Inducible B-regulatory cells (iBREGs) for treatment of Multiple Sclerosis

用于治疗多发性硬化症的诱导型 B 调节细胞 (iBREG)

• 批准号: 8238095
• 负责人: Jacques Galipeau
• 金额: $ 38.75万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8238095
• 关键词: Acute; Address; Adoption; Animal Model; Antibodies; Autoimmune Diseases; Autologous; B-Lymphocytes; Biodistribution; Biological; Biological Products; Biological Testing; Biology; Blood; Catastrophic Illness; Cell Therapy; Cell Transplantation; Cells; Clinic; Clinical; Clinical Research; Clinical Trials; Collecting Cell; Competence; Custom; Data; Development; Disease; Disease remission; Dose; Experimental Autoimmune Encephalomyelitis; Facility Accesses; Frequencies; Funding; Goals; Grant; Human; Immune; Immune response; In Vitro; Infectious Agent; Inflammatory Bowel Diseases; Injectable; Interferons; Interleukin-10; Interleukin-15; Knowledge; Lead; Longevity; Lymphoid Cell; Mediating; Medical; Medicine; Mitoxantrone; Multiple Sclerosis; Mus; Nature; Neuraxis; Organ Transplantation; Orthologous Gene; Outcome; Patients; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phenotype; Pilot Projects; Planet Mars; Population; Production; Property; Proteins; Publishing; Recombinant Proteins; Recombinants; Recruitment Activity; Relapsing-Remitting Multiple Sclerosis; Reporting; Research; Research Personnel; Rheumatoid Arthritis; Role; Scientist; Specimen; Sum; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Transgenes; Translations; Universities; Validation; Work; active method; base; clinical application; copolymer 1; cytokine; effective therapy; graft vs host disease; human subject; improved; in vivo; innovation; man; mouse model; natalizumab; neuroinflammation; novel; peripheral blood; phase 1 study; polarized cell; pre-clinical; research and development; research study; response; subcutaneous; synthetic protein; treatment strategy

DESCRIPTION (provided by applicant): We have generated a completely new class of immune suppressive agents based on a GMCSF and IL15 synthetic protein we called GIFT15. We've validated its use in mice and have further demonstrated that this compound promotes development of inducible B-regulatory cells (aka as iBregs) which leads to remission of EAE in mice. Therefore, the funding of this study will enable us to better understand the mechanism of action of iBregs and GIFT15 in the treatment of EAE. We will also define the safest and most efficient use of iBregs and recombinant GIFT15. In addition, we have generated the human version of GIFT15 and demonstrated its suppressive potential on human immune cells. As an additional step, validation of the mouse cell therapy approach will be achieved using human immune cells collected from MS patients, ex vivo treated with the human GIFT15. Assuming that iBregs or GIFT15 protein therapy leads to clinical benefit with an acceptable toxicity profile in EAE mice, the translational use of the human ortholog of GIFT15 in phase I/II clinical studies could be rapidly initiated based on this pre-clinical work. Indeed, the use of rGIFT15 in the context of MS as part of a therapeutic treatment will serve as the basis for the adoption and validation of this approach for a variety of diseases such as inflammatory bowel disease (IBD), graft-versus-host disease (GVHD), rheumatoid arthritis (RA) or even in the context of cell and organ transplantations. Thus, the utility of the GIFT15 compound as a way to generate suppressive cells in vitro and likely in vivo represents an approach with a wide array of clinical applications for catastrophic illnesses with unmet medical needs, especially MS. In sum, this study will enable us to pursue the characterization of iBregs and GIFT15 protein pharmacological product and will serve as rational for human clinical studies. PUBLIC HEALTH RELEVANCE: The development of innovative biopharmaceutical therapies suppressing the immune response seen in neuroinflammatroy disorders such as multiple sclerosis addresses an important clinical problem with unmet medical needs and serves as the preamble to first-in-man clinical trials. Knowledge gained from the proposed research will lead to improved outcome for patients suffering from autoimmune disorders at large.

描述（由申请人提供）：我们已经产生了一类全新的免疫抑制剂，其基于我们称为GIFT 15的GMCSF和IL 15合成蛋白。我们已经验证了它在小鼠中的用途，并进一步证明了这种化合物促进诱导型B调节细胞（又名iBAE）的发育，从而导致小鼠EAE的缓解。因此，这项研究的资助将使我们能够更好地了解iB和GIFT 15治疗EAE的作用机制。我们还将确定最安全和最有效地使用iBclase和重组GIFT 15。此外，我们已经产生了GIFT 15的人类版本，并证明了其对人类免疫细胞的抑制潜力。作为额外步骤，将使用从MS患者收集的人免疫细胞实现小鼠细胞治疗方法的验证，所述MS患者用人GIFT 15离体处理。假设iBclad或GIFT 15蛋白治疗在EAE小鼠中产生临床益处，具有可接受的毒性特征，基于该临床前工作，可以快速启动GIFT 15的人直系同源物在I/II期临床研究中的翻译使用。事实上，在MS的背景下使用rGIFT 15作为治疗性治疗的一部分将作为采用和验证该方法用于多种疾病的基础，所述疾病例如炎性肠病（IBD）、移植物抗宿主病（GVHD）、类风湿性关节炎（RA）或甚至在细胞和器官移植的背景下。因此，GIFT 15化合物作为在体外和可能在体内产生抑制性细胞的方式的效用代表了一种具有广泛临床应用的方法，用于具有未满足的医疗需求的灾难性疾病，特别是MS。总之，本研究将使我们能够追求iBcl 2和GIFT 15蛋白药理学产物的表征，并将作为人类临床研究的合理性。 公共卫生相关性：抑制神经炎性疾病（如多发性硬化症）中出现的免疫反应的创新生物药物疗法的开发解决了一个重要的临床问题，但医疗需求尚未得到满足，并作为首次人体临床试验的序言。从拟议的研究中获得的知识将改善患有自身免疫性疾病的患者的预后。