THE HYPEREOSINOPHILIC SYNDROMES AND MEPOLIZUMAB

高嗜酸性粒细胞综合征和美泊利珠单抗

• 批准号: 7058239
• 负责人: Gerald J Gleich
• 金额: $ 33.06万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7058239
• 关键词: SDS polyacrylamide gel electrophoresis; T lymphocyte; antigen presentation; biotechnology; blood chemistry; blood disorder chemotherapy; cell differentiation; clinical research; clinical trials; colony stimulating factor; cooperative study; cytokine receptors; eosinophilia; flow cytometry; human subject; human therapy evaluation; immunologic assay /test; immunotherapy; interleukin 5; leukocyte count; longitudinal human study; monoclonal antibody; outcomes research; patient oriented research; polymerase chain reaction; receptor expression

DESCRIPTION (provided by applicant): The term, hypereosinophilic syndromes (HES), refers a spectrum of patients with elevated blood eosinophils. Over the past two decades, certain categories of patients have been recognized as HES subgroups. For example, the syndromes of episodic angioedema associated with eosinophilia, the syndrome of nodules, eosinophilia, rheumatism, dermatitis and swelling, HES associated with T cell clones, and the myeloproliferative variant have been recognized. Patients with T cell clones producing TH2 cytokines show evidence of L-5 production and IL-5 stimulates bone marrow production and activation of eosinophils. Mepolizumab is a high-affinity, specific, humanized monoclonal antibody to IL-5 which rapidly depletes eosinophils from the peripheral blood. This antibody has been administered to patients with several diseases, including asthma, and it is remarkably free of side-effects. The accompanying core clinical protocol describes a trial of mepolizumab for the treatment of HES; this mechanistic proposal seeks to understand the basic mechanisms underlying the response to mepolizumab. Specifically, we will: 1. Determine whether mepolizumab modulates T-cell functions, including their differentiation and cytokine production. 2. Test whether mepolizumab treatment suppresses eosinophil activation, cytokine production and expression of the IL-5 receptor on the eosinophils of treated patients. 3. Determine whether mepolizumab reveals heterogeneity in HES not heretofore recognized. Overall, this is a unique and unprecedented opportunity to conduct a multicenter study involving investigators with considerable experience to investigate the effects of anti-IL-5 administration and to determine which markers of eosinophil activation are best correlated with disease activity. Previous studies have largely been from single institutions, and this will be the first multicenter study. We anticipate the results will shed new light on this disease by defining essentially all HES subtypes and their frequencies, by determining the ability of anti-IL-5 to alter the immunological bases of HES, by identifying and investigating patients not responsive to anti-IL-5 and by identifying the characteristics of patients who can be effectively treated with anti-IL-5.

描述（由申请人提供）：术语嗜酸性粒细胞增多综合征（HES）是指一系列血液嗜酸性粒细胞升高的患者。在过去的二十年中，某些类别的患者已被认为是 HES 亚组。例如，已认识到与嗜酸性粒细胞增多相关的阵发性血管性水肿综合征、结节综合征、嗜酸性粒细胞增多、风湿病、皮炎和肿胀、与T细胞克隆相关的HES以及骨髓增殖性变体。具有产生 TH2 细胞因子的 T 细胞克隆的患者显示出 L-5 产生的证据，并且 IL-5 刺激骨髓产生和嗜酸性粒细胞的激活。美泊利单抗是一种针对 IL-5 的高亲和力、特异性、人源化单克隆抗体，可快速消耗外周血中的嗜酸性粒细胞。这种抗体已被用于患有包括哮喘在内的多种疾病的患者，并且非常没有副作用。随附的核心临床方案描述了美泊利单抗治疗 HES 的试验；该机制提案旨在了解美泊利单抗反应的基本机制。具体来说，我们将： 1. 确定美泊利单抗是否调节 T 细胞功能，包括其分化和细胞因子产生。 2.测试美泊利单抗治疗是否抑制接受治疗的患者的嗜酸性粒细胞活化、细胞因子产生以及嗜酸性粒细胞上IL-5受体的表达。 3. 确定美泊利单抗是否显示出迄今为止尚未认识到的 HES 异质性。总体而言，这是一次独特且前所未有的机会，可以让具有丰富经验的研究人员参与多中心研究，以研究抗 IL-5 给药的效果，并确定哪些嗜酸性粒细胞活化标志物与疾病活动最相关。之前的研究主要来自单一机构，而这将是第一个多中心研究。我们预计这些结果将通过定义基本上所有 HES 亚型及其频率、确定抗 IL-5 改变 HES 免疫基础的能力、通过识别和调查对抗 IL 不敏感的患者，为这种疾病提供新的认识。 -5 并通过识别可以用抗 IL-5 有效治疗的患者的特征。