Chemokine Decoy Receptor for Therapy of Autoimmune Arthritis

用于治疗自身免疫性关节炎的趋化因子诱饵受体

• 批准号: 8370466
• 负责人: Kanneganti Murthy
• 金额: $ 29.83万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8370466
• 关键词: Address; Adoptive Transfer; Adrenal Cortex Hormones; Adverse effects; Affinity; Amino Acids; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Arthritis; Autoimmune Diseases; Autoimmune Process; Behavior; Binding; Biological Models; Blood Cells; CC chemokine receptor 1; CC chemokine receptor 3; CCR1 gene; CCR5 gene; CD4 Positive T Lymphocytes; Cardiovascular system; Cells; Chemokine (C-C Motif) Receptor 5; Chimeric Proteins; Chronic; Clinical; Collaborations; Collagen; Complement 3b Receptors; Control Groups; Digit structure; Disease; Dose; Edema; Erythema; Etanercept; Experimental Autoimmune Encephalomyelitis; Experimental Models; Extracellular Domain; Extravasation; Florida; Freund' s Adjuvant; Functional disorder; Future; Gene Expression; Genetic; Gold; Histologic; Histology; Homologous Gene; Human; IgG1; Immune; Immune Tolerance; Immune response; Immunohistochemistry; Immunosuppression; In Vitro; Inbred DBA Mice; Infiltration; Inflammation; Inflammatory; Injury; Interferons; Interleukin-10; Interleukin-17; Interleukin-2; Interleukin-4; Interleukin-6; Investigation; Joints; Knockout Mice; Leukocytes; Ligand Binding; Ligands; Lipid Peroxidation; Liquid substance; Lymphocyte; Macaca; Macrophage Inflammatory Protein-1; Marketing; Measures; Mediating; Membrane; Methotrexate; Modeling; Monitor; Multiple Sclerosis; Mus; Nature; Neurologic; Neutrophil Infiltration; Onset of illness; Outcome; Pathogenesis; Pathway interactions; Patients; Peroxonitrite; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Plasma; Play; Poly(ADP-ribose) Polymerases; Population; Process; Production; Property; Protein Binding; Proteins; Publishing; RANTES; Regulatory T-Lymphocyte; Relative (related person); Rheumatoid Arthritis; Role; Safety; Serum; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Stromelysin 1; T-Lymphocyte; TNF gene; Technology; Testing; Th1 Cells; Therapeutic; Time; Tissues; Toxicology; analytical method; arthropathies; autoimmune arthritis; base; chemokine; chemokine receptor; clinically relevant; cohort; collagenase 3; cytokine; disability; immunogenicity; in vivo; inhibitor/antagonist; innovation; joint injury; lymph nodes; male; neurobehavioral; neuroinflammation; nonhuman primate; novel; pre-clinical; prevent; protective effect; receptor; receptor binding; receptor coupling; research study; respiratory; treatment effect

DESCRIPTION (provided by applicant): Current therapeutic approaches to rheumatoid arthritis ("RA") (corticosteroids, methotrexate, neutralization of TNF-?) rely upon broad-spectrum immunosuppression, an approach that is not uniformly effective and is frequently associated with significant side-effects. To address this market gap, Radikal Therapeutics (RTX) is developing a novel soluble receptor decoy receptor fusion protein (hR-421) that induces immune tolerance in antigen (Ag)-specific activated T-cells. Constructed from Ig-Fc and the second ecto domain of the CCR5 receptor, hR-421 binds and neutralizes al 3 CCR5-binding chemokine ligands (MIP-?, MIP-?, RANTES) and prevents their binding and activation of the CCR1, CCR3, and CCR5 membrane receptors. In contrast to CCR5 inhibitors, mR-421 (the murine homologue of hR-421) blocks CCR5-independent pro-inflammatory pathways and is effective in CCR5 knock-out mice. Therapy with mR- 421 profoundly suppresses experimental allergic encephalomyelitis (EAE), a classic autoimmune model system, even when treatment is initiated after disease onset. Moreover, Ag-specific effector Th1 cells isolated from EAE donors treated in vivo with mR-421 produce substantially less pro-inflammatory cytokines and suppress EAE in adoptive transfer experiments. This latter effect is driven by the ability of mR-421 to prevent the co-stimulatory signal on Th1 CD4+ T cells. Based on these findings, we hypothesize that R-421 will prevent co-stimulation and thus the downstream proliferation and activation of Th1 CD4+ cells in RA. We now propose to extend the protective effects of the R-421 technology beyond the published findings in neuroinflammation and establish its potential benefit in a clinically-relevant model of RA. Male DBA mice inoculated with collagen in CFA and rechallenged on Day 21 to induce autoimmune arthritis, will be treated with mR-421 (2, 4, 8 mg/kg), an irrelevant IgG1 control, or etanercept (6.25 mg/kg) beginning at the time of significant disease (Day 21), as characterized by an arthritic score of 2 (scale of 0-16). Additionally, we will include a sham control group not exposed to collagen/CFA or treatment. Animals will be monitored for clinical evidence of arthritis over a period of 6 weeks, a timepoint characterized in controls by erythema and edema of the entire paw including digits (score=12). Plasma m-R421 concentrations will be related to clinical outcome, so as to construct a pharmacodynamic profile that will guide future clinical dosing. We expect mR-421 to reduce joint injury, in a dose and plasma concentration dependent fashion, as defined by a reduction in the mean arthritic score that is equivalent or superior to the treatment effect elicited by the gold-standard clinically-approved agent etanercept. These findings are expected to parallel the effects of mR-421 on synovial lipid peroxidation, neutrophil infiltration, pro-inflammatory gene expression peroxynitrite production, poly(ADP-ribose)polymerase formation, and gross and histologic injury scores, and on draining lymph node populations of Th1 and Treg lymphocytes. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis is a devastating autoimmune disease characterized by lifelong disability and inexorable progression. Currently approved agents are partially effective and nearly one-third of patients do not obtain adequate relief. We are developing a novel drug that specifically blocks the specific immune disturbance that underlies this condition. We will test this agent in a clinically-relevant small animal model and determine the most effective dose, in anticipation of definitive large animal studies to confirm its efficacy and safety.

描述(申请人提供)：目前治疗类风湿性关节炎(RA)的方法(皮质类固醇、甲氨蝶呤、中和肿瘤坏死因子？)依赖广谱免疫抑制，这种方法并不总是有效的，而且经常与显著的副作用有关。为了解决这一市场缺口，Radikal Treeutics(RTX)正在开发一种新型的可溶性受体诱骗受体融合蛋白(HR-421)，它可以诱导抗原(Ag)特异性激活的T细胞产生免疫耐受。HR-421由Ig-Fc和CCR5受体的第二个胞外区构建而成，可结合和中和A13 CCR5结合的趋化因子配体(MIP-？、MIP-？、RANTES)，并阻止它们与CCR1、CCR3和CCR5膜受体的结合和激活。与CCR5抑制剂相反，MR-421(HR-421的小鼠同系物)阻断CCR5非依赖的促炎途径，对CCR5基因敲除小鼠有效。MR-421的治疗可以深刻抑制实验性变态反应性脑脊髓炎(EAE)，这是一种经典的自身免疫模型系统，即使在疾病发作后开始治疗也是如此。此外，在过继转移实验中，从经MR-421治疗的EAE供者体内分离的Ag特异性效应Th1细胞产生的促炎细胞因子显著减少，并抑制EAE。后一种作用是由MR-421阻止Th1 CD4+T细胞上的共刺激信号的能力驱动的。基于这些发现，我们假设R-421将阻止共刺激，从而阻止类风湿关节炎患者Th1CD4+细胞的下游增殖和激活。我们现在建议将R-421技术的保护作用扩展到已发表的神经炎症研究成果之外，并在临床相关的RA模型中建立其潜在的益处。雄性DBA小鼠在CFA中接种胶原并在第21天再次激发以诱导自身免疫性关节炎，将在严重疾病(第21天)开始接受MR-421(2，4，8 mg/kg)，无关的IgG1对照，或依那西普(6.25 mg/kg)治疗，其特征是关节炎评分2(0-16分)。此外，我们将包括一个假对照组，不暴露于胶原/CFA或治疗。动物将在为期6周的时间里接受关节炎临床证据的监测，这一时间点的特征是整个爪子(包括脚趾)出现红斑和水肿(得分=12)。血浆m-R421浓度将与临床结果相关，从而构建指导未来临床用药的药效学图谱。我们预计MR-421将以剂量和血浆浓度依赖的方式减少关节损伤，其定义是关节炎平均评分的降低，相当于或优于黄金标准的临床批准药物依那西普所产生的治疗效果。这些发现有望与MR-421对滑膜脂质过氧化、中性粒细胞渗透、促炎基因表达、过氧亚硝酸盐产生、多聚ADP-核糖聚合酶形成、大体和组织学损伤评分以及Th1和Treg淋巴细胞引流淋巴结群的影响平行。 公共卫生相关性：类风湿性关节炎是一种破坏性的自身免疫性疾病，其特征是终生残疾和不可阻挡的进展。目前批准的药物部分有效，近三分之一的患者得不到足够的缓解。我们正在开发一种新药，专门阻断这种疾病背后的特定免疫紊乱。我们将在临床相关的小动物模型中测试这种药物，并确定最有效的剂量，以期在大动物实验中确定其有效性。 和安全。