Human IgG-mediated Anaphylaxis

描述(申请人提供)：治疗性单抗(MAbs)，如英夫利昔单抗，构成了制药行业增长最快的部分。这些单抗的使用提供了实质性的好处，但也会导致免疫球蛋白抗体的产生和过敏反应。小鼠和人类的研究表明，反复滴注这些单抗引起的过敏反应可能是由IgG介导的，而不是由IgE介导的；然而，人类IgG介导的过敏反应的存在从未得到证实。我们开发了一种新的外周血液检测方法，可以区分小鼠IgE-和免疫球蛋白G介导的过敏反应：小鼠免疫球蛋白E-而不是免疫球蛋白G介导的过敏反应与血清中可溶性IL-4R浓度和T细胞IL-4R表达的升高有关，而鼠免疫球蛋白抗体介导的过敏反应与中性粒细胞Fc？RIII表达的降低有关。初步的体外研究表明，这些相同的检测方法将有助于区分人类免疫球蛋白E和免疫球蛋白介导的过敏反应。这项建议将评估是否可以在人体内使用相同的检测方法，以提供证据证明人类免疫球蛋白介导的过敏反应的存在。具体地说，我们将使用这些检测方法、已建立的IgE介导的过敏反应检测方法(血清类胰蛋白酶浓度)、抗英夫利昔单抗抗体的检测方法和临床评估，以评估在英夫利昔单抗抗体阳性的克罗恩病患者(我们的主要终点)和/或对英夫利昔单抗输注产生反应(我们的次要终点)的患者中，是否更容易发生没有IgE介导过敏反应证据的IgG介导的过敏反应。阳性结果将支持人类免疫球蛋白介导的过敏反应的存在，并可能通过确定哪些患者将受益于改变治疗方法或使用可能防止免疫球蛋白介导的过敏反应的药物来改善对这种疾病的诊断和预防。 与公共卫生相关：蛋白质，包括单抗，是增长最快的治疗类别。蛋白质疗法的过敏反应，包括休克(过敏反应)，是使用它们的一个相当大的且日益严重的问题。我们提议的研究将确定过敏反应是否可以由蛋白质疗法的抗体引起。这将通过识别使用特定蛋白质疗法可能导致这种疾病的个体来提高预防过敏反应的能力。

DESCRIPTION (provided by applicant): Therapeutic monoclonal antibodies (mAbs), such as infliximab, constitute the fastest growing segment of the pharmaceutical industry. Use of these mAbs has provided substantial benefits, but can cause development of IgG anti-mAb antibodies and anaphylaxis. Mouse and human studies suggest that anaphylaxis caused by repeated infusion of these mAbs may be mediated by IgG rather than IgE; however, the existence of human IgG-mediated anaphylaxis has never been proven. We have developed novel peripheral blood assays that can distinguish murine IgE- from IgG-mediated anaphylaxis: murine IgE-, but not IgG-mediated anaphylaxis is associated with increases in serum soluble IL- 4R¿ concentration and T cell IL-4R¿ expression, while murine IgG-, but not IgE-mediated anaphylaxis is associated with decreased neutrophil Fc?RIII expression. Preliminary in vitro studies suggest that these same assays will be useful for differentiating human IgE- vs. IgG-mediated anaphylaxis. This proposal will evaluate whether the same assays may be used in vivo in humans to provide evidence for the existence of human IgG-mediated anaphylaxis. Specifically, we will use these assays, an established test for IgE- mediated anaphylaxis (serum tryptase concentration), an assay for IgG anti-infliximab antibodies and clinical evaluation to evaluate whether IgG-mediated anaphylaxis without evidence of IgE-mediated anaphylaxis develops more frequently in infliximab-treated Crohn's disease patients who have IgG antibodies to infliximab (our primary endpoint) and/or in patients who develop reactions to infliximab infusion (our secondary endpoint). A positive result would support the existence of human IgG-mediated anaphylaxis and could lead to improved diagnosis and prevention of this disorder by identifying patients who would benefit from changing therapy or pre-treatment with drugs that may prevent IgG-mediated anaphylaxis. PUBLIC HEALTH RELEVANCE: Proteins, including monoclonal antibodies, are the fastest growing category of therapeutic. Allergic reactions to protein therapeutics, including shock (anaphylaxis), are a considerable and growing problem with their use. Our proposed studies will determine whether anaphylaxis can be caused by IgG antibodies to protein therapeutics. This should improve the ability to prevent anaphylaxis by identifying individuals in whom the use of a specific protein therapeutic is likely to cause this disorder.