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

Abstract

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.