SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。多种自身免疫性疾病的发病机制暗示了自身抗体在疾病过程中的作用。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淋巴细胞的帮助。这些自身抗体反应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、分子模仿、对自身抗原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。SLE可导致关节炎、肾衰竭、心脏、肺和中枢神经系统炎症、血管炎和造血系统改变，如贫血、白细胞减少和血小板减少。目前的SLE发病机制范式始于导致致病自身抗体和自身反应效应B （Blys）和T淋巴细胞产生的遗传易感性。在SLE中，多种针对DNA、组蛋白、核小体、染色质、核糖核蛋白、核糖体、RNA和磷脂的自身抗体（通常是寡克隆）已被表征。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。在转基因小鼠中，BLyS的组成性过表达导致自身免疫样疾病的发展，其特征是高γ球蛋白血症、自身抗体的产生（如抗双链dna抗体）和肾小球肾炎（GLEN） （Gross等人，2000，Khare等人，2000，Mackay等人，1999）。可溶性BLyS受体（TACI-Fc）在自身免疫性疾病动物模型中用作BLyS拮抗剂，结果表明TACI-Fc可抑制NZBWF1小鼠的蛋白尿并延长其生存期（Gross et al., 2000）。在RA动物模型中，TACI-Fc还可降低疾病严重程度（Wang et al., 2001）。在一些RA患者的血清和滑液以及SLE患者的血清中，BLyS水平明显升高。血清BLyS、血清IgG水平和自身抗体（抗dsdna和RF）水平呈正相关（Zhang et al ., 2001; Cheema et al ., 2001）。综上所述，这些数据证明BLyS拮抗剂在SLE中具有潜在的治疗益处。非临床研究表明，在小鼠脾细胞增殖试验中，LymphoStat-B对BlyS具有高亲和力，并抑制BlyS的活性。LymphoStat-B可以识别人和食蟹猴（Macaca fasicularis）的BLyS；淋巴stat - b可识别可溶性BLyS，但不能识别膜结合BLyS。淋巴抑制素- b在小鼠和猴子中耐受良好，剂量高达50mg /kg。在小鼠模型中，静脉给药的淋巴细胞抑制成熟B淋巴细胞和血清IgA的增加。淋巴stat - b是一种重组的全人IgG1？高亲和力结合BLyS并抑制其生物活性的单克隆抗体。LymphoStat-B由亲本抗体D08亲和成熟衍生而来，亲本抗体D08本身是通过筛选与BLyS高亲和结合的噬菌体展示文库衍生而来。LymphoStat-B在NSO小鼠骨髓瘤细胞系中表达，分泌到培养基中，通过一系列色谱和过滤步骤纯化。体外和体内研究表明，LymphoStat-B具有结合BLyS的能力，SLE患者的动物模型和临床前数据表明，BLyS水平升高可能与SLE的发病机制有关。2002年12月，淋巴stat - b的1期多中心双盲临床试验完成了入组和治疗阶段。该试验（方案LBSL01）是一项针对SLE患者的单剂量和双剂量递增研究。该研究旨在评估4种剂量（1,4,10,20mg /kg）的淋巴stat - b单次静脉输注（队列1至4）或间隔21天两次输注（队列5至8）的安全性、耐受性、免疫原性、药代动力学和药效学。在8个队列中，共有57名受试者接受了LymphoStat-B治疗，13名受试者接受了安慰剂治疗。在所有剂量水平下，淋巴stat - b均具有良好的耐受性。不良事件（ae）似乎没有随着剂量增加而显著增加。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.