Human IgG-mediated Anaphylaxis

描述（由申请人提供）：治疗性单克隆抗体（mab），如英夫利昔单抗，构成了制药行业增长最快的部分。使用这些单抗提供了实质性的好处，但可能导致IgG抗单抗抗体和过敏反应的发展。小鼠和人的研究表明，反复输注这些单克隆抗体引起的过敏反应可能是由IgG介导的，而不是IgE；然而，人类igg介导的过敏反应的存在从未得到证实。我们已经开发了一种新的外周血检测方法，可以区分小鼠IgE-和IgG介导的过敏反应：小鼠IgE-而不是IgG介导的过敏反应与血清可溶性IL-4R浓度和T细胞IL-4R表达的增加有关，而小鼠IgG-而不是IgE介导的过敏反应与中性粒细胞Fc？RIII表达式。初步的体外研究表明，这些相同的测定将有助于区分人IgE与igg介导的过敏反应。该提案将评估是否可以在人体内使用相同的测定，以提供证据，证明存在人igg介导的过敏反应。具体地说，我们将使用这些试验，一个既定的测试IgE介导的过敏反应（血清胰蛋白酶浓度），一项IgG抗英夫利昔单抗检测和临床评估，以评估在英夫利昔单抗治疗的克罗恩病患者中，有英夫利昔单抗IgG抗体（我们的主要终点）和/或对英夫利昔单抗输注有反应的患者中，是否更频繁地发生无ige介导的过敏反应。阳性结果将支持人类igg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可能预防igg介导的过敏反应的改变治疗或药物预处理，从而改善对这种疾病的诊断和预防。

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.