IgGenix, Inc, South San Francisco, Calif.
IgGenix, Inc, South San Francisco, Calif.
J Allergy Clin Immunol. 2024 Nov;154(5):1241-1248.e7. doi: 10.1016/j.jaci.2024.07.014. Epub 2024 Jul 26.
Existing therapeutic strategies are challenged by long times to achieve effect and often require frequent administration. Peanut-allergic individuals would benefit from a therapeutic that provides rapid protection against accidental exposure within days of administration while carrying little risk of adverse reactions.
Guided by the repertoire of human IgE mAbs from allergic individuals, we sought to develop a treatment approach leveraging the known protective effects of allergen-specific IgG4 antibodies.
We applied our single-cell RNA-sequencing SEQ SIFTER platform (IgGenix, Inc, South San Francisco, Calif) to whole blood samples from peanut-allergic individuals to discover IgE mAbs. These were then class-switched by replacing the IgE constant region with IgG4 while retaining the allergen-specific variable regions. In vitro mast cell activation tests, basophil activation tests, ELISAs, and an in vivo peanut allergy mouse model were used to evaluate the specificity, affinity, and activity of these recombinant IgG4 mAbs.
We determined that human peanut-specific IgE mAbs predominantly target immunodominant epitopes on Ara h 2 and Ara h 6 and that recombinant IgG4 mAbs effectively block these epitopes. IGNX001, a mixture of 2 such high-affinity IgG4 mAbs, provided robust protection against peanut-mediated mast cell activation in vitro as well as against anaphylaxis upon intragastric peanut challenge in a peanut allergy mouse model.
We developed a peanut-specific IgG4 antibody therapeutic with convincing preclinical efficacy starting from a large repertoire of human IgE mAbs from demographically and geographically diverse individuals. These results warrant further clinical investigation of IGNX001 and underscore the opportunity for the application of this therapeutic development strategy in other food and environmental allergies.
现有的治疗策略需要很长时间才能发挥作用，而且往往需要频繁给药。花生过敏患者将受益于一种治疗方法，该方法能在给药后几天内迅速提供针对意外暴露的保护，同时不良反应风险很小。
根据过敏个体的人类 IgE mAb 库，我们寻求开发一种利用过敏原特异性 IgG4 抗体已知保护作用的治疗方法。
我们应用我们的单细胞 RNA 测序 SEQ SIFTER 平台（IgGenix，Inc，加利福尼亚州旧金山南部）从花生过敏个体的全血样本中发现 IgE mAb。然后，通过用 IgG4 替换 IgE 恒定区，同时保留过敏原特异性可变区，将这些抗体进行类别转换。在体外肥大细胞激活试验、嗜碱性粒细胞激活试验、ELISA 和体内花生过敏小鼠模型中，评估这些重组 IgG4 mAb 的特异性、亲和力和活性。
我们确定了人类花生特异性 IgE mAb 主要针对 Ara h 2 和 Ara h 6 上的免疫优势表位，并且重组 IgG4 mAb 可有效阻断这些表位。IGNX001 是两种高亲和力 IgG4 mAb 的混合物，可在体外有效阻止花生介导的肥大细胞激活，并在花生过敏小鼠模型中防止口服花生挑战引起的过敏反应。
我们从来自不同人群的大量人类 IgE mAb 中开发了一种具有令人信服的临床前疗效的花生特异性 IgG4 抗体治疗方法。这些结果证明了 IGNX001 进一步临床研究的必要性，并强调了在其他食物和环境过敏中应用这种治疗开发策略的机会。
