Abstract
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 frizzled and lipoprotein receptor-related protein receptors and subsequently activate WNT ("Wingless-related integration site" or "Wingless and Int-1" or "Wingless-Int") 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.