Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
J Allergy Clin Immunol. 2021 May;147(5):1838-1854.e4. doi: 10.1016/j.jaci.2020.10.045. Epub 2020 Dec 14.
Mast cell and basophil activation by antigen cross-linking of FcεRI-bound IgE is central to allergy pathogenesis. We previously demonstrated global suppression of this process by rapid desensitization with anti-FcεRIα mAbs.
We sought to determine whether use of monovalent (mv) anti-FcεRIα mAbs increases desensitization safety without loss of efficacy.
mv anti-human (hu) FcεRIα mAbs were produced with mouse-derived immunoglobulin variable regions and huIgG or huIgG C regions and were used to suppress murine IgE-mediated anaphylaxis and food allergy. mAbs were administered as a single dose or as serially increasing doses to mice that express hu instead of mouse FcεRIα; mice that additionally have an allergy-promoting IL-4Rα mutation; and hu cord blood-reconstituted immunodeficient, hu cytokine-secreting, mice that have large numbers of activated hu mast cells. Anaphylaxis susceptibility was sometimes increased by treatment with IL-4 or a β-adrenergic receptor antagonist.
mv anti-hu FcεRIα mAbs are considerably less able than divalent mAbs are to induce anaphylaxis and deplete mast cell and basophil IgE, but mv mAbs still strongly suppress IgE-mediated disease. The mv mAbs can be safely administered as a single large dose to mice with typical susceptibility to anaphylaxis, while a rapid desensitization approach safely suppresses disease in mice with increased susceptibility. Our huIgG variant of mv anti-huFcεRIα mAb is safer than our huIgG variant is, apparently because reduced interactions with FcεRs decrease ability to indirectly cross-link FcεRI.
mv anti-FcεRIα mAbs more safely suppress IgE-mediated anaphylaxis and food allergy than divalent variants of the same mAbs do. These mv mAbs may be useful for suppression of huIgE-mediated disease.
通过 FcεRI 结合的 IgE 交联使肥大细胞和嗜碱性粒细胞活化是过敏发病机制的核心。我们之前证明，通过快速脱敏用抗 FcεRIα mAbs 可使该过程全面受到抑制。
我们旨在确定使用单价（mv）抗 FcεRIα mAbs 是否在不降低疗效的情况下增加脱敏安全性。
使用源自鼠的免疫球蛋白可变区和人 IgG 或人 IgG C 区产生了 mv 抗人（hu）FcεRIα mAbs，并将其用于抑制鼠 IgE 介导的过敏反应和食物过敏。mAbs 被用作单次剂量或连续递增剂量施用于表达 hu 而不是鼠 FcεRIα 的小鼠；此外具有促进过敏的 IL-4Rα 突变的小鼠；以及具有大量活化的 hu 肥大细胞的 hu 脐带血重建的免疫缺陷、hu 细胞因子分泌、小鼠。用 IL-4 或β-肾上腺素能受体拮抗剂治疗有时会增加过敏易感性。
与二价 mAbs 相比，mv 抗 hu FcεRIα mAbs 诱导过敏反应和耗尽肥大细胞和嗜碱性粒细胞 IgE 的能力要低得多，但 mv mAbs 仍可强烈抑制 IgE 介导的疾病。mv mAbs 可以安全地作为单次大剂量施用于对过敏反应具有典型易感性的小鼠，而快速脱敏方法可安全地抑制易感性增加的小鼠的疾病。我们的 mv 抗 huFcεRIα mAb 的 huIgG 变体比我们的 huIgG 变体更安全，显然是因为与 FcεRs 的相互作用减少降低了间接交联 FcεRI 的能力。
与相同 mAbs 的二价变体相比，mv 抗 FcεRIα mAbs 更安全地抑制 IgE 介导的过敏反应和食物过敏。这些 mv mAbs 可能对抑制 huIgE 介导的疾病有用。
