Effects of fc glycosylation on the activity of WNT mimetic agonistic antibodies

Monoclonal antibodies have been explored in a broad range of applications including receptor agonism. Given the importance of receptor conformation in signaling, the agonistic activity of antibodies that engage these receptors are influenced by many parameters. Tetravalent bispecific antibodies that target the FZD and LRP receptors and subsequently activate WNT signaling have been constructed. Because WNT activation stimulates stem cell proliferation and tissue regeneration, immune effector functions should be eliminated from therapeutic antibodies targeting this pathway. Here, we report an unexpected effect of Fc glycosylation on the agonistic activity of WNT mimetic antibodies. Our findings underscore the importance of antibody format, geometry, and epitope in agonistic antibody design, and highlight the need to establish appropriate early discovery screening strategies to identify hits for further optimization.