Antibody Affinity Maturation by Yeast Mating against a Diverse Antigen Library Enhances Antibody Resistance to Viral Mutations

Antibodies suffer from resistance mutations in their targets, which diminishes their efficacy. Most antibody library screens use a single antigen yet should ideally use many antigens to ensure that the hits have broad-binding capacity. As a test case, we used the receptor-binding domain (RBD) of SARS COV-2 and CR3022 as the starting antigen/antibody pair. We screened a CR3022 library against a large panel of RBDs (94) and isolated a hit (C8) that has improved affinity for 95/102 tested RBDs. C8 has improved affinity to variants unseen in the library screening, indicating that C8 is more resistant to future antigen variants. This study, to our knowledge, represents the largest interaction screen (107) performed to date using synthetic agglutination in yeast.