Combined IgE neutralization and Bifidobacterium longum supplementation reduces the allergic response in models of food allergy

Abstract

IgE is central to the development of allergic diseases, and its neutralization alleviates allergic symptoms. However, most of these antibodies are based on IgG1, which is associated with an increased risk of fragment crystallizable-mediated side effects. Moreover, omalizumab, an anti-IgE antibody approved for therapeutic use, has limited benefits for patients with high IgE levels. Here, we assess a fusion protein with extracellular domain of high affinity IgE receptor, FcεRIα, linked to a IgD/IgG4 hybrid Fc domain we term IgETRAP, to reduce the risk of IgG1 Fc-mediated side effects. IgETRAP shows enhanced IgE binding affinity compared to omalizumab. We also see an enhanced therapeutic effect of IgETRAP in food allergy models when combined with Bifidobacterium longum, which results in mast cell number and free IgE levels. The combination of IgETRAP and B. longum may therefore represent a potent treatment for allergic patients with high IgE levels.

Degranulation of Mast Cells as a Target for Drug Development

“…Considering that the use of omalizumab also has a potential risk of anaphylaxis [91], a non-IgG1 agent such as IgE TRAP may be a better combination option for OIT. In fact, IgE TRAP reduced free IgE levels in the sera of CSU patients more effectively than omalizumab in vitro and better controlled high blood IgE levels in cynomolgus monkeys when administered subcutaneously [37]. In an immunogenicity assay conducted by EpiScreen using CD8 + -depleted PBMCs from at least 50 individuals with various HLA types, IgE TRAP showed a T cell response in <10% of donors, comparable to the response observed from omalizumab and trastuzumab (anti-HER2 receptor mAb; Herceptin) used as negative controls [37].…”

“…TSLP alone has little effect on mast cells but enhances IL-33-induced cytokine secretion by mast cells and MCPs [29]. Additionally, allergen sensitization, either through the skin or intestine, induces mast cell activation in an IgE-dependent manner, causing oral allergeninduced anaphylaxis [35][36][37]. Particularly, food allergen sensitization through the skin increases local and systemic levels of IL-33, ultimately inducing the expansion of mast cells in the intestine [38].…”

“…Mast cells can also produce IL-33 upon IgE stimulation, as well as P2RX7 activation by helminth infection [39,40]. The blocking of IgE in a food allergy mouse model reduces Il-33 expression and the number of intestinal mast cells [37].…”

“…Presently, the fusion protein IgE TRAP (GI-301), in which the IgD/IgG4 hybrid Fc domain is linked to the α chain of FcεRI, is being developed as an IgE blocking agent [37]. The α chain of FcεRI of IgE TRAP has a high IgE affinity, about 69 times stronger than that of omalizumab (Table 1).…”

“…The α chain of FcεRI of IgE TRAP has a high IgE affinity, about 69 times stronger than that of omalizumab (Table 1). In addition, the Fc domain of IgE TRAP has no binding sites for FcγRs and complement component 1q (C1q), unlike the IgG1 Fc domain used for all other anti-IgE agents, and therefore, IgE TRAP does not induce ADCC, complement-dependent cytotoxicity (CDC), or IgG-mediated anaphylaxis (Table 1) [37]. A combination approach with omalizumab has been sought to mitigate the potential risk of developing anaphylaxis to OIT.…”