Overcoming antibody-resistant SARS-CoV-2 variants with bispecific antibodies constructed using non-neutralizing antibodies

Abstract

A current challenge is the emergence of SARS-CoV-2 variants, such as BQ.1.1 and XBB.1.5, that can evade immune defenses, thereby limiting antibody drug effectiveness. Emergency-use antibody drugs, including the widely effective bebtelovimab, are losing their benefits. One potential approach to address this issue are bispecific antibodies which combine the targeting abilities of two antibodies with distinct epitopes. We engineered neutralizing bispecific antibodies in the IgG-scFv format from two initially non-neutralizing antibodies, CvMab-6 (which binds to the receptor-binding domain [RBD]) and CvMab-62 (targeting a spike protein S2 subunit epitope adjacent to the known anti-S2 antibody epitope). Furthermore, we created a bispecific antibody by incorporating the scFv of bebtelovimab with our anti-S2 antibody, demonstrating significant restoration of effectiveness against bebtelovimab-resistant BQ.1.1 variants. This study highlights the potential of neutralizing bispecific antibodies, which combine existing less effective anti-RBD antibodies with anti-S2 antibodies, to revive the effectiveness of antibody therapeutics compromised by immune-evading variants.

Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain

“…Different SARS-CoV-2 targeting bsAbs have been described, which show improved neutralization activity compared to the parental mAbs 18,20,21 . The so far described IgG-like bsAbs are of highly diverse formats, such as the CrossMAb constructs [22][23][24][25][26] , DVD-Ig 24,27 , IgG-(scFv)2 21,24,28,29 , Tandem scFv-Fc 28,30,31 , and VH/Fab IgGs 32,33 , many of which require significant engineering and quality control processes to be efficiently produced. Additionally, most of these bsAbs usually target at least one exposed and non-conserved epitope, which can make them susceptible to viral escape.…”