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

• 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
• 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

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(申请人提供)：这项建议的目标是开发一种新的混合双功能细胞因子(“fusokine”)，以促进免疫重建和抑制接受造血干细胞移植的癌症患者的移植物抗宿主病(GVHD)。Fusokine被称为Ha7，由IL-7组成，与来自肝细胞生长因子(HGF)α链的多肽相连。为了提高稳定性和延长体内半衰期，每个细胞因子都被融合到免疫球蛋白分子的Fc上，这些分子被修饰以促进哺乳动物细胞表达过程中异源二聚体的形成。根据IL-7的已知特性，预测Ha7通过刺激T和B淋巴细胞的生成以及维持成熟T细胞的动态平衡来促进免疫重建。在免疫抑制的癌症患者的异基因骨髓移植中，HGF部分将促进造血，同时抑制GVHD。IL-7和HGF联合治疗的另一个好处是保留了免疫抑制癌症患者的胸腺结构和功能。在这项计划中，将产生稳定分泌高水平重组HA7的细胞系，并将提纯Fusokine用于功能研究。它的活性将在体外进行研究，以刺激T细胞功能和HGF活性。HA7将成为 进一步在体内测试，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。HA7还将在同基因白血病小鼠的异基因骨髓移植模型中进行测试。在这个模型中，如果HA7在抑制GVHD的同时促进移植物抗白血病效应，那么它的治疗效果将被证明。这项临床前工作将为未来开发一种新的疗法来恢复免疫系统和预防接受干细胞移植的癌症患者的移植物抗宿主病奠定基础。 公共卫生相关性：该项目的目标是开发一种新的双功能杂交细胞因子，用于接受干细胞移植的癌症患者的免疫重建。