Antibody engineering improves neutralization activity against K417 spike mutant SARS-CoV-2 variants

Background Neutralizing antibodies are approved drugs to treat coronavirus disease-2019 (COVID-19) patients, yet mutations in severe acute respiratory syndrome coronavirus (SARS-CoV-2) variants may reduce the antibody neutralizing activity. New monoclonal antibodies (mAbs) and antibody remolding strategies are recalled in the battle with COVID-19 epidemic. Results We identified multiple mAbs from antibody phage display library made from COVID-19 patients and further characterized the R3P1-E4 clone, which effectively suppressed SARS-CoV-2 infection and rescued the lethal phenotype in mice infected with SARS-CoV-2. Crystal structural analysis not only explained why R3P1-E4 had selectively reduced binding and neutralizing activity to SARS-CoV-2 variants carrying K417 mutations, but also allowed us to engineer mutant antibodies with improved neutralizing activity against these variants. Thus, we screened out R3P1-E4 mAb which inhibits SARS-CoV-2 and related mutations in vitro and in vivo. Antibody engineering improved neutralizing activity of R3P1-E4 against K417 mutations. Conclusion Our studies have outlined a strategy to identify and engineer neutralizing antibodies against SARS-CoV-2 variants.

Automated summary

This study identified and engineered neutralizing antibodies against SARS-CoV-2 variants, using an antibody phage display library made from COVID-19 patients. One specific antibody clone, R3P1-E4, was found to effectively suppress SARS-CoV-2 infection and rescue lethal phenotypes in infected mice. Crystal structural analysis revealed the reasons behind the reduced binding and neutralizing activity of R3P1-E4 towards SARS-CoV-2 variants with K417 mutations, and allowed for the engineering of mutant antibodies with improved neutralizing activity. This research provides a strategy for identifying and improving neutralizing antibodies against SARS-CoV-2 variants.