Chemokine Decoy Receptor: a novel therapy of IBD

趋化因子诱饵受体：炎症性肠病的一种新疗法

• 批准号: 8368023
• 负责人: Kanneganti Murthy
• 金额: $ 22.24万
• 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: 2012-07-20 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8368023
• 关键词: Address; Adoptive Cell Transfers; Adoptive Transfer; Adrenal Cortex Hormones; Adult; Adverse effects; Adverse event; Affinity; Amino Acids; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Appearance; Attenuated; Autoimmune Diseases; Autoimmune Process; Behavior; Binding; Biochemical; Biological Models; Body Weight; Body Weight decreased; CC chemokine receptor 1; CC chemokine receptor 3; CCR1 gene; CCR5 gene; Chemokine (C-C Motif) Receptor 5; Chimeric Proteins; Clinical; Clinical Treatment; Colitis; Complement 3b Receptors; Control Groups; Crohn' s disease; Dexamethasone; Diarrhea; Dinitrobenzenes; Disease; Dose; Experimental Autoimmune Encephalomyelitis; Experimental Designs; Exposure to; Extracellular Domain; Feces; Genetic; Histologic; Homologous Gene; Human; Immune Tolerance; Immunoglobulin G; Immunosuppression; In Vitro; Infiltration; Inflammatory; Inflammatory disease of the intestine; Ingestion; Injury; Intake; Interferons; Interleukin-17; Interleukin-2; Intestinal Mucosa; Intestines; Knockout Mice; Ligand Binding; Ligands; Lipid Peroxidation; Macrophage Inflammatory Protein-1; Marketing; Mediating; Modeling; Monitor; Mus; Nature; Neurologic; Onset of illness; Oral; Pathogenesis; Pathway interactions; Patients; Peroxonitrite; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Poly(ADP-ribose) Polymerases; Process; Production; Property; Protein Binding; RANTES; Recurrence; Relative (related person); Safety; Series; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Sodium Dextran Sulfate; T-Lymphocyte; TNF gene; Technology; Testing; Th1 Cells; Therapeutic; Tissues; Toxicology; United States National Institutes of Health; Universities; base; chemokine; chemokine receptor; clinically relevant; cytokine; design; experimental analysis; healthy volunteer; in vivo; inhibitor/antagonist; innovation; neuroinflammation; neutrophil; novel; pre-clinical; prevent; professor; protective effect; receptor; receptor binding; receptor coupling; research study; volunteer

DESCRIPTION (provided by applicant): Current therapeutic approaches to Crohn's Disease (corticosteroids, neutralization of TNF-?) rely upon broad-spectrum immunosuppression, an approach that is not uniformly effective and is frequently associated with major side-effects. To address this market gap, Radikal Therapeutics 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 all 3 CCR5-binding ligands (chemokines MIP-?, MIP-?, RANTES) and prevents their binding and activation of CCR1, CCR3, and CCR5. 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. The purpose of the current application is to extend the protective effects of the R-421 technology beyond the preliminary findings in neuroinflammation and establish its potential benefit in a clinically-relevant model of Crohn's Disease. The proposed studies are specifically designed to test the hypothesis that mR-421 attenuates preexisting colitis via its suppression of pro-inflammatory cytokines in the intestinal mucosa. Specific Aims: Establish the pharmacodynamic profile of mR-421 in mice utilizing 1) a dextran sulfate sodium (DSS) model and 2) a dintrobenzenesulfonic (DNBS) model of intestinal inflammation Treatment with mR-421 (3, 10, and 30 mg/kg/day QD IP), an irrelevant IgG control (10 mg/kg QD IP), dexamethasone (1 mg/kg QD IP), or anti-murine TNF-? (10 mg/kg QD IP) will begin 7 days after the start of oral DSS or intrarectal DNBS exposure, a timepoint of significant ongoing colitis. A sham group without exposure to DSS or mR-421 will be utilized as a control. Animals will be monitored for body weight and clinical signs of illness: hunched-over appearance, weight loss, loose stools/diarrhea, and bloody stools. After 10 days of therapy, the intestine will be analyzed for biochemical, immunohistochemical, and morphologic parameters indicative of inflammatory injury. Progression to the Phase 2 SBIR will require that with mR-421: 1) dose-dependently ameliorates tissue injury, as demonstrated by > 50% reductions in all of the following injury parameters: lipid peroxidation, neutrophil (PMN) infiltration, peroxynitrite (ONOO-) production, poly(ADP-ribose)polymerase formation, gross and histologic injury scores, and 2) demonstrate a clear mechanism of action, as shown by suppression of mucosal pro-inflammatory cytokines and chemokines in the DNBS and DSS models. All of the above effects of mR-421 must be superior relative to the irrelevant IgG control group and at least non-inferior relative to therapy with an anti-murine TNF-? mAb and dexamethasone (at p<0.05). PUBLIC HEALTH RELEVANCE: Crohn's Disease remains recalcitrant to existing therapies, with a high percentage of patients enduring recurrent bouts of inflammation and intestinal damage. We are developing a novel drug that specifically blocks the inflammatory process in this condition. We will test this agent in a series of clinically-relevant animal models of autoimmune colitis.

描述（由申请人提供）：目前克罗恩病的治疗方法（皮质类固醇、TNF-α的中和）依赖于广谱免疫抑制，这种方法并不统一有效，并且经常与主要副作用相关。为了弥补这一市场空白，Radikal Therapeutics 正在开发一种新型可溶性受体诱饵受体融合蛋白 (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 结合配体（趋化因子 MIP-α、MIP-α、RANTES），并防止它们与 CCR1、CCR3、和 CCR5。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。当前应用的目的是将 R-421 技术的保护作用扩展到神经炎症的初步发现之外，并确定其在克罗恩病临床相关模型中的潜在益处。拟议的研究专门设计用于检验以下假设：mR-421 通过抑制肠粘膜中的促炎细胞因子来减轻先前存在的结肠炎。具体目标： 利用 1) 葡聚糖硫酸钠 (DSS) 模型和 2) 二硝基苯磺酸 (DNBS) 肠道炎症模型在小鼠中建立 mR-421 的药效学特征 用 mR-421（3、10 和 30 mg/ 治疗） kg/天 QD IP）、不相关的 IgG 对照（10 mg/kg QD IP）、地塞米松（1 mg/kg QD IP），或抗鼠TNF-？ （10 mg/kg QD IP）将在开始口服 DSS 或直肠内 DNBS 暴露后 7 天开始，这是严重持续性结肠炎的时间点。未暴露于 DSS 或 mR-421 的假手术组将用作对照。将监测动物的体重和临床疾病体征：驼背外观、体重减轻、稀便/腹泻和血便。治疗 10 天后，将对肠道进行生化、免疫组织化学和形态学参数分析，以指示炎症损伤。进入第 2 期 SBIR 需要 mR-421：1) 剂量依赖性地改善组织损伤，所有以下损伤参数均降低 50% 以上：脂质过氧化、中性粒细胞 (PMN) 浸润、过氧亚硝酸盐 (ONOO) -) 生产、聚（ADP-核糖）聚合酶形成、总体和组织学损伤评分，以及 2) 证明了明确的作用机制，如通过抑制DNBS 和 DSS 模型中的粘膜促炎细胞因子和趋化因子。相对于不相关的 IgG 对照组，mR-421 的所有上述效果必须优于且至少不劣于治疗 与抗鼠TNF-？ mAb 和地塞米松（p<0.05）。 公共健康相关性：克罗恩病对现有疗法仍然难以抵抗，有很高比例的患者遭受反复发作的炎症和肠道损伤。我们正在开发一种新药，专门阻止这种情况下的炎症过程。我们将在一系列临床相关的自身免疫性结肠炎动物模型中测试该药物。