Suppression of IgE-mediated anaphylaxis and food allergy with monovalent anti-FcεRIα monoclonal antibodies

Abstract Background Mast cell and basophil activation by antigen crosslinking of FceRI-bound IgE is central to allergy pathogenesis. We previously demonstrated global suppression of this process by rapid desensitization with anti-FceRIα mAbs. Objective Determine whether use of monovalent (mv) anti-FceRIα mAbs increases desensitization safety without loss of efficacy. Methods mv anti-human (hu) FceRIα mAbs were produced with mouse-derived immunoglobulin V regions and huIgG1 or huIgG4 C regions, and used to suppress murine IgE-mediated anaphylaxis and food allergy. mAbs were administered as a single dose or as serially increasing doses to mice that express hu instead of mouse FceRIα, mice that additionally have an allergy-promoting IL-4Rα mutation, and hu cord blood-reconstituted immunodeficient, hu cytokine-secreting, mice that have large numbers of activated hu mast cells. Anaphylaxis susceptibility was sometimes increased by treatment with IL-4 or a β-adrenergic receptor antagonist. Results mv anti-huFceRIα mAbs have considerably less ability than divalent mAbs to induce anaphylaxis and deplete mast cell and basophil IgE, but still strongly suppress IgE-mediated disease. The mv mAbs can be safely administered as a single large dose to mice with typical susceptibility to anaphylaxis, while a rapid desensitization approach safely suppresses disease in mice with increased susceptibility. Our huIgG4 variant of mv anti-huFceRIα mAb is safer than our huIgG1 variant, apparently because reduced interactions with FcγRs decrease ability to indirectly crosslink FceRI. Conclusion mv anti-FceRIα mAbs more safely suppress IgE-mediated anaphylaxis and food allergy than divalent variants of the same mAbs. These mv mAbs may be useful for suppression of huIgE-mediated disease. Clinical implication Mouse model studies provide evidence that a monovalent monoclonal anti-FceRIα antibody with low Fcγ receptor binding should safely and rapidly suppress IgE-mediated disease.