New monoclonal antibodies (mAbs) identified, target the S2 subunit of the SARS-CoV-2 spike protein and hence prevent viral infection by preventing membrane fusion. n SARS-CoV-2, the S1 subunit of the spike protein helps the virus attach itself to the host receptors, and the S2 subunit is involved in membrane fusion. Most antibodies target the S1 subunit, which is under selective pressure, leading to the emergence of new variants. The S2 subunit is more conserved, however, likely because of low immune pressure and the need to maintain its functionality. the team investigated IgG+ memory B cells from three COVID-19 convalescent sera.
They identified five monoclonal antibodies that bind to spike protein coronaviruses that infect humans, sarbecoviruses, merbecoviruses, and embecoviruses. Of these five, the team selected one named S2P6 for further investigations. This antibody had the highest preference for SARS-CoV-2 and SARS-CoV spike protein, followed by MERS-CoV, and OC43. This shows the potent cross-reactivity of the monoclonal antibody to human-infecting coronaviruses. The antibody completely prevented infection of Vero-E6 cells expressing TMPRSS2, but not cells without TMPRSS2. It was also able to neutralize pseudotyped viruses of the different variants of concern of SARS-CoV-2 and other coronaviruses like SARS-CoV, MERS-CoV, and OC43. Using peptide mapping, the team found that all five identified monoclonal antibodies bind to peptides located in the stem helix in the S2 subunit.
After two passages, antibody neutralization was gone and five different resistant mutations emerged. The researchers found that the S2P6 antibody significantly reduced viral loads in the lungs of Syrian hamsters.
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