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: 10368757
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368757
• 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 Cells; Bone Marrow Transplantation; 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; Measures; Mediating; Metabolic; Methods; Modeling; Multiple Myeloma; NOD/SCID mouse; National Heart, Lung, and Blood Institute; Natural Killer Cells; Opportunistic Infections; Oral; 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; base; bone cell; cancer immunotherapy; capsule; cell killing; chemokine; clinical candidate; efficacy testing; graft failure; healthy volunteer; human cord blood CD34+ cell; immune reconstitution; improved; improved functioning; improved outcome; infection risk; innovation; lead optimization; lead series; leukemia/lymphoma; 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.

项目总结