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

描述(申请人提供)：特应性皮炎(AD)是最常见的炎症性皮肤病，影响多达3%-4%的成年人和25%的儿童，其中大部分属于中到重度AD类别，极难控制。目前对有效的系统治疗有大量未得到满足的需求，AD与Th2和最近描述的Th22T细胞亚群的激活有关，而与银屑病不同的是，它只有最少的Th17成分。在银屑病中，用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对象的疾病逆转，几乎没有与免疫拮抗有关的不良反应。我们推测，新发现的Th22可能通过产生IL-22在AD发病中起关键作用。IL-22促进表皮增殖和抑制表皮分化是AD的主要特征。因此，我们推测IL-22在AD中是一个“驱动”细胞因子，类似于银屑病中的IL-17。ILV-094是一种与IL-22高度特异结合的人IgGIA抗体，是一种有效的IL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。本研究首次探讨阻断IL-22对阿尔茨海默病的临床和生物学效应。我们的具体目标是：1.评估静脉注射IL-22中和抗体ILV-094治疗中重度AD的安全性、耐受性和临床疗效；2.验证AD表皮异常增生和分化异常与IL-22细胞因子有关的假说；3.确定IL-22阻断对抑制Th2和T22激活的影响。这是一项安慰剂对照、双盲、静脉给药ILV-094/安慰剂给AD患者的研究，按2：1的比例分配(有效与安慰剂)。总共将在10周内进行6次静脉注射。患者会 在接下来的10周内继续观察。12周时，通过AD评分(SCORAD)和调查者总体评估(IGA)指数的变化来评估对AD疾病活动性的临床效果。在基线、4周和12周收集活检和血样，用免疫组织化学、RT-PCR和基因芯片进行分析。

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.