Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail
Johanna Hansen, Alina Baum, Kristen E Pascal, Vincenzo Russo, Stephanie Giordano, Elzbieta Wloga, Benjamin O Fulton, Ying Yan, Katrina Koon, Krunal Patel, Kyung Min Chung, Aynur Hermann, Erica Ullman, Jonathan Cruz, Ashique Rafique, Tammy Huang, Jeanette Fairhurst, Christen Libertiny, Marine Malbec, Wen-Yi Lee, Richard Welsh, Glen Farr, Seth Pennington, Dipali Deshpande, Jemmie Cheng, Anke Watty, Pascal Bouffard, Robert Babb, Natasha Levenkova, Calvin Chen, Bojie Zhang, Annabel Romero Hernandez, Kei Saotome, Yi Zhou, Matthew Franklin, Sumathi Sivapalasingam, David Chien Lye, Stuart Weston, James Logue, Robert Haupt, Matthew Frieman, Gang Chen, William Olson, Andrew J Murphy, Neil Stahl, George D Yancopoulos, Christos A Kyratsous
Neutralizing antibodies have become an important tool in treating infectious diseases. Recently, two separate approaches yielded successful antibody treatments for Ebola-one from genetically humanized mice and the other from a human survivor. Here, we describe parallel efforts using both humanized mice and convalescent patients to generate antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, which yielded a large collection of fully human antibodies that were characterized for binding, neutralization, and three-dimensional structure. On the basis of these criteria, we selected pairs of highly potent individual antibodies that simultaneously bind the receptor binding domain of the spike protein, thereby providing ideal partners for a therapeutic antibody cocktail that aims to decrease the potential for virus escape mutants that might arise in response to selective pressure from a single-antibody treatment.
An antibody cocktail against SARS-CoV-2 There is an urgent focus on antibodies that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral spike and prevent the virus from entering host cells. Hansen et al. generated a large panel of antibodies against the spike protein from humanized mice and recovered patients. From this panel, they identified several neutralizing antibodies, including pairs that do not compete for binding to the receptor binding domain. Baum et al. focused in on four of these antibodies. All four are effective against known spike variants. However, by growing a pseudovirus that expresses the spike in the presence of individual antibodies, the authors were able to select for spike mutants resistant to that antibody. In contrast, escape mutants are not selected when pseudovirus is grown in the presence of pairs of antibodies that either do not compete or only partially compete for binding to the RBD. Such a pair might be used in a therapeutic antibody cocktail.
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