Molecular Basis for Nonanaphylactogenicity of a Monoclonal Anti-IgE Antibody

IgE Abs mediate allergic responses by binding to specific high affinity receptors (FceRI) on mast cells and basophils. Therefore, the IgE/FceRI interaction is a target for clinical intervention in allergic disease. An anti-IgE mAb, termed BSW17, is nonanaphylactogenic, although recognizing IgE bound to FceRI, and interferes with binding of IgE to FceRI. Thus, BSW17 represents a candidate Ab for treatment of IgE-mediated disorders. By panning BSW17 against random peptide libraries displayed on phages, we defined mimotopes that mimic the conformational epitope recognized on human IgE. Two types of mimotopes, one within the Ce3 and one within the Ce4 domain, were identified, indicating that this mAb may recognize either a large conformational epitope or eventually two distinct epitopes on IgE. On the basis of alignments of the two mimotopes with the human IgE sequence, we postulate that binding of BSW17 to the Ce3 region predominantly blocks binding of IgE to FceRI, leading to neutralization of IgE. Moreover, binding of BSW17 to the Ce4 region may explain how BSW17 recognizes FceRI-bound IgE, and binding to this region may also interfere with degranulation of IgE sensitized cells (basophils and mast cells). As a practical application of these findings, mimotope peptides coupled to a carrier protein may be used for the development of a peptide-based anti–allergy vaccine by induction of anti-IgE Abs similar to the current approach of using humanized nonanaphylactogenic anti-IgE Abs as a passive vaccine.