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

异基因造血干细胞移植（allo-SCT）是治疗 患有白血病、淋巴瘤和多发性骨髓瘤的患者。但 与移植物抗宿主病（GVHD）相关的问题极大地限制了它的使用 与HLA相同的家族成员或无关供体的患者进行allo-SCT， 许多移植中心。因此，新疗法的发展， 可以预防或治疗GVHD将是一个重大的进步，为患者需要一个异体移植， SCT。 目前，预防GVHD的最常见方法是： S期活性化疗药物如甲氨蝶呤和 钙调神经抑制剂或使用抗体的体内T细胞耗竭方法， 坎帕斯-1H。虽然这些方法可以诱导T细胞耐受性，但它们不会影响T细胞的免疫功能。 诱导的促炎细胞因子和趋化因子的产生 条件治疗和GVHD的发展至关重要。因为大多数新疗法 用于治疗或预防GVHD的方法已经从实体器官移植的研究中产生， 移植，不涉及炎症诱导的条件治疗，我们 我相信一种新的方法，专门针对allo-SCT和并发症， 需要调理处理以开发新的药剂。 NF-？B是由Rel蛋白组成的二聚体，在诱导T细胞增殖中起关键作用。 耐受性和超过200种参与炎症的蛋白质的产生。我们集团 以前发现，难溶性药物，靶向NF-？B的影响不大 在动物模型中，GVHD的发生受到生物利用度的极大限制， 化合物。 在这个提案中，我们已经开始与生物技术公司合作， Theralogics，以评价使用公司许可的TLX 1001预防 或GVHD的治疗。该药物是IKK？和 阻断NF-？B通过干扰I？B。的 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-生物学专家B。这项建议 汇集了两位在GVHD生物学方面经验丰富的研究人员， Serody和Blazar，以及Theralogics的科学家，他们是NF-κ B生物学方面的专家， ? B在Drs Baldwin和Ghosh以及两名外部药理学专家的针对性 William Zamboni博士的治疗和Richard Nash博士的GVHD狗模型。三 提出了研究TLX 1001治疗GVHD的具体目的 在供体脾细胞输注模型中， 非清髓性骨髓移植实验提出了评估 TLX 1001与钙调磷酸酶抑制剂他克莫司的组合。最后，研究 拟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 在查佩尔山的北卡罗来纳州大学进行的临床试验。骨髓或干细胞移植可以是一个挽救生命的程序为个人 某些类型的血癌。在大多数情况下， 骨髓或干细胞移植需要与捐赠者完全匹配， 可能的结果。这是由于供体白色细胞可以与受体发生反应， 在受体细胞上发现的蛋白质，引起称为移植物抗宿主的疾病 疾病（GVHD）。即使有最好的预防性治疗，GVHD也会发生在 大约50%的人接受骨髓或干细胞移植， 完全匹配的捐赠者，并可能导致多种并发症，包括死亡的 收件人。因此，需要预防或治疗GVHD的新形式的疗法来治疗GVHD。 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，可以阻止导致癌症的白色细胞。 GVHD和引起GVHD相关症状的蛋白质。实验 在动物模型中测试化合物的活性，如果成功， 这项工作的长期目标是将这种化合物用于人体临床试验， GVHD的治疗

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.