Antibodies targeting a shared epitope exploit IgE allostery to drive distinct functional outcomes

Abstract

Significance Antibody discovery typically operates on the “same epitope, same function” paradigm. However, for dynamic proteins like immunoglobulin E (IgE), the primary mediator of allergic disease, this approach is overly simplistic. By characterizing four closely related antibodies that recognize the same epitope but induce divergent functional outcomes, we demonstrate that antibodies can act as molecular “switches” to capture distinct conformational states of IgE-Fc. We show that even a single amino acid difference can dictate whether an antibody stabilizes a “bent” or “extended” conformation, thereby controlling inhibition or enhancement of receptor binding. This study provides a mechanistic framework for understanding how allosteric transitions modulate antibody function and suggests that prioritizing conformational capture over epitope diversity is essential for engineering next-generation therapeutics.