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: 7481353
• 负责人: Patrick Michael Flood
• 金额: $ 44.28万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7481353
• 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; Blood typing procedure; Bone Marrow; Bone Marrow Transplantation; Calcineurin inhibitor; Canis familiaris; Catalytic Domain; Cells; Cessation of life; Characteristics; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Condition; 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; Homologous Transplantation; 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; Numbers; Organ Transplantation; Pancytopenia; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase I Clinical Trials; Phosphorylation; Phosphotransferases; Prevention; Prevention approach; Procedures; Production; Proteins; Public Health; Relapse; Research Personnel; Response Elements; Scientist; Signal Pathway; Solid; Specificity; Spiral Computed Tomography; 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; 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

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（由适用提供）：同种异体干细胞移植（Allo-SCT）是患有白血病，淋巴瘤和多发性骨髓瘤的患者的潜在治疗疗法。但是，与基层宿主疾病（GVHD）相关的问题极大地限制了在许多移植中心的HLA相同家庭成员或不相关的供体的患者中使用Allo-SCT。因此，对于需要同种SCT的患者而言，可以预防或治疗GVHD的新疗法的发展将是一个重大进步。 当前，预防GVHD的最常见方法是使用campath -1H等抗体（例如campath -1H）组合S期活性化疗药物（例如方法转移酸盐和钙化抑制剂）或T细胞部署的体内T细胞部署方法的组合。尽管这些方法可以诱导T细胞的耐受性，但它们不会影响促炎细胞因子和趋化因子的产生，这些因子和趋化因子是由调节疗法诱导的，并且对GVHD的发展至关重要。由于大多数用于治疗或预防GVHD的新疗法是由固体器官移植的研究引起的，这些疗法不涉及炎症引起的调理疗法，我们认为一种专门针对Allo-SCT的新方法，需要开发新药物的调理治疗并发症。 NF-（B是由RER蛋白组成的调光，对于诱导T细胞耐受性和200多个参与炎症的蛋白质的产生至关重要。我们的小组以前发现，靶向NF-的固体药物差的固体药物（B对GVHD在动物模型中的出现具有适度的影响），这受到该动物模型的极大限制，这受到了该化合物的综合性的限制。 在此提案中，我们与生物技术公司Theralogics启动了合作，以评估该公司在预防或治疗GVHD方面许可的TLX1001的使用。该药物是IKK催化域的抑制剂，并阻止了NF-的激活（b通过干扰I的磷酸化（b。theralogics al Baldwin PhD的创始人a al Baldwin Phd和首席科学官Sankar Ghosh Ph.D.在国际上经验丰富的专家，在nf-nf-nf-nf-nf。在Drs Serody和Blazar中，与Theralogics的科学家是NF-的专家（B中的Baldwin和Ghosh博士的B中，以及William Zamboni博士的有针对性治疗药理学的两名外部专家，以及Richard Nash博士的GVHD狗模型。为了预防非甲状腺骨髓移植后的GVHD。如果该第二阶段赠款成功，它将在北卡罗来纳大学教堂山分校的临床试验中为这种疗法铺平道路。公共卫生相关性：对于患有某些类型的血液癌的人来说，骨髓或干细胞移植可能是挽救生命的程序。在大多数情况下，接受骨髓或干细胞移植的人需要与供体完美匹配，以获得最佳结果。这是由于以下事实：供体白细胞可以与在受体细胞上发现的蛋白质反应，从而导致疾病称为移植物抗宿主病（GVHD）。即使采用最好的预防疗法，GVHD也发生在大约50％的人中，从完全匹配的供体接受骨髓或干细胞移植，并可能导致多种并发症，包括受体死亡。这是需要更广泛使用移植作为一种治疗形式的新形式的预防或治疗GVHD的疗法。 该提案研究了一种新化合物，该化合物可以阻止引起GVHD的白细胞和引起与GVHD相关的症状的蛋白质。在动物模型中提出了实验，以测试化合物的活性，如果成功，这项工作的长期目标是在人类临床试验中进行GVHD治疗。