Production of a monoclonal antibody targeting the SARS-CoV-2 Omicron spike protein and analysis of SARS-CoV-2 Omicron mutations related to monoclonal antibody resistance.

SARS-CoV-2 mutations have resulted in the emergence of multiple concerning variants, with Omicron being the dominant strain presently. Therefore, we developed a monoclonal antibody (mAb) against the spike (S) protein of SARS-CoV-2 Omicron for therapeutic applications. We established the 1E3H12 mAb, recognizing the receptor binding domain (RBD) of the Omicron S protein, and found that the 1E3H12 mAb can efficiently recognize the Omicron S protein with weak affinity to the Alpha, Beta, and Mu variants, but not to the parental strain and Delta variant. Based on in vitro assays, the mAb demonstrated neutralizing activity against Omicron BA.1, BA.4/5, BQ.1.1, and XBB. A humanized antibody was further produced and proved to have neutralizing activity. To verify the potential limitations of the 1E3H12 mAb due to viral escape of SARS-CoV-2 Omicron variants, we analyzed the emergence of variants by whole genome deep sequencing after serial passage in cell culture. The results showed a few unique S protein mutations in the genome associated with resistance to the mAb. These findings suggest that this antibody not only contributes to the therapeutic arsenal against COVID-19 but also addresses the ongoing challenge of antibody resistance among the evolving subvariants of SARS-CoV-2 Omicron.