Human IgG-mediated Anaphylaxis

描述（由申请人提供）：治疗性单克隆抗体（mAb），如英夫利西单抗，是制药行业增长最快的部分。这些mAb的使用提供了实质性益处，但可能导致IgG抗mAb抗体和过敏反应的产生。小鼠和人类研究表明，重复输注这些mAb引起的过敏反应可能是由IgG而不是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。我们已经开发了新的外周血检测，可以区分小鼠IgE-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-4 R浓度和T细胞IL-4 R表达的增加，而小鼠IgG-，而不是IgE介导的过敏反应与中性粒细胞Fc减少？RIII表达。初步体外研究表明，这些相同的测定将有助于区分人IgE与IgG介导的过敏反应。本提案将评价相同的试验是否可用于人体体内，以提供人IgG介导的过敏反应存在的证据。具体来说，我们将使用这些检测方法，一种已建立的IgE介导的过敏反应检测方法（血清类胰蛋白酶浓度），IgG抗英夫利西单抗抗体测定和临床评价，以评价IgG介导的过敏反应是否在无IgE介导的过敏反应证据的情况下，在存在英夫利西单抗IgG抗体的接受英夫利西单抗治疗的克罗恩病患者中更频繁发生（我们的主要终点）和/或对英夫利西单抗输注发生反应的患者（我们的次要终点）。阳性结果将支持人IgG介导的速发型过敏反应的存在，并可通过识别可从改变治疗或使用可预防IgG介导的速发型过敏反应的药物进行预治疗中获益的患者来改善该疾病的诊断和预防。 公共卫生相关性：蛋白质，包括单克隆抗体，是增长最快的治疗类别。对蛋白质治疗剂的过敏反应，包括休克（过敏反应），是使用蛋白质治疗剂的一个相当大且日益严重的问题。我们提出的研究将确定过敏反应是否可由蛋白质治疗剂的IgG抗体引起。这将提高通过识别使用特定蛋白质治疗可能导致这种疾病的个体来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.