Suppression of IgE-Mediated Disease by Polyclonal Rapid Desensitization

描述（由申请人提供）：该翻译提案使用快速脱敏方法来开发安全、有效和快速的方法来抑制人IgE介导的疾病。我们已经可以通过每小时注射双倍剂量的抗Fc β RIα单克隆抗体（mAb），安全、快速地使小鼠对所有抗原（Ag）脱敏，从剂量太小而不能引起临床反应开始。使用该方案，使用仅结合未被IgE占据的FcεRI的抗Fc εRIα mAb治疗小鼠：（1）快速诱导IgE/Fc εRI信号传导的短暂抑制;（2）缓慢清除所有肥大细胞膜FcεRI和IgE，即使在血清IgE水平较高的小鼠中也是如此。在小鼠中，我们的方法比用Ag快速脱敏更安全，并且可以通过重复注射抗Fc εRIα mAb安全地无限期维持。我们现在将使这种方法适用于人类，使其更快速，更安全。目的1使用与我们的抗小鼠Fc β RI α mAb具有相似特征的抗人（hu）Fc β RIα mAb来脱敏：（1）huIgE处理的表达huFc β RIα而不是小鼠Fc β RI α的转基因小鼠;和（2）缺乏细胞因子受体的免疫缺陷NOD/SCID小鼠 普通吗链，表达转基因huSCF、huIL-3和huGM-CSF，并且已经用 人脐带血细胞（这些小鼠分泌人IgE并产生人肥大细胞和嗜碱性粒细胞）。我们还修改了我们的脱敏方案，使其更适合于潜在的人体使用，皮下注射抗huFc β RIα mAb，而不是腹腔注射。目的2通过使用可去除所有肥大细胞huFcεRI的市售mAb（无论其IgE占用率如何），加速抗huFc εRIα mAb的脱敏。我们还生成了自己的具有这种特性的mAb，以便我们可以在目标3中修改其结构。目的3提高抗人Fc β RIα单抗快速脱敏的安全性。我们通过以下方式进一步抑制快速脱敏过程中可能发生的任何临床反应：（1）抑制H1和H2受体;（2）抑制酪氨酸激酶syk;（3）工程化抗Fc γ RIIb α mAb，使其更积极地与抑制性受体FcγRIIb结合。这些目标的成功完成可以提供一种安全和快速地预防所有Fc γ RI介导的疾病的方法。

DESCRIPTION (provided by applicant): This translational proposal uses a rapid desensitization approach to develop a safe, effective and rapid way to suppress human IgE-mediated disease. We can already safely, rapidly desensitize mice to all antigens (Ags) by injecting them hourly with doubling doses of an anti-FcϵRIα monoclonal antibody (mAb), starting with a dose too small to elicit a clinical reaction. Using this protocol to treat mice with an anti-FcϵRIα mAb that only binds FcϵRI that is not occupied by IgE: (1) rapidly induces short-lived suppression of IgE/FϵRI signaling; and (2) slowly removes all mast cell membrane FcϵRI and IgE, even in mice that have high serum IgE levels. In mice, our approach is safer than rapid desensitization with Ag and can safely be maintained indefinitely by repeated injection of anti-FcϵRIα mAb. We will now adapt this approach to humans, make it more rapid, and make it even safer. Aim 1 uses an anti-human (hu) FcϵRIα mAb that has characteristics similar to our anti-mouse FcϵRIα mAb to desensitize: (1) huIgE-treated transgenic mice that express huFcϵRIα instead of mouse FcϵRIα; and (2) immunodeficient NOD/SCID mice that lack the cytokine receptor common ? chain, express transgenic huSCF, huIL-3, and huGM-CSF and have been reconstituted with human cord blood cells (these mice secrete human IgE and generate human mast cells and basophils). We also modify our desensitization protocol to make it more compatible with potential human use by injecting anti-huFcϵRIα mAb subcutaneously instead of intraperitoneally. Aim 2 accelerates desensitization with antihuFcϵRIα mAb by using a commercially available mAb that removes all mast cell huFcϵRI, regardless of its IgE occupancy. We also generate our own mAb that has this property so that we can modify its structure in Aim 3. Aim 3 increases the safety of rapid desensitization with anti-huFcϵRIα mAb. We further suppress any clinical reactions that might occur during rapid desensitization by: (1) inhibiting H1 and H2 receptors; (2) inhibiting the tyrosine kinase syk; and (3) engineering anti-FcϵRIα mAb to bind more avidly to the inhibitory receptor, FcγRIIb. Successful completion of these aims could provide a way to safely and rapidly protect against all FcϵRI-mediated disease.