Allergen-crosslinked IgE triggers allergy by interacting with its receptor on basophils and mast cells. The anti-IgE monoclonal antibody omalizumab can alleviate allergy by competing with the receptor for IgE binding. However, along with neutralization, omalizumab also inhibits IgE degradation, which is clinically associated with high-dose and total IgE accumulation problems. In this study, we have developed an IgE-eliminating antibody on the basis of omalizumab, which has pH-dependent Fabs and an Fc with high affinity for FcγRIIb. In mice, the antibody rapidly eliminated total serum IgE to baseline levels and caused lower free IgE levels than omalizumab. At low dosages, the antibody also exhibited favorable IgE elimination effects. In addition, the antibody can degrade the corresponding allergen with the removal of IgE, addressing the allergy from its source. Introduction of the M252Y/S254T/T256E (YTE) mutation into this antibody prolongs its serum half-life without reducing potency. Thus, this engineered antibody holds a promising therapeutic option for allergy patients. Mechanistic insights are also included in this study.

中文翻译：

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通过增强 FcγRIIb 结合的 pH 敏感抗体减少循环 IgE 和过敏原


过敏原交联 IgE 通过与嗜碱性粒细胞和肥大细胞上的受体相互作用来触发过敏。抗 IgE 单克隆抗体奥马珠单抗可以通过与受体竞争 IgE 结合来缓解过敏。然而，除了中和作用，奥马珠单抗还抑制 IgE 降解，这在临床上与高剂量和总 IgE 积累问题有关。在这项研究中，我们开发了一种基于奥马珠单抗的 IgE 消除抗体，它具有 pH 依赖性的 Fabs 和对 FcγRIIb 具有高亲和力的 Fc。在小鼠中，该抗体迅速将血清总 IgE 消除至基线水平，并导致游离 IgE 水平低于奥马珠单抗。在低剂量下，该抗体也表现出良好的 IgE 消除效果。此外，该抗体可以通过去除 IgE 来降解相应的过敏原，从源头上解决过敏问题。在该抗体中引入 M252Y/S254T/T256E （YTE） 突变可延长其血清半衰期，而不会降低效力。因此，这种工程抗体为过敏患者提供了有前途的治疗选择。本研究还包括机理见解。