Inhibition of IkK to treat lethal Graft-vs.-Host Disease

抑制 Ikk 可治疗致命的移植物抗宿主病

• 批准号: 7883853
• 负责人: Patrick Michael Flood
• 金额: $ 23.48万
• 依托单位: THERALOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883853
• 关键词: Abbreviations; Acute Graft Versus Host Disease; Address; Adoption; Affect; Allogenic; Animal Model; Animals; Antibodies; Antigens; Behavior Therapy; Binding; Biological Availability; Biology; Biotechnology; Bone Marrow; Bone Marrow Transplantation; Calcineurin inhibitor; Canis familiaris; Catalytic Domain; Cells; Cessation of life; Characteristics; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Control Animal; Cyclosporine; DNA-Binding Proteins; Data; Development; Disease; Doctor of Philosophy; Drug Delivery Systems; Drug Kinetics; Engraftment; Family; Family member; Generations; Genes; Glucocorticoids; Goals; Grant; Hematopoietic Neoplasms; Histocompatibility Antigens; Human; Immune response; In Vitro; Individual; Inflammation; Infusion procedures; Lead; Leukocytes; Licensing; Life; Lymphocyte; Measures; Mediating; Methods; Methotrexate; Minor; Modeling; Monoclonal Antibody Campath-1H; Multiple Myeloma; Mus; New Agents; Non-Hodgkin' s Lymphoma; North Carolina; Nuclear; Organ Transplantation; Pancytopenia; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase I Clinical Trials; Phosphorylation; Phosphotransferases; Prevention; Prevention approach; Procedures; Production; Proteins; Relapse; Research Personnel; Response Elements; Scientist; Signal Pathway; Solid; Specificity; Splenocyte; Stem cell transplant; Symptoms; Syndrome; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; Tacrolimus; Tertiary Protein Structure; Testing; Therapy Clinical Trials; Toxic effect; Transplantation; Universities; Work; chemokine; chemotherapy; comparative efficacy; conditioning; cytokine; dimer; experience; graft vs host disease; human TYRP1 protein; immune function; improved; in vivo; inhibitor/antagonist; leukemia; leukemia/lymphoma; member; novel strategies; prevent; promoter; prophylactic; research study; transcription factor

Allogeneic stem cell transplantation (allo-SCT) is potentially curative therapy for a patients suffering from leukemia, lymphoma and multiple myeloma. However, the problems associated with graft-versus-host disease (GVHD) have greatly limited the use of allo-SCT to patients with either an HLA-identical family member or unrelated donor in many transplant centers. As a consequence, the development of new therapies that could prevent or treat GVHD would be a significant advance for patients needing an allo- SCT. Currently, the most common approaches to the prevention of GVHD are either a combination of S-phase active chemotherapy drugs such as methotrexate and a calcineuring inhibitor or in vivo methods of T cell depletion using antibodies such as Campath -1H. While these approaches can induce T cell tolerance, they do not impact on the generation of proinflammatory cytokines and chemokines that are induced by conditioning therapy and critical to the development of GVHD. As most new therapies for the treatment or prevention of GVHD have arisen from studies in solid organ transplantation, which does not involve inflammation-inducing conditioning therapy, we believe a new approach that focuses specifically on allo-SCT and the complications of conditioning treatment are needed for new agents to be developed. NF-?B is a dimmer composed of Rel proteins and is critical in the induction of T cell tolerance and the generation of over 200 proteins involved in inflammation. Our group has previously found that poorly soluable drugs that target NF-?B have a modest effect on the occurrence of GVHD in animal models, that is greatly limited by the bioavailability of the compound. In this proposal, we have initiated a collaboration with the biotechnology company, Theralogics, to evaluate the use of TLX1001 licensed by the company in the prevention or treatment of GVHD. This drug is an inhibitor of the catalytic domain of IKK ? and blocks the activation of NF-?B by interfering with the phosphorylation of I?B. The founder of TheraLogics Al Baldwin PhD and the chief scientific officer Sankar Ghosh Ph.D. are internationally recognized experts in the biology of NF-?B. This proposal brings together two extremely experienced investigators in the biology of GVHD, in Drs Serody and Blazar, with scientists at Theralogics who are experts on the biology of NF- ?B in Drs Baldwin and Ghosh and two outside experts in the pharmacology of targeted therapy in Dr. William Zamboni and dog models of GVHD in Dr. Richard Nash. Three specific aims are proposed to investigate the use of TLX1001 in the treatment of GVHD in a donor splenocyte infusion model and for the prevention of GVHD after nonmyeloablative marrow transplantation. Experiments are proposed to evaluate the combination of TLX1001 with the calcineurin inhibitor tacrolimus. Finally, studies are proposed to investigate the pharmacokinetics and pharmacodynamics of the compound in dogs after transplantation. If this phase II grant is successful, it will pave the way for clinical trials of this therapy at the University of North Carolina at Chapel Hill. Bone marrow or stem cell transplantation can be a life-saving procedure for individuals with certain types of blood cancers. In most instances an individual receiving a bone marrow or stem cell transplant needs to be perfectly matched with the donor for the best possible result. This is due to the fact that donor white cells can react against the proteins found on the cells of the recipient causing a disease termed graft-versus-host disease (GVHD). Even with the best possible preventative therapies, GVHD occurs in around 50% of the individuals receiving a bone marrow or stem cell transplant from a perfectly matched donor and can cause multiple complications including death of the recipient. Thus, new forms of therapy to prevent or treat GVHD are needed for the broader use of transplantation as a form of therapy. This proposal investigates a new compound that can block the white cells that cause GVHD and the proteins that cause the symptoms associated with GVHD. Experiments are proposed in animal models to test the activity of the compound and if successful the long-term goal of this work is to take this compound in human clinical trials for the treatment of GVHD.

同种异体干细胞移植（allo-SCT）是一种潜在的治疗方法 患有白血病、淋巴瘤和多发性骨髓瘤的患者。然而， 与移植物抗宿主病（GVHD）相关的问题极大地限制了其使用 对具有 HLA 相同家庭成员或无关捐赠者的患者进行同种异体干细胞移植 (allo-SCT) 许多移植中心。因此，新疗法的开发 可以预防或治疗 GVHD 对于需要同种异体的患者来说将是一个重大进步 干细胞移植。 目前，预防 GVHD 最常见的方法是 S期活性化疗药物（例如甲氨蝶呤）和 钙化抑制剂或使用抗体消除 T 细胞的体内方法，例如 坎帕斯-1H。虽然这些方法可以诱导 T 细胞耐受，但它们不会影响 影响促炎细胞因子和趋化因子的产生 调理治疗对于 GVHD 的发生至关重要。与大多数新疗法一样 用于治疗或预防 GVHD 的药物源于对实体器官的研究 移植，不涉及炎症诱导调理治疗，我们 相信一种专门针对同种异体干细胞移植及其并发症的新方法 新制剂的开发需要调理处理。 NF-κB 是由 Rel 蛋白组成的二聚体，对于 T 细胞的诱导至关重要 耐受性以及 200 多种与炎症有关的蛋白质的产生。我们组 之前发现针对 NF-κB 的溶解性差的药物效果有限 动物模型中 GVHD 发生的影响，很大程度上受到生物利用度的限制 的化合物。 在这个提案中，我们发起了与生物技术公司的合作， Theralogics，评估该公司许可的TLX1001在预防中的使用 或 GVHD 的治疗。该药物是 IKK 催化结构域的抑制剂？和 通过干扰 IκB 的磷酸化来阻断 NF-κB 的激活。这 TheraLogics 创始人 Al Baldwin 博士和首席科学官 Sankar Ghosh 博士是国际公认的 NF-κB 生物学专家。这个提议 汇集了两位在 GVHD 生物学领域经验丰富的研究人员，Drs Serody 和 Blazar，以及 Theralogics 的科学家，他们是 NF 生物学专家 ?B 鲍德温博士和戈什博士以及两位目标药理学外部专家 William Zamboni 博士的治疗和 Richard Nash 博士的 GVHD 狗模型。三 提出了研究 TLX1001 在 GVHD 治疗中的用途的具体目标 在供体脾细胞输注模型中以及用于预防移植物抗宿主病（GVHD） 非清髓性骨髓移植。建议进行实验来评估 TLX1001 与钙调神经磷酸酶抑制剂他克莫司的组合。最后，研究是 建议研究该化合物的药代动力学和药效学 移植后的狗。如果第二阶段拨款成功，将为 这种疗法在北卡罗来纳大学教堂山分校进行的临床试验。骨髓或干细胞移植可以成为个人的救命手术 患有某些类型的血癌。在大多数情况下，接受骨头的个人 骨髓或干细胞移植需要与捐赠者完美匹配才能获得最佳效果 可能的结果。这是因为供体白细胞可以对 在受体细胞上发现的蛋白质导致一种称为移植物抗宿主的疾病 疾病（GVHD）。即使采取了最好的预防性治疗，GVHD 仍会发生在 大约 50% 的人接受骨髓或干细胞移植 完美匹配的捐献者可能会导致多种并发症，包括捐献者死亡 接受者。因此，需要新的疗法来预防或治疗 GVHD 更广泛地使用移植作为一种治疗形式。 该提案研究了一种新化合物，可以阻止白细胞导致 GVHD 和引起 GVHD 相关症状的蛋白质。实验 建议在动物模型中测试该化合物的活性，如果成功的话 这项工作的长期目标是将该化合物用于人体临床试验 GVHD 的治疗。