Empowering SARS-CoV-2 variant neutralization with a bifunctional antibody engineered with tandem heptad repeat 2 peptides.

With the global pandemic and the continuous mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the need for effective and broadly neutralizing treatments has become increasingly urgent. This study introduces a novel strategy that targets two aspects simultaneously, using bifunctional antibodies to inhibit both the attachment of SARS-CoV-2 to host cell membranes and viral fusion. We developed pioneering IgG4-(HR2)4 bifunctional antibodies by creating immunoglobulin G4-based and phage display-derived human monoclonal antibodies (mAbs) that specifically bind to the SARS-CoV-2 receptor-binding domain, engineered with four heptad repeat 2 (HR2) peptides. Our in vitro experiments demonstrate the superior neutralization efficacy of these engineered antibodies against various SARS-CoV-2 variants, ranging from original SARS-CoV-2 strain to the recently emerged Omicron variants, as well as SARS-CoV, outperforming the parental mAb. Notably, intravenous monotherapy with the bifunctional antibody neutralizes a SARS-CoV-2 variant in a murine model without causing significant toxicity. In summary, this study unveils the significant potential of HR2 peptide-driven bifunctional antibodies as a potent and versatile strategy for mitigating SARS-CoV-2 infections. This approach offers a promising avenue for rapid development and management in the face of the continuously evolving SARS-CoV-2 variants, holding substantial promise for pandemic control.