This study describes the development of a therapeutic antibody cocktail against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein using both genetically humanized mice and convalescent patients. The researchers isolated a large collection of fully human antibodies from these sources, which were characterized for binding, neutralization, and three-dimensional structure. The goal was to identify pairs of highly potent individual antibodies that could simultaneously bind the receptor binding domain (RBD) of the spike protein, reducing the likelihood of virus escape mutants. The study found that antibodies derived from genetically humanized mice and convalescent humans showed notable similarities and consistencies. The researchers selected nine most potent neutralizing antibodies and confirmed their ability to mediate antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). The study also used cryo-electron microscopy to show that two of the selected antibodies, REGN10933 and REGN10987, can bind to distinct regions of the RBD, making them ideal partners for a therapeutic antibody cocktail. This cocktail is now being tested in human trials.This study describes the development of a therapeutic antibody cocktail against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein using both genetically humanized mice and convalescent patients. The researchers isolated a large collection of fully human antibodies from these sources, which were characterized for binding, neutralization, and three-dimensional structure. The goal was to identify pairs of highly potent individual antibodies that could simultaneously bind the receptor binding domain (RBD) of the spike protein, reducing the likelihood of virus escape mutants. The study found that antibodies derived from genetically humanized mice and convalescent humans showed notable similarities and consistencies. The researchers selected nine most potent neutralizing antibodies and confirmed their ability to mediate antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). The study also used cryo-electron microscopy to show that two of the selected antibodies, REGN10933 and REGN10987, can bind to distinct regions of the RBD, making them ideal partners for a therapeutic antibody cocktail. This cocktail is now being tested in human trials.