Blockade of NF-kappaB for Prevention/Treatment of GVHD

阻断 NF-κB 用于预防/治疗 GVHD

• 批准号: 7108055
• 负责人: Patrick Michael Flood
• 金额: $ 24.45万
• 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 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7108055
• 关键词: conditioning; cytokine; glucocorticoids; inflammation; nuclear factor kappa beta; peptides; prevention; proteins; university

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.

描述（由申请人提供）：同种异体干细胞移植（Allogeneic stem cell transplantation, allo-SCT）是治疗白血病、淋巴瘤和多发性骨髓瘤的潜在疗法。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对具有相同hla的家庭成员或非亲属供体的患者使用同种异体sct。因此，能够预防或治疗GVHD的新疗法的开发对于需要同种异体细胞移植的患者来说将是一个重大的进步。目前，预防GVHD最常见的方法要么是s期活性化疗药物（如甲氨蝶呤）与钙调磷酸酶抑制剂联合使用，要么是使用抗体（如Campath -1H）消耗T细胞的体内方法。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，而促炎细胞因子和趋化因子是由调节疗法诱导的，对GVHD的发展至关重要。由于大多数治疗或预防GVHD的新疗法都来自实体器官移植的研究，而这些研究不涉及炎症诱导调节治疗，我们认为需要开发一种新的方法，专门针对同种异体细胞移植和调节治疗的并发症。NF-(B)是一种由Pel蛋白组成的调光剂，在诱导T细胞耐受和产生200多种与炎症有关的蛋白质中起关键作用。我们的研究小组先前发现，在动物模型中，针对NF-(B)的难溶性药物对GVHD的发生有一定的影响，这在很大程度上受到该化合物的生物利用度的限制。在该提案中，我们已经启动了与生物技术公司TheraLogics的合作，以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，这种肽可以阻断由NF-(B)激活介导的小鼠模型中的破骨细胞生成。我们将评估的第二个化合物是IKKp抑制剂，化合物A，已由拜耳TheraLogics许可。该提案将两位在GVHD生物学方面经验丰富的研究人员serdy博士和Blazar博士与TheraLogics的NF- B生物学专家Baldwin博士和Ghosh博士聚集在一起。这种方法可能会产生许多新的化合物，这些化合物在预防或治疗GVHD方面更有效、更安全，这可能会显著增加那些可能从这种治疗中受益的人使用同种异体细胞移植。如果这些I期研究成功，II期研究将为该疗法在北卡罗来纳大学教堂山分校的临床试验铺平道路。