Peanut-Specific IgG4 mAbs Promote Regulatory Immune Responses Ex Vivo and Improve Oral Immunotherapy in Mice

Peanut allergy remains a clinical challenge, with limited treatment options such as omalizumab (Xolair) and allergen immunotherapy (AIT). However, these are constrained by eligibility and safety concerns. AIT induces protective allergen-neutralizing IgG4 in most, but not all patients. Allergen-neutralizing IgG4 competes with allergen-specific IgE, inhibits FcεRI-mediated mast cell activation, and inhibits IgE-facilitated antigen presentation via CD23. Recent findings suggest that combining omalizumab with AIT enhances safety and reduces side effects. We hypothesize that controlled allergen exposure combined with peanut-specific IgG4 mAbs (MY-4-mAbs) prevents IgE binding to peanut allergens, reduces CD23-mediated allergen presentation and Th2 responses, and skews immunity towards protective allergen-specific IgG while limiting allergen-specific IgE induction.

PBMCs from peanut-allergic donors were exposed to Ara h 2 with or without MY-4-mAbs. Th2 cytokines, Foxp3+ Tregs, and IgE-facilitated allergen binding (FAB) to B cells were assessed. In vivo, peanut-sensitized C3H/HeJ mice underwent oral-AIT with peanut extract with or without MY-4-mAbs and were monitored for anaphylaxis during and after oral-AIT. Additionally, peanut-specific IgG and IgE levels were measured before and after oral-AIT.

Ex vivo, MY-4-mAbs with Ara h 2 suppressed Th2 cytokines, enhanced IL-10 secretion, and inhibited FAB. MY-4-mAbs redirected allergen binding to myeloid antigen-presenting cells and promoted tolerance-associated responses. In vivo, the combination maintained peanut-specific IgG induced during oral-AIT, prevented increases in IgE, and reduced mast cell activation.

Allergen-specific IgG4 mAbs with controlled allergen exposure may improve the safety and efficacy of peanut AIT while promoting tolerance-associated immune responses, which might allow disease modification towards allergen tolerance.