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

描述（由申请人提供）：特应性皮炎（AD）是最常见的炎性皮肤病，影响高达3-4%的成人和25%的儿童，其中大多数属于中度至重度AD类别，并且极难控制。目前，对于有效的全身治疗存在大量未满足的需求，AD与Th 2和最近描述的Th 22 T细胞亚群的活化相关，而与银屑病不同，它具有最少的Th 17组分。在银屑病中，通过IL-17 A细胞因子或其受体的抗体中和IL-17/Th 17可导致大多数治疗受试者的疾病逆转，几乎没有与免疫拮抗相关的不良反应。我们推测新发现的Th 22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是一种与IL-22高度特异性结合的人IgGIA抗体，是IL-22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对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患者静脉给药的安全性、耐受性和临床疗效; 2.检验AD中异常表皮增生和分化异常归因于IL-22细胞因子的假设; 3.确定IL-22阻断对抑制Th 2和T22活化的影响。这是一项安慰剂对照、双盲、IV给予AD患者ILV-094 /安慰剂的研究，分配比例为2：1（活性药物与安慰剂）。将在10周内总共进行6次IV给药。患者将 再随访10周。将通过第12周AD评分（SCORAD）和研究者总体评估（伊加）指数的变化来评价对AD疾病活动的临床影响。将通过免疫组织化学、RTPCR和基因阵列分析在基线、第4周和第12周采集的活检和血液样本。

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.