Eosinophils and Eosinophil Activation in the Pathogenesis of Human Disease

人类疾病发病机制中的嗜酸性粒细胞和嗜酸性粒细胞激活

• 批准号: 9161679
• 负责人: Amy Klion
• 金额: $ 125.83万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9161679
• 关键词: Adrenal gland hypofunction; Adverse effects; Aftercare; Amyotrophic Lateral Sclerosis; Angioneurotic Edema; Antibodies; Apoptosis; Asthma; Benign; Biological; Biological Markers; Blood; Bone Marrow; Bone Tissue; Cells; Cessation of life; Clinical Trials; Clinical Trials Design; Collaborations; Data; Data Analyses; Dermatitis; Development; Diethylcarbamazine; Disease; Disease remission; Disseminated eosinophilic collagen disease; Double-Blind Method; Drug Hypersensitivity; Engineering; Enrollment; Eosinophil Granule Proteins; Eosinophilia; Eosinophilic leukemia; Etiology; Experimental Autoimmune Encephalomyelitis; Extrinsic asthma; Family; Feces; Flow Cytometry; Genetic study; Glucocorticoids; Goals; Helminths; Homeostasis; Hypersensitivity; IgG1; IgG4; Imatinib; In complete remission; Infection; Interleukin-2; Interleukin-5; International; Ligands; Liquid substance; Loa loa; Loiasis; Lymphocyte; Manuscripts; Measures; Methods; Microfilaria; Monitor; Mus; Myeloproliferative disease; Outcome Measure; PDGFRA gene; Paper; Parasitic infection; Pathogenesis; Patient Outcomes Assessments; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Placebo Control; Plasma; Rare Diseases; Reaction; Refractory; Role; Severe Adverse Event; Societies; Sputum; Steroid Resistance; Subgroup; Suspension substance; Suspensions; Symptoms; Syndrome; System; Therapeutic; Tissues; Transgenic Organisms; Urine; Whole Blood; Work; clinical efficacy; cohort; contrast enhanced; cytokine; effective therapy; eosinophil; gastrointestinal; human SIGLEC8 protein; human disease; in vitro Assay; inhibitory surface receptor; mast cell; mastocytosis; meetings; mepolizumab; mouse model; neoplastic; neutrophil; novel; novel diagnostics; open label; pediatric patients; peripheral blood; placebo controlled study; pre-clinical; prevent; receptor; response; stem; targeted treatment; tool

Using a cohort of more than 400 subjects with a wide variety of eosinophilic disorders, ranging from benign eosinophilia to eosinophilic leukemia, we have continued to identify and characterize novel subgroups of patients with eosinophilia. Episodic Angioedema with Eosinophilia (EAE; Gleichs Syndrome) is a rare disorder characterized by episodes of angioedema and eosinophilia that occur at monthly intervals and resolve spontaneously without therapy. Although the etiology of EAE is not yet known, we have demonstrated that multiple lineages, including lymphocytes, neutrophils and mast cells, are involved and may be related to disease pathogenesis (Khoury et al. Haematologica 2015). Whether these cells act directly or promote eosinophilia and eosinophil activation remains to be elucidated. Genetic studies are currently underway. Other subgroups of eosinophilic subjects currently under study include families with autosomal dominant eosinophilia, pediatric patients (Williams et al. J Allergy Clin Immunol 2014:133:AB149, paper submitted), and a cohort of subjects with eosinophilic dermatitis (Khoury et al. J Allergy Clin Immunol 2015:135:AB266). Therapy for eosinophilic disorders remains a primary focus of our group. In the past year, we have reached 50% enrollment in two clinical trials of targeted therapy for the treatment of HES. The first of these is a placebo-controlled, double-blind phase 2 trial of benralizumab (MedImmune/Astra Zeneca), an afucosylated antibody to IL-5 receptor alpha that has shown clinical efficacy in patients with eosinophilic asthma. The current trial stems, in part, from our prior pre-clinical work examining IL-5 receptor levels in patients with eosinophilia and/or mastocytosis (Wilson et al. J Allergy Clin Immunol 2011). To date, 10 of 20 planned subjects have been enrolled, of which 8 have entered the open-label phase of the study. The drug has been well-tolerated and early efficacy results are promising. The second trial is an open-label trial of dexpramipexole (Knopp Biosciences) in patients with steroid-resistant HES. Dexpramipexole was developed for the treatment of amyotrophic lateral sclerosis (ALS). Although it was well tolerated, dexpramipexole failed to show efficacy in a large phase 3 trial for this disease. It did, however, appear to selectively lower blood eosinophils, which prompted the current proof-of-concept open-label phase 2 trial in HES. To date, 5 of the 10 planned subjects have been enrolled. The drug has been well-tolerated and early efficacy results are encouraging. We have also completed enrollment in a new multicenter placebo-controlled, double-blind phase 3 clinical trial of mepolizumab (anti-IL-5 antibody) for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). In addition to the clinical trials described above, we continue to explore standard therapies for HES. We have analyzed data from an ongoing clinical trial of imatinib in subjects with FIP1L1/PDGFRA-positive myeloproliferative neoplasm (FP), PDGFRA-negative HES with myeloproliferative features (MP) and steroid-resistant without myeloproliferative features (SR) (Khoury et al. presented at the annual meeting of the International Eosinophil Society; manuscript submitted). Overall, imatinib response rates were 100% in the FP group (n= 16), 50% in the MP group (n=13) and 0% in the SR group (n=16). The presence of ≥ 4 myeloproliferative features was the sole predictor of response. After ≥ 18 months in complete remission, imatinib was tapered and discontinued in 8 FP and 1 MP subjects. Seven subjects (6 FP, 1 MP) remain in remission off therapy for a median of 29 months (range 14-36). We have also continued to enroll subjects in a double-blind clinical trial designed to assess the utility of a glucocorticoid challenge in determination of glucocorticoid responsiveness in HES and in a clinical trial of mepolizumab (humanized anti-IL-5 antibody) for treatment-refractory HES. Finally, in collaboration with GlaxoSmithKline and ICON, we have begun to collect data for development of a PRO (patient-reported outcome measure) for use in clinical trials in HES. We continue to explore the therapeutic potential of novel antibodies with the potential to target eosinophils, including two antibodies to the inhibitory surface receptors, siglec-8. Siglec-8 is an inhibitory receptor highly expressed on mature eosinophils in blood, bone marrow and tissue. Engagement of the receptor by its ligand or anti-Siglec 8 antibody induces eosinophil apoptosis in the presence of IL-5. Siglec-8 expression was quantified by flow cytometry using whole blood from 38 normal donors (ND) and 58 subjects with HES and was found to be high on eosinophils from normal and HES subjects, irrespective of HES subtype or therapy. Two humanized anti-Siglec-8 antibodies are currently in pre-clinical development, an IgG4 antibody and an IgG1 antibody that has been engineered to cause enhanced ADCC. We have demonstrated that both IgG1 and IgG4 anti-siglec 8 antibodies induce eosinophil apoptosis with similar efficiency in an in vitro assay using whole blood from normal and eosinophilic subjects in the presence of IL-5. In contrast, enhanced ADCC is observed only with the IgG1 antibody and may be limited in patients with very high eosinophil counts and a low NK:EO ratio (Legrand et al. J Allergy Clin Immunol 2015;135:AB221). Murine studies with the two antibodies are currently underway using a humanized IL-2 transgenic NOG mouse model. Helminth infections can be associated with dramatic eosinophilia and complications that are indistinguishable from HES. This is particularly true in loiasis where symptoms are associated with increased eosinophil granule protein levels (indicative of eosinophil activation and degranulation) as well as elevated levels of eosinophil-associated cytokines (Herrick et al. Clin Inf Dis 2015;60:55-63). In some infections, eosinophilia and eosinophil-related symptoms can be exacerbated by effective treatment. For example, treatment of the filarial infection loiasis with diethylcarbamazine (DEC) can be associated with severe adverse events, including death, that are accompanied by a dramatic rise in eosinophilia and are positively correlated with the number of circulating microfilariae in the blood. In the past year, we have enrolled the final subject in a double-blind, placebo-controlled study of the anti-IL-5 antibody, reslizumab, to prevent post-treatment side effects of DEC in patients with Loa loa infection. Finally, in the past year, we have continued to look for biomarkers of eosinophilic disease activity for use in monitoring responses to therapy and helping to dissect out the mechanisms of eosinophil pathogenesis. To this end, we have continued to explore the utility of our multiplex suspension array system developed to simultaneously measure the concentrations of 4 eosinophil granule proteins in serum and plasma (MBP, ECP, EDN and EPO) (Makiya et al. J Immunol Methods 2014) in biological fluids including stool, sputum and urine. Data to date suggest that increased levels of eosinophil granule proteins in stool may be a useful marker of gastrointestinal eosinophilia (Makiya et al. presented at the annual meeting of the International Eosinophil Society 2015) .

使用400多名患有多种嗜酸性疾病的受试者的队列，从良性嗜酸性粒细胞到嗜酸性白血病，我们继续识别和表征嗜酸性粒细胞菌患者的新型亚组。 嗜酸性粒细胞（EAE; Gleichs综合征）的发作性血管性水肿是一种罕见的疾病，其特征是血管性水肿和嗜酸性粒细胞增生的发作，每月以每月的间隔发生并在没有治疗的情况下自发解决。 尽管尚不清楚EAE的病因，但我们已经证明了包括淋巴细胞，中性粒细胞和肥大细胞在内的多个谱系涉及，并且可能与疾病发病机理有关（Khoury等人Heematologica 2015）。这些细胞是直接起作用还是促进嗜酸性粒细胞和嗜酸性粒细胞活化尚待阐明。目前正在进行遗传研究。目前正在研究的嗜酸性粒细胞受试者的其他亚组包括患有常染色体显性嗜酸性粒细胞，儿科患者的家族（Williams等人J Allergy Clin Immunol 2014：133：AB149，论文，提交了论文），以及与嗜酸性粒细胞性嗜酸性性欲炎（Khoury et al an immol and al al an ab2 als and ab2 and and and and and and and and and ab2 and and and and ab26）。 嗜酸性疾病的治疗仍然是我们小组的主要重点。在过去的一年中，我们在针对性治疗的两项临床试验中达到了50％的入学率。其中第一个是安慰剂对照的双盲相2试验（Medimmune/astra Zeneca），这是一种对IL-5受体α的抗糖基化抗体，在嗜酸性粒细胞性哮喘患者中显示出临床疗效。 当前的试验部分源于我们先前的临床前研究，研究了嗜酸性粒细胞增多症患者的IL-5受体水平（Wilson等人Jallergy Clin Immunol 2011）。 迄今为止，已经招募了20名计划的受试者中的10名，其中8个进入了研究的开放标签阶段。 该药物已经耐受耐受性，早期疗效结果是有希望的。第二次试验是对耐药HES患者的右甲己烯（KNOPP Biosciences）的开放标签试验。开发了右氨己烯，用于治疗肌萎缩性侧索硬化症（ALS）。尽管耐受性良好，但在该疾病的大型3期试验中，右甲苯二曲未能显示出疗效。 但是，它确实确实降低了血液嗜酸性粒细胞，这促使当前的概念证明开放标签2期试验在HES中。迄今为止，已经招募了10个计划对象中的5个。该药物已经耐受耐受性，令人鼓舞的是早期疗效结果。我们还完成了新的多中心安慰剂对照，双盲阶段3期临床试验（抗IL-5抗体），用于治疗用聚血管炎（EGPA）治疗嗜酸性粒细胞性肉芽肿病（EGPA）。 除了上述临床试验外，我们还继续探索HES的标准疗法。我们已经分析了伊马替尼正在进行的临床试验的数据，其中FIP1L1/PDGFRA阳性骨髓增生性肿瘤（FP），pDGFRA阴性HES具有脊髓增生性特征（MP）（MP），并且没有骨髓强化的特征（KERINING）（KERINING）（KERINING）（KERINING）（SR）（SR）（SR）（sry and sr an。社会； 总体而言，FP组的伊马替尼反应率为100％（n = 16），MP组为50％（n = 13），在SR组中为0％（n = 16）。 ≥4个骨髓增生特征的存在是响应的唯一预测指标。 完全缓解≥18个月后，伊马替尼在8 FP和1 MP受试者中逐渐减少并停用。 七个受试者（6 fp，1 mp）仍处于29个月的中位数（14-36）中缓解治疗。我们还继续将受试者参与了一项双盲临床试验，旨在评估糖皮质激素挑战在确定HES和Mepolizumab（人源化抗IL-5抗体）的临床试验中的糖皮质激素反应性方面的实用性。最后，与葛兰素史克和图标合作，我们开始收集数据以开发Pro（患者报告的结果指标），以在HES进行临床试验中使用。 我们继续探索新型抗体的治疗潜力，具有靶向嗜酸性粒细胞的潜力，包括两种对抑制性表面受体Siglec-8的抗体。 SIGLEC-8是一种在血液，骨髓和组织中成熟的嗜酸性粒细胞上高度表达的抑制受体。在IL-5存在下，受体通过其配体或抗SigLec 8抗体的参与诱导嗜酸性粒细胞凋亡。通过使用来自38个正常供体（ND）的全血流式细胞仪，通过流式细胞仪和58名患有HES的受试者对SIGLEC-8表达进行定量，并发现来自正常和HES受试者的嗜酸性粒细胞高，而与HES亚型或治疗无关。目前正在临床前发育，一种IgG4抗体和一种经过设计可引起ADCC增强的IgG1抗体的IgG4抗体和IgG1抗体。我们已经证明，IgG1和IgG4抗SigLec 8抗体均诱导嗜酸性粒细胞凋亡，并在IL-5存在下使用正常和嗜酸性粒细胞受试者的全血和体外测定中的效率相似。 相反，仅使用IgG1抗体观察到ADCC的增强，并且在非常高的嗜酸性粒细胞计数和低NK：EO比率的患者中可能受到限制（Legrand等人J Allergy Clin Immunol 2015; 135：AB221）。 目前，使用人源化IL-2转基因NOG小鼠模型正在进行两种抗体研究的鼠研究。 蠕虫感染可能与与HES无法区分的戏剧性嗜酸性粒细胞和并发症有关。 尤其是在冰川症中尤其如此，其中症状与嗜酸性粒细胞颗粒蛋白水平升高（指示嗜酸性粒细胞激活和脱粒的指示）以及嗜酸性粒细胞相关的细胞因子的水平升高（Herrick等人Clin Inf dis; 60：55-63）。在某些感染中，嗜酸性粒细胞和嗜酸性粒细胞相关的症状可以通过有效治疗加剧。例如，用二乙基钙化（DEC）处理丝状感染状态性（DEC）可能与严重的不良事件（包括死亡）相关，这些事件伴随着嗜酸性粒细胞增多症的急剧上升，并且与血液中循环的微部门循环的微部门数量呈正相关。在过去的一年中，我们对抗IL-5抗体Reslizumab进行了双盲，安慰剂对照研究，以防止DEC对LOA LOA感染患者的治疗后副作用。 最后，在过去的一年中，我们继续寻找嗜酸性疾病活性的生物标志物，用于监测对治疗的反应并帮助剖析嗜酸性粒细胞发病机理的机制。为此，我们继续探索开发的多重悬浮阵列系统的实用性，以同时测量血清和血浆中4种嗜酸性粒细胞颗粒蛋白的浓度（MBP，ECP，EDN和EPO）（Makiya等人J immunol方法2014）在生物学流体中的浓度，包括粪便，刺激性，sputum and uline。 迄今为止的数据表明，粪便中嗜酸性粒细胞颗粒蛋白的水平升高可能是胃肠道嗜酸性粒细胞增多的有用标记（Makiya等人。