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（由申请人提供）：当前类风湿性关节炎（“RA”）的治疗方法（皮质类固醇、甲氨蝶呤、TNF-α的中和）依赖于广谱免疫抑制，这种方法并不统一有效，并且经常与显着的副作用相关。为了弥补这一市场空白，Radikal Therapeutics (RTX) 正在开发一种新型可溶性受体诱饵受体融合蛋白 (hR-421)，可诱导抗原 (Ag) 特异性激活的 T 细胞的免疫耐受。 hR-421 由 Ig-Fc 和 CCR5 受体的第二个胞外结构域构成，可结合并中和所有 3 个 CCR5 结合趋化因子配体（MIP-α、MIP-α、RANTES），并防止它们与 CCR1、CCR3 和 CCR5 膜受体的结合和激活。与 CCR5 抑制剂相反，mR-421（hR-421 的鼠同源物）可阻断不依赖于 CCR5 的促炎途径，并且对 CCR5 敲除小鼠有效。即使在疾病发作后开始治疗，mR-421 治疗也能显着抑制实验性过敏性脑脊髓炎 (EAE)（一种经典的自身免疫模型系统）。此外，从 EAE 供体中分离出的 Ag 特异性效应 Th1 细胞，在体内用 mR-421 处理后，产生的促炎细胞因子显着减少，并在过继转移实验中抑制 EAE。后一种效应是由 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 RA 中 Th1 CD4+ 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结果之外，并在 RA 临床相关模型中确定其潜在益处。用 CFA 中的胶原蛋白接种并在第 21 天重新激发以诱导自身免疫性关节炎的雄性 DBA 小鼠，将在出现重大疾病时（第 21 天）开始接受 mR-421（2、4、8 mg/kg）（一种不相关的 IgG1 对照）或依那西普（6.25 mg/kg）治疗，其特征为关节炎评分为 2（0-16 级）。此外，我们将包括一个未暴露于胶原蛋白/CFA 或治疗的假对照组。将在6周的时间内监测动物的关节炎临床证据，在该时间点，对照的特征是包括手指在内的整个爪子出现红斑和水肿（评分=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剂量的药效学特征。我们预计 mR-421 会以剂量和血浆浓度依赖性方式减少关节损伤，定义为平均关节炎评分的降低相当于或优于临床批准的金标准药物依那西普所引起的治疗效果。这些发现预计与 mR-421 对滑膜脂质过氧化、中性粒细胞浸润、促炎基因表达过氧亚硝酸盐产生、聚（ADP-核糖）聚合酶形成、总体和组织学损伤评分以及对 Th1 和 Treg 淋巴细胞引流淋巴结群的影响相似。 公众健康相关性：类风湿性关节炎是一种毁灭性的自身免疫性疾病，其特征是终身残疾和不可阻挡的进展。目前批准的药物部分有效，近三分之一的患者没有获得足够的缓解。我们正在开发一种新药，专门阻止这种情况下的特定免疫紊乱。我们将在临床相关的小动物模型中测试该药物并确定最有效的剂量，以期进行最终的大动物研究以确认其功效 和安全。