Safe, rapid suppression of IgE-mediated allergy with monovalent (mv) anti-human (hu) FceRIa monoclonal antibody (mAb)

Abstract

Abstract Background Mast cells and FceRI, the high affinity IgE receptor (R), are central to allergy pathogenesis. Strong FceRI crosslinking induces severe allergy while low-level crosslinking removes IgE from mast cells and desensitizes them. Hypothesis IgE-mediated allergy can be safely suppressed by a mv anti-FceRIa mAb that persistently crosslinks FceRI to a limited extent. Methods We tested our hypothesis with: 1) divalent (dv) anti-huFceRIa mAbs that bind FceRI regardless of its association with IgE; 2) mv Fab/Fc derivatives of these mAbs, which do not directly crosslink FceRI; 3) mice that express hu, instead of mouse FceRIa; hu FceRIa mice that also have a mutant, hyperresponsive IL-4 receptor; and immunodeficient, human stem cell factor/IL-3/GM-CSF-secreting mice that develop large numbers of activated human mast cells following hu cord blood cell reconstitution; and 4) IL-4 and propranolol treatment that increases sensitivity to mast cell-released mediators. Results 1) A single injection of mv anti-huFceRIa mAb protects our mice against IgE-mediated anaphylaxis and food allergy. 2) A rapid desensitization approach increases the safety of administration of this mv mAb. 3) The mv mAb decreases mast cell responsiveness to FceRI crosslinking and causes loss of most IgE. 4) Protection is maintained and increased by repeated injection of mv anti-huFceRIa mAb. 5) FcgRs are required for FceRI crosslinking by mv anti-FceRIa mAb. 6) Rapid desensitization with mv anti-FceRIa mAb provides a better combination of safety and efficacy than rapid desensitization with dv anti-FceRIa mAb or with a relevant allergen. Conclusion Desensitization with mv anti-huFceRIa mAb is a promising therapy for the suppression of hu IgE-mediated allergy.