Development of Fully Human, Bispecific Antibodies that Effectively Block Omicron Variant Pseudovirus Infections

The emergence of highly immune invasive and transmissible variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has decreased the effectiveness of existing vaccines. It is, therefore, critical to develop effective and safe therapeutics for SARS-CoV-2 infections, especially for the most vulnerable and immunocompromised patients. Neutralizing antibodies have been shown to be successful at preventing severe disease from early SARS-CoV-2 strains, although their efficacy has diminished with the emergence of new variants. Here, we aim to develop fully human and broadly neutralizing monoclonal (mAb) and bispecific (BsAb) antibodies against SARS-CoV-2 and its variants. Specifically, we first identified two antibodies from human transgenic mice that bind to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and are capable of neutralizing SARS-CoV-2 and variants of concern with high to moderate affinity. Two non-competing clones with the highest affinity and functional blocking of ACE2 binding were then selected to be engineered into two BsAbs, which were then demonstrated to have relatively improved affinity, ACE2 blocking ability, and pseudovirus inhibition against several variants, including Omicron (B.1.1.529). Our findings provide one mAb candidate and two bsAb candidates for consideration of further clinical development and suggest that the bispecific format may be more effective than mAbs for SARS-CoV-2 treatment.