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（由申请人提供）：该提案的目的是开发一种新型的混合双功能细胞因子（“ fusokine”），以促进免疫重建，并抑制正在接受造血干细胞移植的癌症患者中的癌症患者的移植物抗宿主病（GVHD）。该fusokine称为HA7，由IL-7组成，该IL-7与源自肝细胞生长因子（HGF）α链的肽相关。为了提高稳定性并延伸体内半衰期，每个细胞因子融合了IgG分子的FC，这些IgG分子被修饰以促进哺乳动物细胞表达期间异二聚体的形成。基于IL-7的已知特性，HA7通过刺激T和B细胞淋巴细胞以及成熟T细胞的稳态维持来促进免疫重构。 HGF部分将增强造血，并在免疫抑制癌症患者的同种异体骨髓移植中抑制GVHD。通过IL-7和HGF联合治疗所预测的另一个好处是保留免疫抑制癌症患者的胸腺结构和功能。在此提案中，将产生稳定的细胞系，分泌高水平的重组HA7，并将熔融因子纯化用于功能研究。将在体外研究其活性，以刺激T细胞功能和HGF活性。 ha7会 进一步在体内进行了测试，以评估给定同性骨髓移植（BMT）的免疫抑制小鼠中的免疫结构。 HA7还将在同种异体BMT模型中进行测试，该模型还具有同性白血病的同种异体BMT。在此模型中，如果HA7抑制GVHD，则可以在促进移植物 - 抗脉络膜效应的同时抑制HA7的治疗功效。这项临床前工作将为未来开发一种新型疗法的发展奠定基础，以恢复免疫系统并防止接受干细胞移植的癌症患者的GVHD。 公共卫生相关性：该项目的目的是开发一种新型的双功能杂交细胞因子，用于对正在进行干细胞移植的癌症患者的免疫重建。