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（由申请人提供）：同种异体干细胞移植（allo-SCT）对于患有白血病、淋巴瘤和多发性骨髓瘤的患者来说是一种潜在的治愈疗法。然而，在许多移植中心，与移植物抗宿主病（GVHD）相关的问题极大地限制了同种异体干细胞移植（allo-SCT）在具有HLA相同家庭成员或无关供体的患者中的使用。因此，开发能够预防或治疗 GVHD 的新疗法对于需要异体 SCT 的患者来说将是一个重大进步。 目前，预防 GVHD 最常见的方法是联合使用 S 期活性化疗药物（例如甲氨蝶呤）和钙化抑制剂，或者使用 Campath -1H 等抗体进行体内 T 细胞耗竭方法。虽然这些方法可以诱导 T 细胞耐受，但它们不会影响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是由调理治疗诱导的，对 GVHD 的发展至关重要。由于大多数治疗或预防 GVHD 的新疗法都源于实体器官移植的研究，不涉及炎症诱导的调理治疗，因此我们认为，需要开发一种专门针对异基因 SCT 和调理治疗并发症的新方法。 NF-(B 是由 Rel 蛋白组成的二聚体，对于诱导 T 细胞耐受以及生成 200 多种与炎症相关的蛋白质至关重要。我们小组之前发现，针对 NF-(B) 的溶解性差的药物对动物模型中 GVHD 的发生影响不大，这在很大程度上受到该化合物的生物利用度的限制。 在该提案中，我们发起了与生物技术公司Theralogics的合作，评估该公司授权的TLX1001在预防或治疗GVHD方面的用途。该药物是 IKK 催化结构域的抑制剂，通过干扰 I(B 的磷酸化来阻断 NF-(B 的激活)。TheraLogics 的创始人 Al Baldwin 博士和首席科学官 Sankar Ghosh 博士是国际公认的 NF-(B 生物学专家。该提案汇集了两位在 GVHD 生物学方面经验丰富的研究人员， Serody 和 Blazar 博士、Theralogics 科学家，Baldwin 和 Ghosh 博士是 NF-（B 级）生物学专家，William Zamboni 博士是靶向治疗药理学专家，Richard Nash 博士是 GVHD 狗模型。提出了三个具体目标，以研究 TLX1001 在供体脾细胞输注模型中治疗 GVHD 的用途，以及 用于预防非清髓性骨髓移植后的 GVHD。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，建议研究该化合物在移植后狗体内的药代动力学和药效学。如果第二阶段拨款成功，将为该疗法在英国大学进行临床试验铺平道路。 北卡罗来纳州教堂山。 公共卫生相关性：骨髓或干细胞移植对于患有某些类型血癌的个体来说可以是一种挽救生命的手术。在大多数情况下，接受骨髓或干细胞移植的个人需要与捐赠者完美匹配，以获得最佳结果。这是因为供体白细胞可以与受体细胞上发现的蛋白质发生反应，从而导致称为“疾病”的疾病。 移植物抗宿主病（GVHD）。即使采用最好的预防性治疗，接受完美匹配供体骨髓或干细胞移植的个体中仍有约 50% 会发生 GVHD，并可能导致多种并发症，包括受体死亡。因此，为了更广泛地使用移植作为一种治疗形式，需要新的治疗形式来预防或治疗 GVHD。 该提案研究了一种新化合物，该化合物可以阻断引起 GVHD 的白细胞以及引起 GVHD 相关症状的蛋白质。建议在动物模型中进行实验来测试该化合物的活性，如果成功，这项工作的长期目标是在人体临床试验中使用该化合物来治疗 GVHD。