A Novel Immunological-Directed Biotherapy for Treating Rheumatoid Arthritis

项目摘要 我们的目标是开发一种新的，免疫导向的L。基于乳酸菌益生菌的治疗剂， 类风湿性关节炎（RA）。类风湿关节炎是一种慢性全身性炎症性疾病， 人口1，2.虽然许多器官受到影响，在类风湿关节炎，滑膜关节主要是折磨衰弱 炎症大约一半的RA患者随着疾病的进展而致残。 RA的治疗仍然是一个显著未满足的医疗需求。尽管有非常有效的治疗方法， 细胞因子和免疫细胞，没有治疗可以诱导长期的疾病缓解38。TNF-α拮抗剂可以 有效地消除炎症并减轻软骨和骨的破坏7 -10。但部分患者 对抗TNF治疗无效或复发。长期治疗会使患者 癌症和机会性感染11 -14。此外，目前许多治疗RA的方法，无论多么有效， 使患者终生接受昂贵的生物治疗，伴随着医源性并发症的风险。为 基于这些原因，我们正在开发一种口服免疫疗法，可以调节自身抗原特异性调节性T细胞 （THEORY）以提供旁观者耐受性。这种方法的两个主要目标是：1）“关闭”免疫系统 2）平衡效应细胞关系，以防止复发， 慢性炎症 最初设想作为人类大肠杆菌疫苗，我们发现来自大肠杆菌的定植因子抗原I（CFA/I） 人肠毒素E.当口服给药时，大肠杆菌能有效诱导自身抗原特异性T细胞增殖22，56-58。到 避免了与产生大量CFA/I蛋白相关的挑战， 通过研究CFA/I口服给药后的药代动力学（PK）和药效学（PD）特性，我们 发展了一个L. Lactis-CFA/I表达产物（称为R-2487），并在多种情况下验证其功效。 自身免疫模型R-2487在动物模型研究中有效减轻关节炎症状，沿着 干燥综合征、糖尿病和多发性硬化症的实验模型17，30，59，60.先前SBIR和种子 投资资金和FDA的IND前会议使我们能够将R-2487定位为临床试验。 此快速通道应用程序的重点是通过完成首次人体验证来获得R-2487的人体验证 1期RA概念验证临床试验。具体目的是：1）最终确定R-2487临床供应包装，2） 准备并向FDA提交IND，3）完成1期概念验证临床试验，4）分析患者 给药前/后的样品以评价药效学变化和生物标志物，5）进行2期临床试验， 生产规模扩大开发，以准备R-2487进行更大规模的确证性试验。 R-2487的成功商业化将为治疗RA提供深刻的医学进步。

Project Summary Our goal is to develop a novel, immunological-directed L. lactis probiotic-based therapeutic for the treatment of rheumatoid arthritis (RA). RA is a chronic, systemic inflammatory disorder affecting up to 1% of the US population1, 2. While many organs are affected in RA, the synovial joints are primarily afflicted with debilitating inflammation. Approximately half of all RA patients become disabled as the disease progresses. Treatment of RA remains a significant unmet medical need. Despite highly effective therapies targeting cytokines and immune cells, no therapy can induce long-term disease remission38. TNF-α antagonists can effectively diminish inflammation and attenuate destruction of cartilage and bone7-10. However, some patients either fail to respond to, or relapse with, anti-TNF therapy. Prolonged treatment can make patients susceptible to cancer and opportunistic infections11-14. Moreover, many current treatments for RA, no matter how effective, consign patients to a lifetime of costly biologic therapies with attendant risks for iatrogenic complications. For these reasons, we are developing an oral immunotherapy that regulates auto-Ag-specific regulatory T cells (Tregs) to provide bystander tolerance. The two main goals of this approach are: 1) to “switch off” the immune response against the host’s own tissues and 2) balance the effector cell relationships to prevent relapses of chronic inflammation. Originally conceived as a human diarrheal vaccine, we discovered that colonization factor antigen I (CFA/I) from human enterotoxigenic E. coli is effective at inducing auto-Ag-specific Tregs when administered orally22, 56-58. To avoid challenges associated with producing large quantities of CFA/I protein and improve the mucosal pharmacokinetic (PK) and pharmacodynamic (PD) properties of CFA/I following oral administration, we developed an L. lactis-CFA/I expressing product (referred to as R-2487) and validated its efficacy in multiple autoimmune models. R-2487 was effective at reducing arthritis symptoms in animal model studies, along with experimental models of Sjögren’s syndrome, diabetes, and multiple sclerosis17, 30, 59, 60. Prior SBIR and Seed investment funding and an FDA pre-IND meeting has enabled us to position R-2487 ready for clinical testing. This Fast Track application is focused on obtaining human validation for R-2487 by completing a first-in-human Phase 1 RA proof-of-concept clinical trial. The Specific Aims are: 1) finalize R-2487 clinical supply packaging, 2) prepare and file an IND with the FDA, 3) complete a Phase 1 proof-of-concept clinical trial, 4) analyze patient samples before/after dosing to evaluate pharmacodynamic changes and biomarkers, 5) perform Phase 2 clinical manufacturing scale up development to ready R-2487 for larger confirmatory trial. Successful commercialization of R-2487 will provide a profound medical advancement for treating RA.