Novel, broad and potent spike-specific human monoclonal antibodies inhibit SARS-CoV-2 Omicron sub-lineages

Abstract The continuous emergence of SARS-CoV-2 variants of concern with mutated spike receptor binding domains has rendered many therapeutic mAbs ineffective. To date, there are no clinically authorized therapeutic antibodies effective against the predominant circulating sub-lineages BQ and XBB. Here, we report the isolation of broad and potent neutralizing HuMabs from a Danish healthcare worker infected with SARS-CoV-2 early in the pandemic. These HuMabs include a novel and genetically unique non-RBD-specific HuMab (K501SP6) which can neutralize Omicron sub-lineages BQ and XBB, and an RBD-specific HuMab (K501SP3) with high potency towards earlier circulating variants but was escaped by Omicron sub-lineages BA.5, BQ and XBB through F486 and E484 substitutions. Characterizing SARS-CoV-2 spike-specific HuMabs, including broadly reactive non-RBD-specific HuMabs, can give insight into the immune mechanisms involved in neutralization and immune evasion, which can be a valuable addition to already existing SARS-CoV-2 therapies.