Abstract

Coronavirus disease 2019 (COVID-19) is an evolving global public health crisis in need of therapeutic options. Passive immunization with monoclonal antibodies (mAbs) represents a promising therapeutic strategy capable of conferring immediate protection from SARS-CoV-2 infection. We describe the discovery and characterization of neutralizing SARS-CoV-2 IgG and VHH antibodies from four large-scale phage libraries, each constructed synthetically utilizing shuffled CDR loops from natural human and llama antibody repertoires. Among these, one neutralizing IgG bound a unique epitope on the N-terminal domain of the SARS-CoV-2 spike protein. Several neutralizing VHH antibodies target a rare epitope that resists mutagenic escape by SARS-CoV-2 variants of concern. We demonstrate that synthetic phage libraries can rapidly yield SARS-CoV-2 S1 antibodies with therapeutically desirable features, including high affinity, unique binding sites, and potent neutralizing activity in vitro, and a capacity to limit disease in vivo.