A Novel Hybrid Multifunctional Cytokine for Immune Reconstitution

用于免疫重建的新型混合多功能细胞因子

基本信息

批准号：
8251936
负责人：
SUSAN C WRIGHT
金额：
$ 22.79万
依托单位：
PANORAMA RESEARCH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8251936
关键词：
Aging Allogeneic Bone Marrow Transplantation Allogenic Animals Architecture Autologous B-Lymphocytes Biological Assay Biological Preservation Bone Marrow Transplantation Cancer Burden Cancer Patient Cell physiology Characteristics Clinical Combined Modality Therapy Competence Cytotoxic agent Development Foundations Future Genetic Goals Graft-Versus-Tumor Induction HIV Half-Life Hematopoiesis Hematopoietic Stem Cell Transplantation Hepatocyte Growth Factor Hybrids Immune Immune system Immunoglobulin G Immunologic Deficiency Syndromes Immunosuppression In Vitro Infection Interleukin-7 Link Lymphopoiesis Maintenance Mammalian Cell Mature T-Lymphocyte Modeling Morbidity - disease rate Mus Patients Peptides Phase Production Property Radiation Recombinants Regimen Stem cell transplant Syngeneic Bone Marrow Transplantation T-Lymphocyte Testing Therapeutic Therapeutic immunosuppression Thymic epithelial cell Thymus Gland TimeLine Transplantation Transplantation Conditioning Treatment Efficacy Ursidae Family Work base cytokine graft vs host disease immune function immunosuppressed improved in vitro activity in vivo irradiation leukemia mortality mouse model novel phase 2 study pre-clinical prevent reconstitution stable cell line tumor

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to develop a novel hybrid bifunctional cytokine ("fusokine") to promote immune reconstitution and inhibit graft-versus-host disease (GVHD) in cancer patients undergoing hematopoietic stem cell transplantation. The fusokine, termed Ha7, consists of IL-7 linked to a peptide derived from the alpha chain of hepatocyte growth factor (HGF). To improve stability and extend in vivo half-life each cytokine is fused to the Fc of IgG molecules that were modified to promote the formation of heterodimers during mammalian cell expression. Based on the known properties of IL-7, Ha7 is predicted promote immune reconstitution by stimulating T and B cell lymphopoiesis as well as homeostatic maintenance of mature T cells. The HGF moiety will enhance hematopoiesis, as well as inhibit GVHD in the setting of allogeneic bone marrow transplantation in immunosuppressed cancer patients. Another benefit predicted from the combined treatment with both IL-7 and HGF is the preservation of thymic architecture and function in immunosuppressed cancer patients. In this proposal, stable cell lines secreting high levels of recombinant Ha7 will be produced and the fusokine will be purified for functional studies. Its activity will be studied in vitro for stimulation of T cell functions and HGF activity. Ha7 will be further tested in vivo to evaluate immune reconstitution in immunosuppressed mice given syngeneic bone marrow transplantations (BMT). Ha7 will also be tested in a model of allogeneic BMT in mice that also bear a syngeneic leukemia. In this model, therapeutic efficacy of Ha7 will be demonstrated if it suppresses GVHD while promoting the graft-versus-leukemia effect. This preclinical work will provide the foundation for future development of a novel therapy to restore the immune system and prevent GVHD in cancer patients undergoing stem cell transplantation. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop a novel bifunctional hybrid cytokine for immune reconstitution of cancer patients undergoing stem cell transplantation.

描述（由申请人提供）：本提案的目标是开发一种新型混合双功能细胞因子（“fusokine”），以促进接受造血干细胞移植的癌症患者的免疫重建并抑制移植物抗宿主病（GVHD）。 Fusokine 称为 Ha7，由与肝细胞生长因子 (HGF) α 链衍生的肽连接的 IL-7 组成。为了提高稳定性并延长体内半衰期，每种细胞因子都与 IgG 分子的 Fc 融合，这些分子经过修饰以促进哺乳动物细胞表达过程中异二聚体的形成。根据 IL-7 的已知特性，Ha7 预计可通过刺激 T 和 B 细胞淋巴细胞生成以及成熟 T 细胞的稳态维持来促进免疫重建。 HGF 部分将增强造血功能，并在免疫抑制癌症患者的同种异体骨髓移植中抑制 GVHD。 IL-7 和 HGF 联合治疗预计的另一个好处是免疫抑制癌症患者胸腺结构和功能的保存。在该提案中，将产生分泌高水平重组Ha7的稳定细胞系，并纯化fusokine用于功能研究。将在体外研究其活性，以刺激 T 细胞功能和 HGF 活性。哈7将是进一步进行体内测试，以评估接受同基因骨髓移植（BMT）的免疫抑制小鼠的免疫重建情况。 Ha7 还将在同样患有同基因白血病的小鼠的同种异体 BMT 模型中进行测试。在该模型中，如果 Ha7 抑制 GVHD 同时促进移植物抗白血病效应，则将证明其治疗功效。这项临床前工作将为未来开发一种新疗法奠定基础，以恢复接受干细胞移植的癌症患者的免疫系统并预防 GVHD。公共健康相关性：该项目的目标是开发一种新型双功能混合细胞因子，用于接受干细胞移植的癌症患者的免疫重建。