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

Background: Mast cell and basophil activation by antigen cross linking of Fc epsilon RI-bound IgE is central to allergy pathogenesis. We previously demonstrated global suppression of this process by rapid desensitization with anti-Fc epsilon RI alpha mAbs. Objectives: We sought to determine whether use of monovalent (mv) anti-Fc epsilon RI alpha mAbs increases desensitization safety without loss of efficacy. Methods: mv anti-human (hu) Fc epsilon RI alpha mAbs were produced with mouse-derived immunoglobulin variable regions and huIgG(1) or huIgG(4) C regions and were 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 Fc epsilon RI alpha; mice that additionally have an allergy-promoting IL-4Ra mutation; and hu cord blood-reconstituted immunodeficient, hu cytokinesecreting, mice that have large numbers of activated hu mast cells. Anaphylaxis susceptibility was sometimes increased by treatment with IL-4 or a b-adrenergic receptor antagonist. Results: mv anti-hu Fc epsilon RI alpha mAbs are considerably less able than divalent mAbs are to induce anaphylaxis and deplete mast cell and basophil IgE, but mv mAbs still strongly suppress IgEmediated 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 huIgG(4) variant of mv anti-huFc epsilon RI alpha mAb is safer than our huIgG(1) variant is, apparently because reduced interactions with Fc epsilon Rs decrease ability to indirectly cross-link Fc epsilon RI. Conclusions: mv anti-Fc epsilon RI alpha mAbs more safely suppress IgEmediated anaphylaxis and food allergy than divalent variants of the same mAbs do. These mv mAbs may be useful for suppression of huIgE-mediated disease.

Automated summary

Monovalent anti-huFc epsilon RI alpha mAbs have advantages in safety over divalent mAbs, with weaker abilities to induce allergic reactions and deplete IgE, but still effectively suppress IgE-mediated diseases.