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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 多种自身免疫性疾病的发病机制表明自身抗体参与了疾病过程。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，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。 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、分子拟态、对自身抗原的耐受性改变或异常细胞凋亡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 B 淋巴细胞 (BlyS) 功能异常。 SLE 可导致关节炎、肾衰竭、心脏、肺和中枢神经系统炎症、血管炎和造血改变，如贫血、白细胞减少和血小板减少。当前 SLE 发病机制的范式始于遗传倾向，导致致病性自身抗体和自身反应性效应 B (Blys) 和 T 淋巴细胞的产生。在 SLE 中，针对 DNA、组蛋白、核小体、染色质、核糖核蛋白、核糖体、RNA 和磷脂的多种自身抗体（通常是寡克隆）已得到表征。 当前文献支持开发 BLyS 拮抗剂治疗自身免疫性疾病的基本原理。 转基因小鼠中BLyS的组成型过度表达导致自身免疫样疾病的发展，其特征在于高丙种球蛋白血症、自身抗体产生（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）。 在自身免疫性疾病动物模型中用作 BLyS 拮抗剂的可溶性 BLyS 受体 (TACI-Fc) 表明 TACI-Fc 可以抑制 NZBWF1 小鼠的蛋白尿并延长其存活时间（Gross 等，2000）。 TACI-Fc 还可以降低 RA 动物模型中疾病的严重程度（Wang 等，2001）。 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和血清IgG水平以及自身抗体（抗dsDNA和RF）水平之间存在正相关性（Zhang等人，2001和Cheema等人，2001）。 总而言之，这些数据提供了 BLyS 拮抗作用对 SLE 具有潜在治疗益处的证据。 非临床研究表明，LymphoStat-B 对 BlyS 具有高亲和力，并在小鼠脾细胞增殖测定中抑制 BLyS 的活性。 LymphoStat-B 可识别人类和食蟹猴 (Macaca fasularis) BLyS； LymphoStat-B 识别可溶性但不识别膜结合的 BLyS。 已发现 LymphoStat-B 在小鼠和猴子中的耐受性良好，剂量高达 50 mg/kg。 LymphoStat-B 静脉注射可抑制小鼠模型中由 rhuBLyS 诱导的成熟 B 淋巴细胞和血清 IgA 的增加。 LymphoStat-B 是一种重组、全人源 IgG1？以高亲和力结合 BLyS 并抑制其生物活性的单克隆抗体。 LymphoStat-B 是通过亲本抗体 D08 的亲和力成熟而衍生的，D08 本身是通过筛选与 BLyS 具有高亲和力结合的噬菌体展示文库而衍生的。 LymphoStat-B 在 NSO 小鼠骨髓瘤细胞系中表达，分泌到培养基中，并通过一系列层析和过滤步骤进行纯化。 LymphoStat-B 的体外和体内研究已证明其结合 BLyS 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 的发病机制有关。 LymphoStat-B 的 1 期、多中心、双盲临床试验于 2002 年 12 月完成入组和治疗阶段。该试验（方案 LBSL01）是针对 SLE 受试者的单次和双次剂量递增研究。 该研究旨在评估单次静脉输注（队列 1 至 4）或间隔 21 天 2 次输注（队列 5 至 8）的 4 剂（1、4、10、20 mg/kg）LymphoStat-B 的安全性、耐受性、免疫原性、药代动力学和药效学。 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。 LymphoStat-B 在所有剂量水平下通常耐受性良好。 与剂量增加相关的不良事件（AE）似乎并未显着增加。更详细的结果见临床前研究/进展报告。