Abstract Antibody therapies represent a valuable tool to reduce COVID-19 deaths and hospitalizations. Multiple antibody candidates have been granted emergency use authorization by the Food and Drug Administration and many more are in clinical trials. Most antibody therapies for COVID-19 are engineered to bind to the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein and disrupt its interaction with angiotensin-converting enzyme 2 (ACE2). Notably, several SARS-CoV-2 strains have accrued mutations throughout the RBD that improve ACE2 binding affinity, enhance viral transmission and escape some existing antibody therapies. Here, we measure the binding affinity of 33 therapeutic antibodies against a large panel of SARS-CoV-2 variants and related strains of clinical significance using AlphaSeq, a high-throughput yeast mating-based assay to determine epitopic residues, determine which mutations result in loss of binding and predict how future RBD variants may impact antibody efficacy.