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Molecular Basis for Nonanaphylactogenicity of a Monoclonal Anti-IgE Antibody¹

Michael P. Rudolf2 3^*, Adrian W. Zuercher2 4^*, Andreas Nechansky, Christine Ruf, Monique Vogel^*, Sylvia M. Miescher^*, Beda M. Stadler^* and Franz Kricek^5,

^* Institute of Immunology and Allergology, Inselspital, University of Bern, Bern, Switzerland; and Novartis Forschungsinstitut GmbH, Vienna, Austria

IgE Abs mediate allergic responses by binding to specific high affinity receptors (FcRI) on mast cells and basophils. Therefore, the IgE/FcRI interaction is a target for clinical intervention in allergic disease. An anti-IgE mAb, termed BSW17, is nonanaphylactogenic, although recognizing IgE bound to FcRI, and interferes with binding of IgE to FcRI. 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 C3 and one within the C4 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 C3 region predominantly blocks binding of IgE to FcRI, leading to neutralization of IgE. Moreover, binding of BSW17 to the C4 region may explain how BSW17 recognizes FcRI-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.