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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该提案是为了响应 Catalyze 产品的融资机会公告 RFA-HL-20-027 小分子和生物制剂的定义 - 初步产品/先导系列鉴定（R33 - 临床试验不允许）授予机制。造血干细胞移植已成为首选治疗方法用于血液系统恶性肿瘤和某些遗传性疾病。脐带血已成为一种有吸引力的替代骨髓或外周血作为移植用造血干细胞的来源。由于一个不太严格的 HLA 匹配要求，脐带血移植允许患者接受其他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，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。寻找提高率的方法通过脐带血移植进行免疫重建将转化为改善的结果以及更广泛的对成年患者的适用性。提高脐带血细胞植入率的努力包括针对介导细胞归巢、外渗和保留在骨髓中的细胞粘附级联。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。我们开发了一系列小分子，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。我们已经证明了- 使用家庭代表成员的概念，在人类移植后服用这种化合物将 CD34+ 脐带血细胞注入 NOD-SCID 小鼠会导致骨髓中 CD34+ 细胞的植入增加外周血中 CD45+ 细胞计数增加。这些化合物的给药剂量可以独立于细胞并且大规模合成通常成本低廉。这比其他的有优势技术，因为不需要对细胞进行预处理或操作，这意味着更实惠和普遍可转化的疗法。尽管前景光明，但我们的先导化合物口服生物利用度较低部分原因是它被 CYP3A4 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间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 CYP3A4 的结构警报产生下一代化合物的活性，可降低代谢负担并改善口服药代动力学。如果成功，这应该会导致确定临床候选者以进入研究性新药 (IND) 支持研究。