MULTIPLE DOSES OF TRX1 (ANTI-CD4 MAB) WHEN ADMINISTERED BY INTRAVENOUS INFUSION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 引言 皮肤红斑狼疮(CLE)是一种异质性自身免疫性疾病，主要影响皮肤，但也可能累及毛发和粘膜。发病机制的一部分涉及自身免疫，其特征是出现自身反应性T细胞，表现出自我耐受性的丧失。 TRX1是人源化的IgG1？与人类淋巴细胞抗原CD4反应的单抗。CD4是一种单体糖蛋白，表达在T效应淋巴细胞亚群上，称为T辅助细胞。这些细胞在适应性免疫的协调中起着核心作用，既是强大的B细胞介导的体液反应所必需的，也是产生强大的CD8细胞毒性淋巴细胞所必需的。虽然目前已知Trx1的作用机制(S)，但Trx1可能导致对抗原刺激的低反应性。 主要目标： 1.研究经静脉(IV)输注多剂量TRX1治疗慢性肺水肿患者的耐受性、安全性和药代动力学。 次要目标： 1.通过对细胞因子释放、CD4饱和/表达、淋巴细胞亚群分析和其他免疫功能指标(如对召回抗原和新抗原的反应)的影响来表征TRX1的药效学(PD)。 1)评估TRX1是否对病毒复活有影响。 2.通过检测抗TRX1抗体来鉴定TRX1是否具有免疫原性。 探索性目标： 1.确定TRX1是否能耐受同时给予抗原噬菌体X174(PhiX)的受试者。 2.确定TRX1是否降低Clasi分数。 3.确定TRX1是否减少皮质类固醇和/或羟氯喹的使用。 4.检测CLE各亚型的血清学基因表达。 5.队列3用药前后检测原发灶(S)的各项免疫组织学参数。 6.检测队列3给药前后原发皮损(S)的基因和蛋白质组表达谱。 研究设计 这是一项1b期、开放标签、剂量递增的连续队列研究，研究对象为慢性肺水肿患者静脉输注四种TRX1的耐受性、安全性和药代动力学。TRX1将通过静脉输注进行为期两小时的治疗。三组受试者将在第1、5、9和13天接受0.5、1.5 mg/kg和3.0 mg/kg的剂量。第二组和第三组的第一剂直到前一组的最后一剂后21天才开始，前一组的所有安全数据已收到并审查。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. INTRODUCTION Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease that affects primarily the skin, but may also involve the hair and mucous membranes. Part of the pathogenesis involves autoimmunity characterized by the appearance of autoreactive T cells that exhibit the loss of self-tolerance. TRX1 is a humanized IgG1? monoclonal antibody that reacts with the human lymphocyte antigen CD4. CD4 is a monomeric glycoprotein expressed on a subpopulation of T effector lymphocytes known as T-helper cells. These cells play a central role in the orchestration of adaptive immunity, being required for both robust B-cell mediated humoral responses as well as the generation of potent CD8+ cytotoxic lymphocytes. While the mechanism(s) of action of TRX1 is now known, TRX1 may cause hyporesponsiveness to antigen stimulation. PRIMARY OBJECTIVES: 1. Characterize the tolerability, safety, and pharmacokinetics of multiple doses of TRX1 when given by intravenous (IV) infusion to subjects with CLE. SECONDARY OBJECTIVES: 1. Characterize the Pharmacodynamics (PD) of TRX1 via effects on: cytokine release, CD4 saturation/expression, lymphocyte subset analysis, and other markers of immune function (e.g. responses to recall antigens and neoantigens). 1) Evaluate whether TRX1 has an effect on viral reactivation. 2. Characterize whether TRX1 is immunogenic by measurement of anti-TRX1 antibodies. EXPLORATORY OBJECTIVES: 1. Determine whether TRX1 can tolerize subjects to a concurrently administered antigen, bacteriophage ?X174 (PhiX). 2. Determine whether TRX1 decreases the CLASI score. 3. Determine whether TRX1 decreases the use of corticosteroids and/or hydroxychloroquine. 4. Measure serological gene expression for the sub-types of CLE. 5. Measure various immunohistology parameters in the primary lesion(s) pre- and post-dose for Cohort 3. 6. Measure gene and proteomic expression profiles in the primary lesion(s) pre- and post dose for Cohort 3. STUDY DESIGN This is a Phase 1b, open-label, dose-escalation, consecutive cohort study of the tolerability, safety, and pharmacokinetics of four IV infusions of TRX1 in subjects with CLE. TRX1 will be administered via IV infusion over a period of two hrs. Three cohorts of subjects will receive doses of 0.5, 1.5 mg/kg, and 3.0 mg/kg on Days 1, 5, 9, and 13. First doses of Cohort 2 and 3 will not begin until 21 days after the last dose of the previous cohort and all safety data from the prior cohort has been received and reviewed.