Function and Cryo-EM structures of broadly potent bispecific antibodies against multiple SARS-CoV-2 Omicron sublineages

The SARS-CoV-2 variant, Omicron (B.1.1.529), rapidly swept the world since its emergence. Compared with previous variants, Omicron has a high number of mutations, especially those in its spike glycoprotein that drastically dampen or abolish the efficacy of currently available vaccines and therapeutic antibodies. Several major sublineages of Omicron involved, including BA.1, BA.2, BA.2.12.1, BA.3 and BA.4/BA.5, rapidly changing the global and regional landscape of the pandemic. Although vaccines are available, therapeutic antibodies remain critical for infected and especially hospitalized patients. To address this, we have designed and generated a panel of human/humanized therapeutic bispecific antibodies against Omicron and its sub-lineage variants, with activity spectrum against other lineages. Among these, the top clone CoV2-0213 has broadly potent activities against multiple SARS-CoV-2 ancestral and Omicron lineages, including BA.1, BA.1.1, BA.2, BA.2.12.1, BA.3 and BA.4/BA.5. We have solved the cryo-EM structure of the lead bi-specific antibody CoV-0213 and its major Fab arm MB.02. Three-dimensional structural analysis shows distinct epitope of antibody – spike receptor binding domain (RBD) interactions, and demonstrates that both Fab fragments of the same molecule of CoV2-0213 can target the same spike trimer simultaneously, further corroborating its mechanism of action. CoV2-0213 represents a unique and potent broad-spectrum SARS-CoV-2 neutralizing bispecific antibody (nbsAb) against the currently circulating major Omicron variants (BA.1, BA.1.1, BA.2, BA.2.12.1, BA.3 and BA.4/BA.5), while maintaining activity against certain ancestral lineages (WT/WA-1, Delta), and to some degree other β-coronavirus species (SARS-CoV). CoV2-0213 is primarily human and ready for translational testing as a countermeasure against the ever-evolving pathogen. ### Competing Interest Statement The authors have declared no competing interest.