DOSE RESPONSE STUDY OF BG9273(LFA 3 & IGG1 FUSION PROTEIN)

这是一项多中心、随机、多剂量、剂量递增的研究，由Krueger博士和他在其他大学的合作者设计。 目的是确定中重度斑块状银屑病受试者每周一次持续12周接受独特药理学药物BG 9712给药的耐受性与剂量和血浆浓度之间的关系。 银屑病是一种皮肤炎性疾病，其特征在于皮肤最表层（表皮）的过度增殖和该层的炎症。 银屑病的炎症性质由皮肤真皮-表皮交界处的活化T淋巴细胞和抗原呈递细胞介导。 这些细胞迁移到该区域发生在过度增殖开始之前。 临床研究表明，银屑病斑块的消退是通过表皮T细胞的耗竭进行的。 将活化的人T细胞注射到携带来自银屑病患者皮肤未受累部位的移植物的小鼠中，导致移植皮肤中银屑病斑块病变的发展。 类似的注射到正常皮肤的移植物中不会产生这种效果。 T细胞的激活需要至少两个信号。第一种是由T细胞受体与抗原的接合驱动的信号。 第二种信号，称为共刺激信号，由抗原呈递细胞上的共刺激配体与T细胞上的其受体的接合产生。 一个关键的共刺激信号是由T细胞受体CD 2与其配体LFA-3的相互作用提供的，LFA-3位于抗原呈递细胞上。 这项研究的假设是，独特的融合蛋白（LFA-3/IgG 1）可以阻断银屑病皮损中的T细胞活化。 本研究基于Krueger博士使用BG 9712对GCRC进行的早期研究。 最初的I期毒性研究在这里进行，现在计划进行疗效和药代动力学研究。

This is a multi-center, randomized, multi-dose, dose-escalation study designed by Dr. Krueger and his collaborators at other universities. The objective is to define the relationship of tolerability to the dose and plasma concentration of a unique pharmacologic agent, BG9712, administered once weekly for twelve weeks to subjects with moderate to severe plaque psoriasis. Psoriasis is an inflammatory disorder of the skin, characterized by hyperproliferation of the most superficial layers of the skin (the epidermis) and inflammation of this layer. The inflammatory nature of psoriasis is mediated by activated T-lymphocytes and antigen-presenting cells at the dermal-epidermal junction of the skin. Migration of these cells into the area occurs before the hyperproliferation begins. Clinical studies have indicated that regression of psoriatic plaques is proceeded by a depletion of epidermal T-cells. Injection of activated human T-cells into mice carrying grafts from uninvolved sites of skin from patients with psoriasis results in the development of psoriatic plaque lesions in the engrafted skin. Similar injections into grafts of normal skin do not produce this effect. Activation of T-cells requires at least two signals. The first is a signal driven by engagement of the T-cell receptor with antigen. The second signal, designated a co-stimulatory signal, results from the engagement of a costimulatory ligand on the antigen-presenting cell, with its receptor on the T-cell. A key costimulatory signal is provided by the interaction of the T-cell receptor CD2 with its ligand, LFA-3, which is on the antigen-presenting cell. The hypothesis underlying this study is that the unique fusion protein (LFA-3/IgG1) can block T-cell activation in psoriatic skin lesions. This study builds upon earlier studies done by Dr. Krueger on the GCRC with BG9712. The original phase I toxicity studies with the drug were carried out here, and now efficacy and pharmacokinetic studies are planned.