Abstract
Human coronaviruses such as SARS-CoV, MERS-CoV, and SARS-CoV-2 have recurrently emerged as significant pathogens, causing severe respiratory illnesses and presenting challenges to monoclonal antibody therapeutics due to their rapid evolution, particularly the diverse variants of SARS-CoV-2. In this study, we utilized ‘Knob-into-Hole’ and ‘IgG-scFv’ technologies to engineer bispecific antibodies (bsAbs) that target both the viral receptor and spike protein, enhancing their neutralization breadth and potency. Our bsAbs, combining anti-SARS-CoV-2 or anti-MERS-CoV antibodies with an anti-ACE2 antibody, demonstrated effective neutralization across a range of SARS-CoV-2 variants, SARS-CoV and MERS-CoV in both pseudovirus and authentic virus assays. Notably, the ‘IgG-scFv’ bsAbs format exhibited superior binding and neutralization capabilities compared to the ‘Knob-into-Hole’ configurations. The most effective of these, ‘IgG-scFv’ H11B11_m336, displayed exceptional neutralization potency against a panel of 24 pseudotyped Beta-Coronaviruses, with IC50 values ranging from 0.001 to 0.183 μg/mL. Overall, our findings underscore the potential of bsAbs as an effective strategy to meet the immediate challenges posed by existing and emerging pathogens, thereby enhancing global pandemic preparedness.
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