Ultra-potent RBM-specific single-domain antibody broadly neutralizes multiple SARS-CoV-2 variants with picomolar activity.

SARS-CoV-2 infection remains a cause of severe illness in high-risk individuals, with few antiviral agents currently available. The emergence of new SARS-CoV-2 variants accumulating an increasing number of mutations significantly challenges the development of effective therapeutics. We describe broadly neutralizing single-domain antibody 1p1B10 having picomolar activity against both previously circulating SARS-CoV-2 variants, including Wuhan D614G, Alpha, Beta, Gamma, Delta and Omicron BA.1, BA.2, BA.5, and more recent variants - XBB.1, XBB.1.5, XBB.1.9, XBB.1.16, JN.1 and KS.1. We explained this broad activity by solving a high-resolution crystal structure of the S-protein RBD complex with the 1p1B10 antibody. The RBD/1p1B10 interface is unaffected by accumulated mutations and substantially overlaps with the RBD/ACE2 interface. 1p1B10 acts through binding to RBD both in open and closed conformations and blocking SARS-CoV-2 attachment to cells via direct competition with the ACE2 receptor. Therapeutic 1p1B10-Fc administration at a low dose of 1 mg/kg substantially reduced viral load in the lungs of Syrian hamsters after challenge with evolutionary distant SARS-CoV-2 variants and completely protected hACE2 mice against lethal SARS-CoV-2 infection. Overall, the findings make 1p1B10 a promising candidate for etiotropic treatment of COVID-19.