Rappazzo et al. engineered a human monoclonal antibody against SARS-like sarbecoviruses to improve neutralization potency against SARS-CoV-2 and other SARS-like viruses which could become epidemic. Antibodies from the memory B cells of a 2003 SARS survivor were isolated, and directed evolution was utilized to obtain affinity-matured antibodies which had improved neutralization ability against SARS-CoV-2 S. The ADG-2 antibody was identified as a lead therapeutic candidate due to its potent neutralization activity of clade 1 sarbecoviruses, which included viruses with the potential for direct transmission to humans. Measurement of ADG-2’s apparent binding affinity to 17 sarbecovirus receptor binding domains (RBD) showed that ADG-2 had high affinity to every clade 1 sarbecovirus RBD which had detectable hACE2 binding. Tests against naturally circulating SARS-CoV-2 variants with single amino acid substitutions in the RBD revealed that ADG-2 bound all 36 variants at 50% or more of WT SARS-CoV-2. Using an in vivo mouse model of SARS and COVID-19, prophylactic treatment with ADG-2 prior to challenge resulted in minimal weight loss, no change in Penh (measure of airway resistance), no signs of gross pathology, and prevention of viral replication. By these same variables, therapeutic use of ADG-2 after viral challenge was not as effective as prophylactic administration, but still more effective than the control.