SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

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。 多种自身免疫性疾病的发病机制与自身抗体有关。许多与自身免疫性疾病相关的特异性自身抗体似乎是抗原选择的，需要与常规B淋巴细胞抗体反应相关的T淋巴细胞帮助。至于这些自身抗体反应是如何启动的，机制尚不清楚。然而，B淋巴细胞(BLyS)存活时间延长、分子拟态、对自身抗原的耐受性改变或异常凋亡被认为是潜在的触发机制。 SLE是一种以自身抗体产生和B淋巴细胞(BLyS)功能异常为特征的慢性自身免疫性疾病。系统性红斑狼疮可导致关节炎、肾功能衰竭、心脏、肺和中枢神经系统炎症、血管炎和造血改变，如贫血、白细胞减少和血小板减少。目前SLE发病机制的范例始于导致致病自身抗体和自身反应性效应器B(BLyS)和T淋巴细胞产生的遗传易感性。在SLE中，针对DNA、组蛋白、核小体、染色质、核糖核蛋白、核糖体、RNA和磷脂的各种自身抗体(通常是寡克隆抗体)已经被鉴定。 目前的文献支持开发BLyS拮抗剂治疗自身免疫性疾病的基本原理。BlyS在转基因小鼠中的结构性过表达会导致自身免疫性疾病的发展，其特征是高丙种球蛋白血症、自身抗体的产生(例如，抗双链DNA[抗dsDNA]抗体)和肾小球肾炎(Glen)(Gross等人，2000，Khare等人，2000，和Mackay等人，1999)。可溶性BLyS受体(TACI-Fc)作为BLyS拮抗剂在自身免疫性疾病动物模型中的应用表明，TACI-Fc可以抑制蛋白尿并延长NZBWF1小鼠的生存时间(Gross等，2000)。在类风湿性关节炎的动物模型中，TACI-FC还降低了疾病的严重性(Wang等人，2001年)。部分RA患者血清、滑液及SLE患者血清中BLyS水平明显升高。血清BLyS与血清免疫球蛋白水平和自身抗体(抗dsDNA和RF)水平呈正相关(Zhang等人，2001和Cheema等人，2001)。综上所述，这些数据为BLyS拮抗剂在SLE中具有潜在的治疗益处提供了证据。 非临床研究表明，LymphStat-B对BLyS具有高亲和力，并在小鼠脾细胞增殖试验中抑制BLyS的活性。LymphStat-B识别人和食蟹猴的BLyS；LymphStat-B识别可溶性的BLyS，但不识别膜结合的BLyS。研究发现，LymphStat-B在小鼠和猴子身上的耐受性最高可达50毫克/公斤。静脉注射LymphStat-B可抑制rhuBLyS诱导的小鼠成熟B淋巴细胞和血清IgA水平的升高。 LymphStat-B是一种重组的、完全人类的IgG1？与BLyS高亲和力结合并抑制其生物活性的单抗。LymphStat-B是亲本抗体D08亲和成熟得到的，D08本身是通过筛选与BLyS高亲和力结合的噬菌体展示文库而获得的。LymphStat-B在NSO小鼠骨髓瘤细胞系中表达，分泌到培养液中，经一系列层析和过滤步骤纯化。体外和体内研究已经证明了其与BLyS结合的能力，动物模型和SLE患者的临床前数据表明，BLyS水平升高可能与SLE的发病有关。 LymphStat-B的A期、多中心、双盲临床试验于2002年12月完成登记和治疗阶段。该试验(LBSL01方案)是一项针对SLE受试者的单剂量和双剂量递增研究。本研究旨在评价4种剂量(1、4、10、20 mg/kg)的LymphStat-B单次静脉滴注(第1~4组)或间隔21天2次静脉滴注(第5~8组)的安全性、耐受性、免疫原性、药代动力学和药效学。共有57名受试者接受了LymphStat-B，13名受试者接受了8个队列的安慰剂治疗。 LymphStat-B在所有剂量水平下总体耐受性良好。与增加剂量相关的不良事件(AEs)似乎没有显著增加。更详细的结果见临床前研究/进展报告。

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. The pathogenesis of a variety of autoimmune diseases has implicated autoantibodies as contributing to the disease process. Many of the specific autoantibodies associated with autoimmune diseases appear to be antigen selected and require T lymphocyte help associated with conventional B lymphocyte antibody responses. The mechanism as to how these autoantibody responses are initiated is unclear. However, prolonged survival of B lymphocytes (BLyS), molecular mimicry, altered tolerance to self-antigens or abnormal apoptosis have been proposed as potential triggering mechanisms. SLE is a chronic autoimmune disorder characterized by autoantibody production and abnormal B lymphocyte (BlyS) function. SLE can lead to arthritis, kidney failure, heart, lung, and central nervous system inflammation, vasculitis, and hemopoeitic changes such as anemia, leukopenia, and thrombocytopenia. The current paradigm of SLE pathogenesis begins with a genetic predisposition leading to the production of pathogenic autoantibodies and autoreactive effector B (Blys) and T lymphocytes. In SLE, a variety of autoantibodies (usually oligoclonal) directed against DNA, histones, the nucleosome, chromatin, ribonucleoproteins, ribosomes, RNA and phospholipids have been characterized. The rationale for developing a BLyS antagonist for treatment of autoimmune disease is supported in the current literature. Constitutive overexpression of BLyS in transgenic mice results in the development of autoimmune-like disease characterized by hypergammaglobulinemia, autoantibody production (e.g., anti-double stranded-DNA [anti-dsDNA] antibodies), and glomerulonephritis (GLEN) (Gross et al., 2000, Khare et al., 2000, and Mackay et al., 1999). Soluble BLyS receptor (TACI-Fc) used as a BLyS antagonist in an animal model of autoimmune disease shows that TACI-Fc inhibits proteinuria in and prolongs the survival of NZBWF1 mice (Gross et al., 2000). TACI-Fc also reduces disease severity in an animal model of RA (Wang et al., 2001). Elevated BLyS levels are evident in the serum and synovial fluid of some RA patients and the serum of SLE patients. A positive correlation exists between serum BLyS and serum IgG levels and autoantibody (anti-dsDNA and RF) levels (Zhang et al, 2001 and Cheema et al, 2001). Taken together, these data provide evidence that BLyS antagonism has potential therapeutic benefit in SLE. Non-clinical studies demonstrated that LymphoStat-B has high affinity for BlyS and inhibits the activity of BLyS in a murine splenocyte proliferation assay. LymphoStat-B recognizes both human and cynomolgus (Macaca fasicularis) monkey BLyS; LymphoStat-B recognizes soluble, but not membrane bound BLyS. LymphoStat-B has been found to be well-tolerated in mice and monkeys at doses up to 50 mg/kg. LymphoStat-B, given intravenously, inhibits an increase in mature B lymphocytes and serum IgA induced by administration of rhuBLyS in a mouse model. LymphoStat-B is a recombinant, fully human, IgG1? monoclonal antibody that binds BLyS with high affinity and inhibits its biological activity. LymphoStat-B was derived by affinity maturation of a parental antibody, D08, which itself was derived from screening a phage display library for high affinity binding to BLyS. LymphoStat-B is expressed in the NSO mouse myeloma cell line, secreted into culture media, and purified by a series of chromatography and filtration steps. In vitro and in vivo studies of LymphoStat-B have demonstrated its ability to bind BLyS, and animal models and preclinical data in SLE patients indicate elevated BLyS levels may be associated with the pathogenesis of SLE. A Phase 1, multi-center, double blind clinical trial of LymphoStat-B completed enrollment and the treatment phase in December 2002. The trial (Protocol LBSL01) was a single and double dose-escalation study in subjects with SLE. The study was designed to evaluate the safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics of 4 doses (1, 4, 10, 20 mg/kg) of LymphoStat-B administered as a single intravenous infusion (Cohorts 1 to 4) or 2 infusions 21 days apart (Cohorts 5 to 8). A total of 57 subjects received LymphoStat-B and 13 subjects received placebo across 8 cohorts. LymphoStat-B was generally well tolerated at all dose levels. There does not appear to be a significant increase in adverse events (AEs) that correlates with increasing dose. More detailed results are in the preclinical studies/progress report.