partner for further reinforcing the cocktail as pan-SARS-CoVs therapeutics.
Highlights
The ongoing pandemic of coronavirus disease 19 (COVID-19) has spurred an unprecedented public health crisis worldwide
To gain insights into the epitopes recognized by P17, we used a competitive Surface plasmon resonance (SPR)-based epitope binding assay to map the antigenic sites present on the SARS-CoV-2 S trimer through H014, which binds a conserved epitope on one side of the receptor binding domain (RBD), distinct from the receptor binding motif (RBM).[12]
The CM5 sensor labeled with SARS-CoV-2 S trimer was saturated with H014 and flooded with P17 in the flowthrough, or the sensor was first saturated with P17 followed by a flow of H014 over it
Summary
The ongoing pandemic of coronavirus disease 19 (COVID-19) has spurred an unprecedented public health crisis worldwide. There have been more than 18 million confirmed cases of COVID19 around the world, including about 700 thousand deaths according to the World Health Organization. The etiological agent of COVID-19 has been identified as a novel human coronavirus named severe acute respiratory syndrome coronavirus 2 (SARSCoV-2).[1,2,3] SARS-CoV-2 infection in humans results in a wide range of symptoms spanning from flu-like mild symptoms to more severe forms of pneumonia, acute respiratory distress syndrome, multiple organ failure, and even death. There is no licensed vaccine or approved antiviral drug for treating COVID-19. New prophylactic and therapeutic strategies to combat human infections are urgently needed
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