Researchers have developed a cocktail of antibodies targeting the SARS-CoV-2 spike protein, combining antibodies from genetically humanized mice and convalescent humans. This approach aims to create a therapeutic cocktail that reduces the risk of virus escape mutants. The study involved generating antibodies through two methods: immunizing genetically humanized mice with SARS-CoV-2 spike protein and isolating antibodies from B cells of convalescent patients. The resulting antibodies were characterized for binding, neutralization, and structure. The study found that antibodies from both sources could bind to the receptor binding domain (RBD) of the spike protein, making them ideal for a cocktail therapy. Over 200 antibodies were isolated, with more than 200 neutralizing antibodies showing high potency. These antibodies were analyzed for their ability to neutralize SARS-CoV-2 and block ACE2 receptor binding. The study also identified pairs of noncompeting antibodies that could be combined to form a cocktail, reducing the risk of viral escape. Structural analysis using hydrogen-deuterium exchange mass spectrometry (HDX-MS) revealed that the antibodies bind to distinct regions of the RBD, confirming their noncompeting nature. Cryo-electron microscopy confirmed that the two antibodies in the cocktail can simultaneously bind to different regions of the RBD, making them effective in neutralizing the virus. The study highlights the importance of using a combination of antibodies to enhance therapeutic efficacy and reduce the risk of viral escape. The developed cocktail is now being tested in human trials. The research underscores the potential of antibody-based therapies in combating SARS-CoV-2, with the goal of creating a treatment that is both effective and resistant to viral mutations.Researchers have developed a cocktail of antibodies targeting the SARS-CoV-2 spike protein, combining antibodies from genetically humanized mice and convalescent humans. This approach aims to create a therapeutic cocktail that reduces the risk of virus escape mutants. The study involved generating antibodies through two methods: immunizing genetically humanized mice with SARS-CoV-2 spike protein and isolating antibodies from B cells of convalescent patients. The resulting antibodies were characterized for binding, neutralization, and structure. The study found that antibodies from both sources could bind to the receptor binding domain (RBD) of the spike protein, making them ideal for a cocktail therapy. Over 200 antibodies were isolated, with more than 200 neutralizing antibodies showing high potency. These antibodies were analyzed for their ability to neutralize SARS-CoV-2 and block ACE2 receptor binding. The study also identified pairs of noncompeting antibodies that could be combined to form a cocktail, reducing the risk of viral escape. Structural analysis using hydrogen-deuterium exchange mass spectrometry (HDX-MS) revealed that the antibodies bind to distinct regions of the RBD, confirming their noncompeting nature. Cryo-electron microscopy confirmed that the two antibodies in the cocktail can simultaneously bind to different regions of the RBD, making them effective in neutralizing the virus. The study highlights the importance of using a combination of antibodies to enhance therapeutic efficacy and reduce the risk of viral escape. The developed cocktail is now being tested in human trials. The research underscores the potential of antibody-based therapies in combating SARS-CoV-2, with the goal of creating a treatment that is both effective and resistant to viral mutations.