Blockade of NF-kappaB for Prevention/Treatment of GVHD

描述（由申请人提供）：异基因干细胞移植（allo-SCT）是白血病、淋巴瘤和多发性骨髓瘤患者的潜在治愈性疗法。然而，与移植物抗宿主病（GVHD）相关的问题极大地限制了在许多移植中心将allo-SCT用于具有HLA相同家族成员或无关供体的患者。因此，开发可以预防或治疗GVHD的新疗法对于需要allo-SCT的患者来说将是一个重大进步。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）和钙调磷酸酶抑制剂的组合，或使用抗体（如Campath-1H）的体内T细胞耗竭方法。虽然这些方法可以诱导T细胞耐受，但它们不影响由条件治疗诱导的促炎细胞因子和趋化因子的产生，这些促炎细胞因子和趋化因子对GVHD的发展至关重要。由于大多数用于治疗或预防GVHD的新疗法都来自实体器官移植的研究，不涉及炎症诱导的预处理治疗，我们认为需要一种专门针对allo-SCT和预处理治疗并发症的新方法来开发新药物。NF-β B是由Pel蛋白组成的二聚体，并且在诱导T细胞耐受性和产生超过200种参与炎症的蛋白质中是关键的。我们的小组先前已经发现，靶向NF-β B的难溶性药物在动物模型中对GVHD的发生具有适度的影响，这受到化合物的生物利用度的极大限制。在这项提案中，我们与生物技术公司TheraLogics合作，评估该公司许可的两种药物在预防或治疗GVHD中的使用。NEMO结合肽（NBD肽）通过干扰IKK（与IKK（和IKK（）的相互作用来阻断NF-B的活化。TheraLogics的首席科学官Sankar Ghosh博士先前发现该肽可以阻断由NF-β B活化介导的小鼠模型中的破骨细胞生成。我们将评估的第二种化合物将是IKKp抑制剂化合物A，该化合物已获得拜耳TheraLogics的许可。这项提案汇集了两位在GVHD生物学方面非常有经验的研究人员，Serody博士和Blazar博士，以及TheraLogics的科学家，他们是NF-（B）生物学方面的专家，Baldwin博士和Ghosh博士。这种方法可以产生许多新的化合物，这些化合物对于预防或治疗GVHD更有效，更安全，这可以显着增加那些可以从这种疗法中受益的个体对allo-SCT的使用。如果这些I期研究成功，II期研究将为查佩尔山的北卡罗来纳州大学进行这种疗法的临床试验铺平道路。

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 drug, such as methotrexate, and a calcineurin 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 Pel 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 two agents licensed by the company in the prevention or treatment of GVHD. NEMO-binding peptides (NBD peptides) block the activation of NF-(B by interfering with the interaction of IKK( with IKK( and IKK(. The chief scientific officer of TheraLogics, Sankar Ghosh Ph.D. has previously found that this peptide can block osteoclastogenesis in murine models mediated by the activation of NF-(B. The second compound we will evaluate will be the IKKp inhibitor, Compound A, that has been licensed by TheraLogics from Bayer. 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. This approach may allow the generation of a number of new compounds that are both more effective and safer for the prevention or treatment of GVHD, which could significantly increase the use of allo-SCT for those individuals who could benefit from this therapy. If these phase I studies are successful, phase II studies will pave the way for clinical trials of this therapy at the University of North Carolina at Chapel Hill.