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

这是一个多中心，随机，多剂量，剂量递增的研究由克鲁格博士和他在其他大学的合作者设计。目的是确定一种独特的药理学药物BG9712的剂量和血浆浓度与耐受性的关系，BG9712每周给药一次，持续12周，用于中度至重度斑块性银屑病患者。牛皮癣是一种皮肤炎症性疾病，其特征是皮肤最浅层（表皮）的过度增生和这一层的炎症。银屑病的炎症性是由活化的t淋巴细胞和皮肤真皮-表皮交界处的抗原呈递细胞介导的。这些细胞在增生开始前就已迁移到该区域。临床研究表明，银屑病斑块的消退是由表皮t细胞的耗竭引起的。将活化的人类t细胞注射到携带牛皮癣患者皮肤未受损伤部位移植物的小鼠体内，可导致移植物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。激活t细胞至少需要两个信号。第一种是由t细胞受体与抗原结合而产生的信号。第二种信号被称为共刺激信号，由抗原呈递细胞上的共刺激配体与t细胞上的受体结合而产生。一个关键的共刺激信号是由t细胞受体CD2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。本研究的假设基础是独特的融合蛋白（LFA-3/IgG1）可以阻断银屑病皮损中t细胞的激活。这项研究建立在Krueger博士对BG9712的GCRC早期研究的基础上。最初的I期药物毒性研究是在这里进行的，现在正在计划药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.