A Novel Immunologically Enhanced Probiotic for Treating Rheumatoid Arthritis

一种用于治疗类风湿关节炎的新型免疫增强益生菌

• 批准号: 10548878
• 负责人: Gary Fanger
• 金额: $ 92.27万
• 依托单位: RISE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-23 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548878
• 关键词: Affect; Anti-Tumor Necrosis Factor Therapy; Antibiotics; Arthralgia; Arthritis; Attenuated; Autoimmune Diseases; Autoimmunity; Bacteria; Bacterial Infections; Benchmarking; Biological Assay; Biological Markers; Biological Response Modifier Therapy; Blood; Cartilage; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Collagen Arthritis; Colony-forming units; Combined Modality Therapy; Data; Development; Diabetes Mellitus; Diarrhea; Disabled Persons; Disease; Disease Progression; Disease remission; Dose; Drug Kinetics; Effector Cell; Enzyme-Linked Immunosorbent Assay; Equilibrium; Experimental Models; Food; Formulation; Freeze Drying; Genome; Genomics; Goals; Growth; Histocompatibility Antigens Class II; Human; Iatrogenesis; Immune response; Immunologics; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Industry; Inflammation; Inflammatory; Inflammatory Response; Intestines; Investments; Lactococcus lactis; Malignant Neoplasms; Measures; Medical; Methodology; Modeling; Monitor; Monoclonal Antibodies; Mucous Membrane; Multiple Sclerosis; Mus; Operon; Opportunistic Infections; Oral; Oral Administration; Organ; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology and Toxicology; Phase; Population; Predisposition; Probiotics; Property; Proteins; Quality Control; Recombinants; Regulatory T-Lymphocyte; Relapse; Rheumatoid Arthritis; Risk; Safety; Salmonella; Schedule; Sjogren' s Syndrome; Small Business Innovation Research Grant; Syndrome; Synovial joint; TNF gene; Therapeutic; Tissues; Toxicology; Vaccines; Work; adaptive immune response; alternative treatment; animal efficacy; antagonist; bacterial vector; bone; cell bank; clinical application; clinical candidate; colonization factor antigens; commercialization; cost; cytokine; design; drug development; effective therapy; effector T cell; efficacy study; enterotoxigenic Escherichia coli; expression vector; immunoregulation; improved; in vivo; innovation; integration site; interest; life time cost; manufacture; manufacturing run; novel; optimal treatments; pharmacokinetics and pharmacodynamics; pre-Investigational New Drug meeting; prevent; product development; protein purification; prototype; research clinical testing; success; targeted treatment

Project Summary Our goal is to commercialize R-2487 as a novel, orally administered therapy for long-term disease remission 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 T-B interactions, no therapy can induce long-term disease remission34. 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 immunotherapeutic 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 in an enduring manner and 2) maximally balance the relationships between effector cells of different lineages to prevent relapses of chronic inflammation. Such an approach will provide patients long-term remission and increased safety without systemic immunosuppression. Originally conceived as a human diarrheal vaccine, we found that colonization factor antigen I (CFA/I) from human enterotoxigenic E. coli (ETEC) is effective at inducing auto-Ag-specific T regulatory cells18, 22, 54, 55, 56. CFA/I administered orally as purified protein or delivered via an L. lactis or Salmonella bacterial vector was effective at preventing and treating multiple experimental models for arthritis16, 18, 33, 57, as well as models for Sjogren’s syndrome, diabetes, and multiple sclerosis17, 58, 59. To avoid challenges associated with producing sufficient quantities of recombinant CFA/I and to improve the mucosal PK/PD properties of CFA/I following oral administration, we successfully developed a new L. lactis strain (referred to as R-2487) that expresses functional CFA/I from a genome-integrated expression operon. We also validated that R-2487 possesses the important key design features for a viable biotherapeutic candidate including functionality on human cells. Now that we have met with the FDA in the context of a pre-IND meeting to finalize our product development strategy, this Phase II SBIR application is intended to build upon our success and advance R-2487 towards the IND filing stage. The objectives are: 1) produce sufficient quantities of R-2487 to support in vivo development, 2) develop PK assays to measure R-2487 and CFA/I protein intestinal exposure, 3) determine the optimal oral dose and PK/PD for R-2487 in mice, 4) prepare a GMP master cell bank and manufacture R-2487 for GLP pharm/tox studies, and 5) perform GLP toxicology studies with R-2487 to enable IND filing.

项目摘要 我们的目标是将R-2487作为一种新颖的口服治疗，用于长期疾病的缓解 类风湿关节炎（RA）。 RA是一种慢性全身性炎症性疾病，影响多达1％的美国 人口1，2。虽然许多器官在RA中受到影响，但滑膜关节主要遭受衰弱的折磨 炎。随着疾病的进展，大约一半的RA患者成为残疾人。 RA的治疗仍然是巨大的未满足的医疗需求。尽管靶向高效的疗法 细胞因子和T-B相互作用，没有治疗可以诱导长期疾病缓解34。 TNF-α拮抗剂可以 有效减少注射并减少软骨和骨的破坏7。但是，有些患者 要么无法反应抗TNF疗法，要么转发。长时间的治疗可以使患者敏感 癌症和机会性感染11-14。此外，无论多么有效，当前对RA的治疗 将患者委托患有昂贵的生物疗法，具有医源性并发症的风险。为了 这些原因，我们正在开发一种口服免疫治疗性，以调节自动特异性调节性T细胞 （Tregs）提供旁观者的容忍度。这种方法的两个主要目标是：1）“关闭”免疫 以持久的方式对宿主自己的组织的反应和2）最大平衡关系 在不同谱系的效应细胞之间，以防止慢性炎症中继。这样的方法将 为患者提供长期缓解和增加安全性，而无需全身免疫抑制。 我们最初被认为是人类腹泻疫苗，我们发现定植因子抗原I（CFA/I）来自 人肠毒素大肠杆菌（ETEC）在诱导的自动特异性T调节细胞中有效18、22、54、55、56。 CFA/I口服作为纯化蛋白质或通过L.乳酸乳杆菌或沙门氏菌载体传递 有效预防和治疗关节炎16、18、33、57的多个实验模型以及模型 Sjogren综合征，糖尿病和多发性硬化症17，58，59。避免与生产有关的挑战 足够数量的重组CFA/I并改善口服后CFA/I的粘膜PK/PD特性 行政管理，我们成功地开发了一种新的乳酸乳杆菌菌株（称为R-2487） 来自基因组集成表达歌剧的功能CFA/I。我们还验证了R-2487拥有 可行的生物治疗候选者的重要关键设计特征，包括人类细胞的功能。 现在，我们已经在预定会议的背景下与FDA会面，以最终确定我们的产品开发 策略，此II阶段SBIR应用程序旨在基于我们的成功并将R-2487推向 IND归档阶段。目标是：1）生产足够数量的R-2487来支持体内开发， 2）开发PK分析以测量R-2487和CFA/I蛋白肠暴露，3）确定最佳口服 小鼠R-2487的剂量和PK/PD，4）准备GMP主细胞库并制造GLP的R-2487 Pharm/TOX研究和5）使用R-2487进行GLP毒理学研究以实现IND归档。