The pandemic of COVID-19 continues worldwide with many variants arising, especially SARS-CoV-2 Delta (B. 1.617. 2) and Omicron (B. 1.1. 529) variants of concern (VOCs). According to WHO, Omicron has spread in almost all the countries with a doubling time less than Delta VOC. Equipped with increased transmissibility and decreased responses to neutralizing monoclonal antibodies (mAbs), 1–3 Omicron’s frequency has risen from 0.8% of all sequenced SARS-CoV-2 viral samples to 98.3% in just 40 days (https://covid. cdc. gov/covid-data-tracker/# variant-proportions), faster than Delta. Effective therapies that can limit the transmissibility of SARS-CoV-2 Omicron and Delta VOCs are therefore in urgent need. There is no mAb or small molecule therapies specifically designed to block the spreading of Omicron or Delta VOCs. Although Delta variant was reported susceptible to bamlanivimab plus etesevimab treatment in laboratory studies and also in two Delta vaccine breakthrough individuals, 4 such treatment regimen showed no effect on SARS-CoV-2 Gamma (P. 1) and Beta VOCs (B. 1.351), and its distribution was paused briefly in the United States because of that (FDA). Omicron VOC was reported to escape the current neutralizing mAbs designed against the original version. 1–3 Since the proportions of circulating VOCs evolve rapidly, it is important to develop a therapy that could potentially control the spreading of the current and future SARS-CoV-2 VOCs.

In our previous study, 3E8, a mAb targeting human angiotensin-converting enzyme 2 (hACE2), could block the S1-subunits binding to ACE2 and pseudo-typed virus infection of ACE2-expressing cells from multiple coronaviruses, including SARS-CoV-2 VOC Gamma and Beta, without markedly affecting the physiological activities of hACE2 or causing severe toxicities in hACE2 “knock-in” mice. 3E8 also blocked the live SARS-CoV-2 infection of Vero E6 cells and in a prophylactic mouse model of COVID-19. 5 In this study, we showed that 3E8 could potentially block Delta and Omicron VOCs, demonstrating further that it was a potent and “broad-spectrum” blocker of all coronaviruses that utilize hACE2 as entry receptors. The binding affinities of 6× His-tagged S1 proteins of wildtype (WT), Delta, Kappa (B. 1.617. 1) and Omicron variants of SARS-CoV-2, as well as 3E8 to Fc-tagged hACE2 were measured. The EC50 values by ELISA were determined to be> 4, 0.497, 0.216,> 33, and 0.029 μg/ml (Fig. 1 a), and the apparent dissociation constant (KD) by biolayer interferometry (BLI) were 16.2, 5.03, 4.85, 7.40, and 1.6 nM, respectively (Fig. 1 b). They could also bind to HEK293/hACE2/EGFP cells ectopicallyexpressing hACE2 and Vero E6 cells endogenously-expressing