Rapid desensitization of humanized mice with anti-human FcεRIα monoclonal antibodies.

Abstract Background Anaphylaxis is classically mediated by allergen crosslinking of IgE bound to the α chain of FceRI, the mast cell/basophil high affinity IgE receptor. Allergen crosslinking of the IgE/FceRI 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 FceRIα monoclonal antibody (mAb). Objective Use humanized mice to extend these results to humans. Methods We actively immunized huFceRIα/F709 mice, which express human (hu) instead of mouse FceRIα and a mutant IL-4 receptor that lacks inhibitory function. We passively immunized huFceRIα 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-huFceRIα mAbs that bind FceRIα regardless of its association with IgE (non-competing mAbs), and/or mAbs that compete with IgE for huFceRIα binding (competing mAbs). Anaphylaxis was induced by intravenous injection of antigen or anti-huIgE mAb. Results Anti-huFceRIα 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 huFceRIα mice and egg-allergic huFceRIα/F709 mice with anti-FceRIα mAbs safely removed >98% of IgE from peritoneal mast cells and completely suppressed IgE-mediated anaphylaxis. Rapid desensitization of reNSGS mice with anti-FceRIα mAbs also safely removed ∼98% of mast cell IgE and prevented IgE-mediated anaphylaxis. Conclusion Rapid desensitization with anti-FceRIα mAbs may be a safe, effective, and practical way to prevent IgE-mediated anaphylaxis.