Repolarization of Activated Th1 Cells: a Novel Means to Treat IBD

活化 Th1 细胞的复极化：治疗 IBD 的新方法

基本信息

批准号：
8051928
负责人：
Kanneganti Murthy
金额：
$ 26.3万
依托单位：
RADIKAL THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-15 至 2013-01-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8051928
关键词：
Acute Adoptive Transfer Adrenal Cortex Hormones Adult Animal Model Animals Antigens Appearance Attenuated Autoimmune Diseases Autoimmune Process Autoimmunity Bacterial Translocation Biochemical Biological Models Body Weight Body Weight decreased CD4 Positive T Lymphocytes CXCL11 gene CXCR3 gene Calcineurin inhibitor Callithrix Cell Line Cells Cellular Immunity Chimeric Proteins Chinese Hamster Ovary Cell Chronic Clinical Clinical Trials Colitis Crohn&apos s disease Dexamethasone Diarrhea Disease Dose Double-Blind Method Equilibrium Euthanasia Excision Experimental Autoimmune Encephalomyelitis Experimental Models Feces Feedback Functional disorder Future Genes Histology Homologous Gene Human IL2RA gene Immune Tolerance Immunity Immunologics Immunomodulators Immunosuppressive Agents Infection Inflammation Inflammatory Inflammatory disease of the intestine Injury Intestines Investigation Islets of Langerhans Transplantation Life Ligand Binding Louisiana Malignant Neoplasms Medical Methotrexate Modeling Monitor Mucositis Mus Neutrophil Infiltration Occult blood screen Onset of illness Operative Surgical Procedures Patients Pharmaceutical Preparations Pharmacology Phase Placebo Control Predisposition Primates Process Production Quality of life Randomized Rattus Recurrence Refractory Regulatory T-Lymphocyte Relative (related person)Rodent Safety Serum-Free Culture Media Sirolimus Small Business Innovation Research Grant Steroids T-Lymphocyte TNF gene Testing Th1 Cells Therapeutic Tissues Toxicology Treatment Protocols United States National Institutes of Health Universities Work analytical method chemokine clinically relevant effective therapy improved in vivo innovation meetings nonhuman primate novel pre-clinical prevent prospective recombinase research study restoration

项目摘要

DESCRIPTION (provided by applicant): Current treatment regimens for Crohn's Disease (CD) are unsatisfactory, as evidenced by the high percentage of complications in the disease, frequently necessitating debilitating intestinal resection. CD is thought to result from both an excess of pathogenic Th1/Th17 cells and a deficiency of tolerance-inducing antigen (Ag) specific T regulatory CD4+ cells, in particular Tr1 cells (FOXp3-CD25-IL-10high, FOXp3-CD25-IL-4high). In the absence of suitable levels of regulatory T-cells, the impact of pathogenic Th1/Th17 cells is unopposed, resulting in mucosal inflammation and injury. Beyond a threshold loss of mucosal integrity, bacterial translocation from the gut lumen takes place, which then elicits a positive feedback loop of submucosal infection, inflammation, tissue injury, and greater barrier dysfunction. To meet this need, Radikal Therapeutics is developing a novel fusion protein (hR-411) that induces targeted immune tolerance in antigen (Ag)-specific activated T-cells. hR-411 is constructed from Ig-Fc and CXCL11, a CXCR3-binding ligand that has been recently identified as a counter- regulatory chemokine. Therapy with mR-411, the murine homologue of hR-411, profoundly suppresses experimental allergic encephalomyelitis (EAE), a classic autoimmune model system in rodents, even when treatment is initiated after disease onset. Moreover, Ag-specific effector Th1 cells isolated from EAE donors treated in vivo with mR-411 redirect their polarization into Tr1 cells and suppress EAE in adoptive transfer experiments. In contrast to pan-suppressive immunomodulators, mR-411 induces tolerance that is Ag-specific for the active disease yet preserves generalized immunity to previously encountered antigens. Phase 1 Specific Aim: Establish that mR-411 dose-dependently attenuates established colitis in an adoptive T-cell transfer model of intestinal inflammation We will carry out a dose-escalation placebo-controlled investigation of mR-411 in recombinase-activating gene-1 deficient (RAG-/-) mice rendered colitic via the adoptive transfer of CD4+CD45RBhigh T-cells. Treatment with mR-411 or dexamethasone will begin 4 weeks after adoptive T-cell transfer. mR-411 is expected to dose-dependently improve gut histology score and prevent neutrophil infiltration. Phase 2 Specific Aim: Establish the pre-clinical safety of hR-411, as demonstrated by GLP studies of toxicology and safety pharmacology in rats and primates. We will develop: 1) a high-producing CHO cell line for production of hR-411 in serum-free media, 2) validated analytical methods to support manufacturing in- process and release testing, and 3) GMP-grade batches of hR-411 drug substance and product to support GLP toxicology and safety pharmacology studies and GCP clinical trials. We will then undertake acute safety pharmacology and subacute and chronic toxicology investigations in Marmoset non-human primates. 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 yet does not interfere with general immunity. We will test this agent in a clinically-relevant animal model of autoimmune colitis.

描述（由申请人提供）：目前克罗恩病（CD）的治疗方案并不令人满意，该病并发症的比例很高，经常需要进行使人衰弱的肠道切除术。 CD 被认为是由于致病性 Th1/Th17 细胞过多和耐受诱导抗原 (Ag) 特异性 T 调节性 CD4+ 细胞缺乏所致，特别是 Tr1 细胞（FOXp3-CD25-IL-10high、FOXp3-CD25-IL） -4高）。在缺乏适当水平的调节性 T 细胞的情况下，致病性 Th1/Th17 细胞的影响不受阻碍，导致粘膜炎症和损伤。超过粘膜完整性丧失的阈值，细菌就会从肠腔移位，从而引发粘膜下感染、炎症、组织损伤和更大的屏障功能障碍的正反馈循环。为了满足这一需求，Radikal Therapeutics 正在开发一种新型融合蛋白 (hR-411)，它可以在抗原 (Ag) 特异性激活的 T 细胞中诱导靶向免疫耐受。 hR-411 由 Ig-Fc 和 CXCL11 构建而成，CXCL11 是一种 CXCR3 结合配体，最近被鉴定为反调节趋化因子。使用 hR-411 的鼠类同源物 mR-411 进行治疗，可以深度抑制实验性过敏性脑脊髓炎 (EAE)（啮齿类动物的一种经典自身免疫模型系统），即使在疾病发作后开始治疗也是如此。此外，从 EAE 供体中分离出的 Ag 特异性效应 Th1 细胞在体内用 mR-411 处理后，将其极化重新定向到 Tr1 细胞中，并在过继转移实验中抑制 EAE。与泛抑制性免疫调节剂相比，mR-411 诱导针对活动性疾病的 Ag 特异性耐受，同时保留对先前遇到的抗原的普遍免疫力。第一阶段的具体目标：确定 mR-411 在肠道炎症过继性 T 细胞转移模型中剂量依赖性地减轻已建立的结肠炎我们将对重组酶激活基因 1 中的 mR-411 进行剂量递增安慰剂对照研究通过过继转移 CD4+CD45RBhigh T 细胞，缺陷型 (RAG-/-) 小鼠出现结肠炎。 mR-411 或地塞米松治疗将在过继 T 细胞移植后 4 周开始。预计 mR-411 可以剂量依赖性地改善肠道组织学评分并防止中性粒细胞浸润。第 2 阶段具体目标：确定 hR-411 的临床前安全性，如大鼠和灵长类动物毒理学和安全药理学 GLP 研究所证明的那样。我们将开发：1) 用于在无血清培养基中生产 hR-411 的高产 CHO 细胞系，2) 经过验证的分析方法，以支持生产过程和放行测试，以及 3) GMP 级批次的 hR- 411种原料药和产品支持GLP毒理学和安全药理学研究以及GCP临床试验。然后，我们将对狨猴非人类灵长类动物进行急性安全药理学以及亚急性和慢性毒理学研究。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，可以专门阻止这种情况下的炎症过程，但不会干扰一般免疫力。我们将在临床相关的自身免疫性结肠炎动物模型中测试该药物。