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（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进行同种异体细胞移植的患者来说将是一个重大的进步。