SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

系统性红斑狼疮 (SLE)

• 批准号: 7604597
• 负责人: MICHELLE A PETRI
• 金额: $ 0.02万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2007-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7604597
• 关键词: Adverse event; Affinity; Anemia; Animal Model; Antibodies; Antibody Formation; Antigens; Apoptosis; Arthritis; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Binding; Biological; Biological Assay; Cell Line; Chromatin; Chromatography; Chronic; Clinical Research; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Culture Media; DNA; Data; Development; Disease; Dose; Double-Blind Method; Drug Kinetics; Enrollment; Filtration; Funding; Genetic Predisposition to Disease; Glomerulonephritis; Grant; Heart; Histones; Human; Hypergammaglobulinemia; IgG1; Immunoglobulin A; Immunoglobulin G; In Vitro; Inflammation; Infusion procedures; Institution; Kidney Failure; Lead; Leukopenia; Libraries; Literature; Lung; Lupus Erythematosus; Macaca; Mature B-Lymphocyte; Membrane; Molecular Mimicry; Monkeys; Monoclonal Antibodies; Multiple Myeloma; Mus; Neuraxis; Nucleosomes; Pathogenesis; Patients; Personal Satisfaction; Phage Display; Pharmacodynamics; Phase; Phospholipids; Placebos; Process; Production; Progress Reports; Protein Overexpression; Proteinuria; Protocols documentation; RNA; Recombinants; Research; Research Personnel; Resources; Ribonucleoproteins; Ribosomes; Safety; Screening procedure; Series; Serum; Severity of illness; Source; Splenocyte; Synovial Fluid; Systemic Lupus Erythematosus; T-Lymphocyte; Therapeutic; Thrombocytopenia; Transgenic Mice; United States National Institutes of Health; Vasculitis; anti-dsDNA antibodies; anti-dsDNA autoantibody; cohort; day; design; ds-DNA; immunogenicity; in vivo; intravenous administration; mouse model; pre-clinical; preclinical study; receptor; response

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 多种自身免疫性疾病的发病机理已将自身抗体引起疾病过程。许多与自身免疫性疾病相关的特定自身抗体似乎是抗原选择，并且需要与常规B淋巴细胞抗体反应相关的T淋巴细胞帮助。 尚不清楚这些自身抗体反应如何启动这些自身抗体反应的机制。 然而，已经提出，B淋巴细胞（BLYS），分子模仿，对自我抗原或异常凋亡的耐受性的长期存活已被认为是潜在的触发机制。 SLE是一种慢性自身免疫性疾病，其特征是自身抗体产生和异常B淋巴细胞（BLYS）功能。 SLE可以导致关节炎，肾衰竭，心脏，肺和中枢神经系统炎症，血管炎和炎症性变化，例如贫血，白细胞减少和血小板减少症。 SLE发病机理的当前范式始于遗传易感性，导致致病性自身抗体的产生，自动反应性效应子B（BLYS）和T淋巴细胞。在SLE中，已经表征了针对DNA，组蛋白，染色质，核糖核蛋白，核糖体，RNA和磷脂的多种自身抗体（通常是寡聚）。 目前的文献中支持了开发Blys拮抗剂治疗自身免疫性疾病的理由。 在转基因小鼠中blys的组成性过表达导致自身免疫性疾病的发展，其特征是高γ-球蛋白血症，自身抗体产生（例如，抗双重滞留-DNA [抗DSDNA]抗体）和肾小球肾炎（Glen）（Glen）（glen）（Gromerlulone）（Gromerullulone）（Gromerulne）（Gromerullulone）（Gromerlulone）（gross）（gross et al。 1999）。 在自身免疫性疾病的动物模型中，可溶性泡泡受体（TACI-FC）用作Blys拮抗剂，表明TACI-FC抑制蛋白尿并延长NZBWF1小鼠的存活（Gross等，2000）。 Taci-FC还降低了RA动物模型中的疾病严重程度（Wang等，2001）。 在一些RA患者的血清和滑液中，Blys水平升高和SLE患者血清的滑液很明显。 血清BLYS与血清IgG水平与自身抗体（抗DSDNA和RF）水平之间存在正相关（Zhang等，2001和Cheema等，2001）。 综上所述，这些数据提供了证据，表明Blys拮抗作用在SLE中具有潜在的治疗益处。 非临床研究表明，淋巴结子-B对Blys具有高亲和力，并抑制在鼠脾脏增殖测定法中Blys的活性。 淋巴结杆-B识别人类和cynomolgus（Macaca fasicularis）猴子blys;淋巴结子-B识别可溶性，但不能识别膜结合的腹膜。 已经发现淋巴结杆-B在小鼠和猴子的剂量高达50 mg/kg的小鼠中耐受性良好。 静脉注射淋巴结杆-B抑制了小鼠模型中Rublys诱导的成熟B淋巴细胞和血清IgA的增加。 淋巴结队B是重组，完全人类的IgG1？单克隆抗体与高亲和力结合并抑制其生物学活性。 淋巴结子-B是通过亲和力成熟的父母抗体D08的成熟而得出的，该抗体本身源自筛选噬菌体显示库以使其与Blys高亲和力结合。 在NSO小鼠骨髓瘤细胞系中表达淋巴结杆-B，分泌到培养基中，并通过一系列色谱和过滤步骤纯化。体外和体内研究淋巴结杆菌B已证明其结合Blys的能力，而SLE患者的动物模型和临床前数据表明，升高的Blys水平可能与SLE的发病机理有关。 2002年12月的淋巴结队B完成入学率和治疗阶段的1阶段，多中心的双中心，双盲临床试验。该试验（协议LBSL01）是SLE受试者的单剂量和双剂量渗透研究。 该研究旨在评估4剂（1、4、10、20 mg/kg）的淋巴结杆菌（1、4、10、20 mg/kg）的安全性，耐受性，药代动力学和药效学，该淋巴结杆菌为单次静脉输液输注（同龄人1至4）或2 21天21天（COHORTS 21天）。 共有57名受试者接受了淋巴结子-B，13名受试者在8个队列中接受了安慰剂。 通常在所有剂量水平上均能耐受淋巴结杆-B。 与剂量增加相关的不良事件（AE）似乎没有显着增加。更详细的结果是临床前研究/进度报告。