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: 10357904
• 负责人: Gary Fanger
• 金额: $ 100万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10357904
• 关键词: Affect; Anti-Tumor Necrosis Factor Therapy; Antibiotics; Arthralgia; 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 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; I-antigen; Iatrogenesis; Immune; Immune response; Immunologics; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Industry; Inflammation; Inflammatory; Inflammatory Response; Intestines; Investments; Lactococcus; Malignant Neoplasms; Measures; Medical; Methodology; Modeling; Monitor; Monoclonal Antibodies; Mucous Membrane; Mus; Operon; Oral; Oral Administration; Organ; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology and Toxicology; Phase; Population; Probiotics; Property; Proteins; Quality Control; Recombinants; Regulatory T-Lymphocyte; Relapse; Rheumatoid Arthritis; Risk; Running; 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; base; 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; meetings; novel; optimal treatments; pharmacokinetics and pharmacodynamics; prevent; product development; 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作为一种新型的口服治疗药物商业化，用于长期缓解 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调节剂，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 以持久的方式对抗宿主自身组织的反应，2）最大限度地平衡关系 在不同谱系的效应细胞之间，以防止慢性炎症的复发。这种做法将 为患者提供长期缓解和增加的安全性，而无需全身免疫抑制。 最初设想作为一种人大肠杆菌疫苗，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.大肠杆菌（ETEC）在诱导自身抗原特异性T调节细胞方面是有效的18，22，54，55，56。 CFA/I作为纯化蛋白口服给药或通过L.乳酸菌或沙门氏菌细菌载体， 有效预防和治疗关节炎的多种实验模型16，18，33，57，以及 干燥综合征，糖尿病和多发性硬化症17，58，59。避免与生产相关的挑战 足够量的重组CFA/I，并改善口服后CFA/I的粘膜PK/PD特性 管理，我们成功开发了一种新的L.乳酸菌菌株（称为R-2487），其表达 来自基因组整合表达操纵子的功能性CFA/I。我们还验证了R-2487具有 包括在人细胞上的功能性的可行生物素候选物的重要关键设计特征。 现在，我们已经在IND前会议的背景下与FDA会面，以最终确定我们的产品开发 战略，这第二阶段SBIR应用旨在建立在我们的成功和推进R-2487朝着 IND申请阶段。目标是：1）生产足够量的R-2487以支持体内开发， 2)开发PK测定以测量R-2487和CFA/I蛋白质肠道暴露，3）确定最佳口服 小鼠中R-2487的剂量和PK/PD，4）制备GMP主细胞库并生产用于GLP的R-2487 药理学/毒理学研究，和5）用R-2487进行GLP毒理学研究，以实现IND申报。