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

Background 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. Methods 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. Results 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. Conclusions 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.