Rapid desensitization of humanized mice with anti-human Fc epsilon RI alpha monoclonal antibodies

Background: Anaphylaxis is classically mediated by allergen cross-linking of IgE bound to the alpha chain of Fc epsilon RI, the mast cell/basophil high affinity IgE receptor. Allergen cross-linking of the IgE/Fc epsilon RI complex activates these cells, inducing release of disease-causing mediators, cytokines, and enzymes. We previously demonstrated that IgE-mediated anaphylaxis could be safely prevented in wild-type BALB/c mice by rapid desensitization with anti-mouse Fc epsilon RI alpha mAb. Objective: This study sought to use humanized mice to extend these results to humans. Methods: We actively immunized huFc epsilon RI alpha/F709 mice, which express human (hu) instead of mouse Fc epsilon RI alpha and a mutant IL-4 receptor that lacks inhibitory function. We passively immunized huFc epsilon RI alpha mice, as well as human cord blood-reconstituted reNSGS mice, which are immune-deficient, produce mast cell-stimulating human cytokines, and develop numerous human mast cells. For desensitization, we used anti-huFc epsilon RI alpha mAbs that bind Fc epsilon RI alpha regardless of its association with IgE (noncompeting mAbs), and/or mAbs that compete with IgE for huFc epsilon RI alpha binding (competing mAbs). Anaphylaxis was induced by intravenous injection of antigen or anti-huIgE mAb. Results: Anti-huFc epsilon RI alpha mAb rapid desensitization was safer and more effective than allergen rapid desensitization and suppressed anaphylaxis more rapidly than omalizumab or ligelizumab. Rapid desensitization of naive, IgE-sensitized huFc epsilon RI alpha mice and huFc epsilon RI alpha/F709 mice that were egg-allergic with anti-Fc epsilon RI alpha mAbs safely removed >98% of IgE from peritoneal mast cells and completely suppressed IgE-mediated anaphylaxis. Rapid desensitization of reNSGS mice with anti-Fc epsilon RI alpha mAbs also safely removed similar to 98% of mast cell IgE and prevented IgE-mediated anaphylaxis. Conclusions: Rapid desensitization with anti-Fc epsilon RI alpha mAbs may be a safe, effective, and practical way to prevent IgE-mediated anaphylaxis.