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）：当前的克罗恩病治疗方法（皮质类固醇，TNF-？中和））依赖于广泛的免疫抑制，这种方法是不均匀有效的，并且经常与主要副作用有关。为了解决这一市场差距，Radikal Therapeutics正在开发一种新型的可溶性受体诱饵受体融合蛋白（HR-421），该蛋白（HR-421）诱导抗原（AG）特异性活化T-细胞中的免疫耐受性。 HR-421由IG-FC和CCR5受体的第二个ECTO结构域构建，结合并中和所有3个CCR5结合配体（趋化因子mip-？,, mip-？rantes），并防止其结合和激活CCR1，CCR3和CCR5。与CCR5抑制剂相反，MR-421（HR-421的鼠同源物）阻止了CCR5无关的促炎途径，并且在CCR5敲除小鼠中有效。 MR-421治疗深刻抑制了经典的自身免疫模型系统的实验过敏性脑脊髓炎（EAE），即使在疾病发作后开始治疗。此外，用MR-421在体内治疗的EAE供体中分离的Ag特异性效应Th1细胞产生的促炎性细胞因子大大降低并抑制EAE在过继的转移实验中。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，并在克罗恩病的临床上建立其潜在的好处。拟议的研究专门设计用于检验以下假设：MR-421通过抑制肠粘膜促炎性细胞因子的抑制作用。具体目的：在利用1）硫酸葡萄糖钠（DSS）模型和2）肠磺酸（DNBS）模型（DNBS）模型的小鼠中建立MR-421的药效学特征，该模型对肠炎症（DNBS）模型进行了MR-421（3、10和30 mg/kg/kg/kg/kg/kg/kg/kg/kg/kg/kg/kg/kg/kg qd ip），imrele qd imele qud qd qd qd qd qd qd Q.地塞米松（1 mg/kg QD IP）或抗毛线TNF-？ （10 mg/kg QD IP）将在口服DSS或直肠内部DNBS暴露后7天开始，这是明显的持续结肠炎的时间点。不接触DSS或MR-421的假小组将被用作对照。将监测动物的体重和疾病的临床迹象：驼背外观，体重减轻，粪便宽松/腹泻和血腥的粪便。经过10天的治疗后，将分析肠子的生化，免疫组织化学和形态学参数，指示炎症性损伤。 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)如抑制DNB和DSS模型中粘膜促炎细胞因子和趋化因子的抑制作用所表明的清晰的作用机理。 MR-421的所有上述效应必须相对于无关的IgG对照组，至少相对于治疗， 与抗乳明TNF-？ mab和地塞米松（p <0.05）。 公共卫生相关性：克罗恩病仍然是现有疗法的顽固性，其中很大比例的患者持续反复发生炎症和肠道损害。我们正在开发一种新型药物，该药物在这种情况下专门阻止炎症过程。我们将在一系列与自身免疫性结肠炎的临床动物模型中测试该药物。