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: 7643877
• 负责人: Patrick Michael Flood
• 金额: $ 45.44万
• 依托单位: THERALOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643877
• 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; public health relevance; research study; transcription factor

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述(申请人提供)：异基因干细胞移植(allo-SCT)是一种潜在的治疗白血病、淋巴瘤和多发性骨髓瘤患者的方法。然而，与移植物抗宿主病(GVHD)相关的问题已经极大地限制了异基因干细胞移植的使用，无论是在许多移植中心的家庭成员相合的患者还是没有血缘关系的供者。因此，能够预防或治疗移植物抗宿主病的新疗法的开发对需要异基因干细胞移植的患者来说将是一个重大的进步。 目前，最常见的预防移植物抗宿主病的方法要么是S期活性化疗药物(如甲氨蝶呤和一种钙化抑制剂)的组合，要么是体内使用抗体如Camath-1H的T细胞耗竭方法。虽然这些方法可以诱导T细胞耐受，但它们不影响条件疗法诱导的促炎细胞因子和趋化因子的产生，这些细胞因子和趋化因子对GVHD的发展至关重要。由于大多数治疗或预防GVHD的新疗法都是从实体器官移植的研究中产生的，而不涉及炎症诱导的条件性疗法，我们认为需要一种专门针对异基因干细胞移植和条件性疗法的并发症的新方法来开发新的药物。 核因子-(B)是一种由Rel蛋白组成的二聚体，在诱导T细胞耐受和产生200多种参与炎症的蛋白质中起关键作用。我们的团队之前已经发现，针对NF-(B)的难溶药物在动物模型中对GVHD的发生有适度的影响，这在很大程度上受到该化合物的生物利用度的限制。 在这项提案中，我们发起了与生物技术公司Theralogics的合作，以评估该公司许可的TLX1001在预防或治疗GVHD方面的使用。该药物是IKK催化区域的抑制剂，并通过干扰I(B)的磷酸化来阻止NF-(B)的激活。TheraLogics Al Baldwin PhD的创始人Al Baldwin PhD和首席科学官Sankar Ghosh Ph.D.是国际公认的NF-(B)生物学专家。研究TLX1001在供者脾细胞输注模型中治疗移植物抗宿主病和预防非清髓性骨髓移植后移植物抗宿主病中的应用有三个具体目的。建议进行实验以评估TLX1001与钙调神经磷酸酶抑制剂他克莫司的联合作用。最后，建议对该化合物在犬移植后的药代动力学和药效学进行研究。如果第二阶段拨款成功，它将为北卡罗来纳大学教堂山分校的这种疗法的临床试验铺平道路。公共卫生相关性：对于某些类型的血癌患者来说，骨髓或干细胞移植可能是一种挽救生命的方法。在大多数情况下，接受骨髓或干细胞移植的人需要与捐赠者完美匹配，才能获得最好的结果。这是因为供者的白细胞可以对受体细胞上发现的蛋白质产生反应，从而导致一种称为移植物抗宿主病(GVHD)的疾病。即使采用最好的预防性治疗，接受完全匹配的捐赠者的骨髓或干细胞移植的个体中也有大约50%会发生移植物抗宿主病，并可能导致多种并发症，包括受者死亡。因此，需要新的治疗形式来预防或治疗移植物抗宿主病，以便更广泛地使用移植作为一种治疗形式。 这项提案研究了一种新的化合物，它可以阻止导致GVHD的白细胞和导致GVHD相关症状的蛋白质。建议在动物模型中进行实验，以测试该化合物的活性，如果成功，这项工作的长期目标是将该化合物用于治疗GVHD的人类临床试验。