Optimization of small molecule integrin activators to enhance cord blood transplant

优化小分子整合素激活剂以增强脐带血移植

• 批准号: 10573229
• 负责人: Ronald J Biediger
• 金额: $ 54.7万
• 依托单位: TEXAS HEART INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573229
• 关键词: Address; Adhesions; Adult; Animal Model; Antigen Presentation; Applications Grants; Award; Biological Assay; Biological Availability; Biological Products; Blood Cells; Bone Marrow; Bone Marrow Cell Transplantation; Bone Marrow Cells; C57BL/6 Mouse; CD34 gene; CYP1A2 gene; CYP2C19 gene; CYP2C9 gene; CYP2D6 gene; CYP3A4 gene; CYP3A5 gene; Cell Adhesion; Cell Adhesion Molecules; Cell Count; Cell Transplantation; Cells; Characteristics; Clinical Trials; Data; Disadvantaged; Dose; Drug Interactions; Drug Kinetics; Engraftment; Ensure; Extravasation; Family; Family member; Formulation; Funding; Funding Mechanisms; Funding Opportunities; Future; Genetic Diseases; Goals; Grant; Hematologic Neoplasms; Hematology; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homing; Hospitalization; Human; Hydrolase; Immunotherapy; Incidence; Integrin alpha4beta1; Integrins; Investigational Drugs; Isoenzymes; Lead; Leukocytes; Lymphoma; Measures; Mediating; Metabolic; Methods; Modeling; Multiple Myeloma; NOD/SCID mouse; National Heart, Lung, and Blood Institute; Natural Killer Cells; Opportunistic Infections; Oral; Oral Administration; PTPRC gene; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Plasma; Positioning Attribute; Predisposition; Preparation; Process; Reagent; Regimen; Sampling; Selectins; Series; Small Business Technology Transfer Research; Source; Technology; Time; Translating; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Vaccination; Vaccine Clinical Trial; Vascular Cell Adhesion Molecule-1; adhesion receptor; analog; cancer immunotherapy; capsule; cell killing; chemokine; clinical candidate; efficacy testing; functional improvement; graft failure; healthy volunteer; human cord blood CD34+ cell; immune reconstitution; improved; improved outcome; infection risk; innovation; lead optimization; lead series; leukemia; liquid chromatography mass spectrometry; meetings; mindfulness; mortality; mouse model; new technology; next generation; novel; peripheral blood; pre-clinical; preconditioning; procedure cost; programs; receptor; reconstitution; response; small molecule; stem cell engraftment; stem cells; trafficking; transplant model; vaccine immunotherapy

PROJECT SUMMARY This proposal is in response to the funding opportunity announcement RFA-HL-20-027 for the Catalyze: Product Definition for Small Molecules and Biologics - Preliminary Product/Lead Series Identification (R33 - Clinical Trial Not Allowed) granting mechanism. 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 family of small molecules that can activate integrins on cord blood cells, facilitating their interaction with their counter-receptors in the bone marrow. We have demonstrated proof-of- concept using a representative member of the family that dosing such a compound 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. These compounds can be dosed independently of the cells and are typically 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. Although promising, our lead compound suffers from low oral bioavailability in part due to it being metabolized by CYP3A4. These issues make it less attractive for cord blood transplant due to potential drug-drug interactions as well as the multi-day dosing regimen that will likely be required based on preclinical animal models. This R33 grant proposal includes aims to address the structural alerts for CYP3A4 activity to generate a next generation compound with decreased metabolic liabilities and improved oral pharmacokinetics. If successful, this should result in identifying a clinical candidate to progress into Investigational New Drug (IND)-enabling studies.

项目摘要 本提案是对催化剂的资助机会公告RFA-HL-20-027的回应：产品 小分子和生物制剂的定义-初步产品/电极导线系列识别（R33 -临床试验 不允许）授予机制。造血干细胞移植已成为首选的治疗方法 治疗血液恶性肿瘤和某些遗传疾病脐带血已成为一种吸引人的 骨髓或外周血作为移植用造血干细胞来源的替代品。由于 不太严格的HLA匹配要求，脐带血移植允许患者接受治疗， 找不到合适的捐赠者。不幸的是，这些制剂中的干细胞较少，这导致 免疫重建速度延迟。这可能导致机会性感染的发生率更高 这增加了移植失败率和移植相关死亡率。找到一种方法来提高利率 脐带血移植的免疫重建将转化为改善的结果以及更广泛的 适用于成年患者。提高脐带血细胞植入率的努力包括针对 细胞粘附级联，其介导骨髓中的细胞归巢、外渗和滞留。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来协调 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。这些预处理步骤的缺点是它们需要 额外的时间、专业知识和费用。到目前为止，由于缺乏合适的免疫调节剂，整联蛋白尚未被靶向。 试剂我们已经开发了一个小分子家族，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的相互作用。我们已经证明了- 使用该家族的代表性成员的概念是，在移植人 CD 34+脐带血细胞进入NOD-SCID小鼠导致骨髓中CD 34+细胞的植入增加 外周血中CD 45+细胞计数增加。这些化合物可以独立于细胞给药 并且大规模合成通常不昂贵。这将比其他 技术，因为不需要对细胞进行预处理或操作，这意味着更经济实惠的 和普遍可翻译的疗法。虽然前景看好，但我们的先导化合物口服生物利用度低 部分原因是它被CYP 3A 4代谢。这些问题使得脐带血移植的吸引力降低 由于潜在的药物相互作用以及可能需要的多日给药方案， 在临床前动物模型上。该R33拨款提案旨在解决CYP 3A 4的结构警报 产生具有降低的代谢负债和改善的口服给药的下一代化合物的活性 药代动力学如果成功，这将导致确定临床候选人，以进入 研究性新药（IND）-使能研究。