A Novel Immunological-Directed Biotherapy for Treating Rheumatoid Arthritis

项目摘要 我们的目标是开发一种新型的，免疫导向的乳酸乳杆菌益生菌为基础的治疗方法 类风湿关节炎(RA)。RA是一种慢性系统性炎症性疾病，影响美国高达1%的地区 人口1，2.虽然类风湿性关节炎的许多器官都受到影响，但滑膜关节主要是虚弱的 发炎。随着疾病的发展，大约一半的类风湿关节炎患者会致残。 类风湿性关节炎的治疗仍然是一个重要的未得到满足的医疗需求。尽管靶向治疗非常有效 细胞因子和免疫细胞，没有任何治疗方法可以导致疾病的长期缓解38。肿瘤坏死因子-α拮抗剂可以 有效消炎，减轻软骨、骨质破坏7-10。然而，一些患者 要么对抗肿瘤坏死因子治疗无效，要么复发。长期治疗会使患者变得易感。 癌症和机会性感染11-14。此外，目前许多治疗类风湿性关节炎的方法，无论多么有效， 让患者接受终生昂贵的生物治疗，伴随着医源性并发症的风险。为 出于这些原因，我们正在开发一种口服免疫疗法，它可以调节自身抗原特异的调节性T细胞 (Tregs)提供旁观者容忍度。这种方法的两个主要目标是：1)“关闭”免疫系统 对宿主自身组织的反应和2)平衡效应细胞关系以防止复发 慢性炎症。 最初被认为是一种人类腹泻疫苗，我们发现来自 当口服22，56-58时，人产肠毒素大肠杆菌能有效地诱导自身抗原特异性Tregs。至 避免与大量生产CFA/I蛋白相关的挑战，并改善粘膜 CFA/I口服给药后的药代动力学和药效学特性 开发了乳酸乳杆菌-CFA/I表达产物(简称R-2487)，并在多个 自身免疫模型。R-2487在动物模型研究中有效地减少关节炎症状，以及 干燥综合征、糖尿病和多发性硬化的实验模型17、30、59、60。之前的SBIR和种子 投资资金和FDA的Pre-IND会议使我们能够将R-2487定位为临床测试准备。 此Fast Track应用程序专注于通过完成首次人工验证来获得R-2487的人工验证 第1阶段类风湿关节炎概念验证临床试验。具体目标是：1)最终确定R-2487临床用品包装，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 服药前/服药后样本以评估药效学变化和生物标志物，5)进行二期临床 制造规模扩大开发，为R-2487进行更大规模的验证性试验做好准备。 R-2487的成功商业化将为治疗类风湿性关节炎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.