A small molecule integrin activator to enhance cord blood transplant

增强脐带血移植的小分子整合素激活剂

• 批准号: 9907800
• 负责人: Upendra Marathi
• 金额: $ 93.6万
• 依托单位: 7 HILLS PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907800
• 关键词: Adhesions; Adult; Antifungal Agents; Applications Grants; Biodistribution; Biological Assay; Biological Availability; Blood Cells; Blood specimen; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; CD34 gene; CYP3A4 gene; Canis familiaris; Cell Adhesion; Cell Adhesion Molecules; Cell Count; Cell Transplantation; Cells; Clinical; Clinical Research; Clinical Trials; Cyclic GMP; Development; Disadvantaged; Dose; Drug Interactions; Drug Kinetics; Engraftment; Enzymes; Extravasation; Family; Food; Formulation; Funding; Future; Genetic Diseases; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homing; Homologous Transplantation; Hospitalization; Incidence; Integrin alpha4beta1; Integrins; Investigational Drugs; Investigational New Drug Application; Ketoconazole; Lead; Leukocytes; Lipids; Liver; Mediating; Modeling; Multiple Myeloma; Mus; NOD/SCID mouse; Opportunistic Infections; Oral; PTPRC gene; Parents; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Preparation; Procedures; Process; Production; Rattus; Reagent; Regimen; Research Design; Risk; Running; Safety; Schedule; Selectins; Small Business Technology Transfer Research; Source; Stem cell transplant; Subgroup; Technology; Testing; Thyroid Function Tests; Thyroid Hormones; Thyroxine; Time; Toxic effect; Toxicology; Translating; Transplantation; Triiodothyronine; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; United States Food and Drug Administration; adhesion receptor; base; bone cell; capsule; carcinogenicity; chemokine; cost; design; genotoxicity; graft failure; graft vs host disease; human cord blood CD34+ cell; immune reconstitution; improved; improved functioning; improved outcome; infection risk; inhibitor/antagonist; leukemia/lymphoma; liver function; meetings; migration; mortality; new technology; peripheral blood; phase 1 study; pre-clinical; preconditioning; receptor; reconstitution; response; safety study; small molecule; stability testing; stem cells; trafficking; transplant model

PROJECT SUMMARY This proposal is in response to the parent announcement for Phase II STTR (R42) grant applications. Hematopoietic stem cell transplantation has become a preferred treatment for hematological malignancies and certain genetic disorders. Umbilical cord blood has become an appealing alternative to bone marrow or peripheral blood as a source of hematopoietic stem cells for transplant. Due to a less stringent HLA match requirement, cord blood transplant has allowed patients to be treated that otherwise could not find a suitable donor. Unfortunately, there are fewer stem cells in these preparations which results in delayed rates of immunological reconstitution. This can lead to a higher incidence of opportunistic infections which increases the rate of graft failures and transplant related mortalities. Finding a means to improve the rate of immune reconstitution with cord blood transplants would translate to improved outcomes as well as broader applicability to adult patients. Efforts to improve the rate of engraftment of cord blood cells include targeting the cell adhesion cascade which mediates cell homing, extravasation and retention in the bone marrow. This process is coordinated through the function of chemokines as well as the selectin and integrin families of cell adhesion molecules. Promising results have been generated by treating the cells ex-vivo to improve the function of the selectin- and chemokine-mediated processes. A drawback to these preconditioning steps is they require additional time, expertise and expense. As yet the integrins have not been targeted due to a lack of suitable reagents. We have developed a unique small molecule that can activate integrins on cord blood cells, facilitating their interaction with their counter-receptors in the bone marrow. This compound can enhance all phases of the adhesion cascade including cell rolling, firm adhesion, and migration. It can be dosed independently of the cells and is inexpensive to synthesize on a large-scale. This would have an advantage over other technologies as no preconditioning or manipulations of the cells would be required meaning a more affordable and universally translatable therapy. We have demonstrated proof-of-concept in our phase I studies that dosing 7HP349 following transplant of human CD34+ cord blood cells into NOD-SCID mice leads to increased engraftment of CD34+ cells in the bone marrow and increased CD45+ cell counts in peripheral blood. Our phase II proposal includes aims to refine the dosing schedule and preclinical formulation and toxicity studies required to file an Investigational New Drug application with the Food and Drug Administration.

项目概要 该提案是对第二阶段 STTR (R42) 拨款申请母公司公告的回应。 造血干细胞移植已成为血液系统恶性肿瘤的首选治疗方法 某些遗传疾病。脐带血已成为骨髓或骨髓的有吸引力的替代品 外周血作为移植用造血干细胞的来源。由于 HLA 匹配不太严格 要求，脐带血移植使无法找到合适的患者得到治疗 捐助者。不幸的是，这些制剂中的干细胞较少，导致细胞增殖速度延迟。 免疫学重建。这可能导致机会性感染的发生率更高，从而增加 移植失败率和移植相关死亡率。寻找提高免疫率的方法 脐带血移植重建将转化为改善的结果以及更广泛的适用性 给成年患者。提高脐带血细胞植入率的努力包括靶向细胞 介导细胞归巢、外渗和保留在骨髓中的粘附级联。这个过程 通过趋化因子以及细胞粘附的选择素和整合素家族的功能进行协调 分子。通过离体处理细胞以改善细胞的功能，已经产生了有希望的结果 选择素和趋化因子介导的过程。这些预处理步骤的一个缺点是它们需要 额外的时间、专业知识和费用。迄今为止，由于缺乏合适的整合素，整合素尚未被靶向。 试剂。我们开发了一种独特的小分子，可以激活脐带血细胞上的整合素， 促进它们与骨髓中的反受体相互作用。这种化合物可以增强所有 粘附级联阶段包括细胞滚动、牢固粘附和迁移。可以按剂量服用 独立于细胞，并且大规模合成成本低廉。这会有一个优势 优于其他技术，因为不需要对细胞进行预处理或操作，这意味着更多 负担得起且普遍可转化的疗法。我们在第一阶段研究中展示了概念验证 将人 CD34+ 脐带血细胞移植到 NOD-SCID 小鼠后给予 7HP349 会导致 骨髓中 CD34+ 细胞的植入增加，外周血中 CD45+ 细胞计数增加 血。我们的第二阶段提案包括完善给药方案和临床前配方的目标 向食品和药物管理局提交新药研究申请所需的毒性研究。