Application of a Method for Engineering Multivalent Antibodies to Substantially Enhance Functional affinity of Clinical Trial Anti-SARS-CoV-2 Antibodies

Abstract Infection by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes COVID-19 disease. Therapeutic antibodies are being developed that interact with the viral spike proteins to limit viral infection of epithelium. We have applied a method to dramatically improve the performance of anti-SARS-CoV-2 antibodies by enhancing avidity through multimerization using simple engineering to yield tetrameric antibodies. We have re-engineered six anti-SARS-CoV-2 antibodies using the human p53 tetramerization domain, including three clinical trials antibodies casirivimab, imdevimab and etesevimab. The method yields tetrameric antibodies, termed Quads, that retain efficient binding to the SARS-CoV-2 spike protein and show up to two orders of magnitude enhancement in neutralization of pseudovirus infection. The tetramerization method is simple and general and its application is a powerful methodological development for SARS-CoV-2 antibodies that are currently in pre-clinical and clinical investigation.