A Study of ILV-94 (Anti-22 Antibody) Administered via IV in Atopic Dermatitis

ILV-94（抗 22 抗体）静脉注射治疗特应性皮炎的研究

• 批准号: 8701238
• 负责人: Emma Guttman
• 金额: $ 63.89万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701238
• 关键词: Adult; Adverse effects; Affect; Antibodies; Atopic Dermatitis; Binding; Biological; Biological Markers; Biological Models; Biopsy; Blood specimen; Categories; Child; Clinical; Clinical Trials; Coupled; Coupling; Data; Disease; Disease remission; Dose; Double-Blind Method; Down-Regulation; Drug Kinetics; Elements; Event; Future; Genes; Human; Hyperplasia; Immune; Immune Targeting; Immunohistochemistry; Inflammation; Inflammatory; Institutional Review Boards; Interleukin-17; Intervention; Intravenous; Lead; Life; Measures; Molecular; Monoclonal Antibodies; Outcome; Outcome Measure; Pathogenesis; Pathway interactions; Patients; Pharmacodynamics; Phase; Phenotype; Placebo Control; Placebos; Production; Proteins; Psoriasis; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Safety; Skin; Specificity; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Tissues; Toxic effect; base; clinical effect; clinical efficacy; cytokine; disease phenotype; indexing; inflammatory modulation; insight; interleukin-22; intravenous administration; keratinocyte; neutralizing antibody; novel; placebo controlled study; public health relevance; receptor; response; skin disorder; skin lesion; therapeutic development; therapeutic target; translational study

DESCRIPTION (provided by applicant): Atopic dermatitis (AD) is the most common inflammatory skin disorder, affecting up to 3-4% of adults and 25% of the children, most of which are part of the moderate-to-severe AD category, and which is extremely difficult to control. Currently there is a large unmet need for effective systemic treatment AD is associated with activation of Th2 and the recently described Th22 T-cell subsets, while unlike psoriasis, it has minimal Th17 component. In psoriasis neutralization of IL-17/Th17 by antibodies to IL-17A cytokine or to its receptor can lead to disease reversal in majority of treated subjects, with few adverse effects related to immune antagonism. We hypothesize that the newly discovered Th22, has a key pathogenic role in AD through the production of IL-22. IL-22 promotes epidermal hyperplasia and inhibits epidermal differentiation, which are major features of AD. Thus, we postulate that IL-22 is a "driver" cytokine in AD, analogous to IL-17 in psoriasis. ILV-094, a human IgGIA antibody that binds with high specificity to IL-22 is a potent neutralizer of IL 22 activity. Multiple studies showed that ILV-094 has favorable pharmacokinetics and toxicity profiles. This study is the first to explore the clinical and biological effects of blocking IL-22 n AD. Our specific aims are: 1 .To assess the safety, tolerability and clinical efficacy of intravenous (IV) administration of an IL-22 neutralizing antibody ILV-094 to subjects with moderate-to-severe AD; 2.To test the hypothesis that the abnormal epidermal hyperplasia and differentiation abnormalities in AD are attributable to IL-22 cytokine; and 3.To determine the impact of IL-22 blockade on suppression of Th2 and T22 activation. This is a placebo-controlled, double-blind, study of IV administration of ILV-094 / placebo to AD patients, assigned in a 2:1 ratio (active vs. placebo). A total of 6 IV doses will be administered over 10 weeks. Patients will be followed for 10 additional weeks. The clinical effects on AD disease activity will be evaluated by change in the Scoring of AD (SCORAD) and investigator's global assessment (IGA) indices at week 12. Biopsies and blood samples collected at baseline, and weeks 4 and 12, will be analyzed by immunohistochemistry, RTPCR and gene arrays.

描述（申请人提供）：特应性皮炎（AD）是最常见的炎症性皮肤病，影响高达 3-4% 的成人和 25% 的儿童，其中大多数属于中重度 AD 类别，且极难控制。目前，对于有效的全身治疗存在大量未满足的需求，AD 与 Th2 和最近描述的 Th22 T 细胞亚群的激活有关，而与银屑病不同的是，AD 具有最少的 Th17 成分。在银屑病中，IL-17A细胞因子或其受体的抗体中和IL-17/Th17可以导致大多数治疗受试者的疾病逆转，并且与免疫拮抗相关的不良反应很少。我们假设新发现的 Th22 通过产生 IL-22 在 AD 中具有关键的致病作用。 IL-22促进表皮增生并抑制表皮分化，这是AD的主要特征。因此，我们假设 IL-22 是 AD 中的“驱动”细胞因子，类似于银屑病中的 IL-17。 ILV-094 是一种人 IgGIA 抗体，与 IL-22 高度特异性结合，是 IL 的有效中和剂 22 活动。多项研究表明 ILV-094 具有良好的药代动力学和毒性特征。本研究首次探讨了阻断IL-22 n AD的临床和生物学效应。我们的具体目标是： 1.评估IL-22中和抗体ILV-094对中重度AD受试者静脉（IV）给药的安全性、耐受性和临床疗效； 2.检验AD表皮异常增生和分化异常与IL-22细胞因子有关的假设； 3.确定IL-22阻断对Th2和T22激活抑制的影响。这是一项安慰剂对照、双盲研究，对 AD 患者静脉注射 ILV-094/安慰剂，按 2:1 的比例分配（活性药物与安慰剂）。 10 周内将总共注射 6 剂静脉注射剂。患者会 再跟踪 10 周。将通过第 12 周时 AD 评分 (SCORAD) 和研究者总体评估 (IGA) 指数的变化来评估对 AD 疾病活动性的临床影响。将通过免疫组织化学、RTPCR 和基因阵列对基线、第 4 周和第 12 周收集的活检和血液样本进行分析。