GENE THERAPY WITH MAB DRIVATIVES EXPRESSED ON TUMORS

使用在肿瘤上表达的 MAB 驱动程序进行基因治疗

• 批准号: 6093701
• 负责人: JEFFREY A LEDBETTER
• 金额: $ 33.75万
• 依托单位: PACIFIC NORTHWEST RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-03 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6093701
• 关键词: CD antigens; T cell receptor; T lymphocyte; animal tissue; antigen antibody reaction; antireceptor antibody; antitumor antibody; biological signal transduction; cytotoxic T lymphocyte; flow cytometry; gene expression; gene therapy; helper T lymphocyte; immunoglobulin genes; immunologic assay /test; leukocyte activation /transformation; monoclonal antibody; neoplasm /cancer genetics; neoplasm /cancer therapy; neoplastic cell; receptor expression; tissue /cell culture; transfection /expression vector; tumor antigens

DESCRIPTION: (Applicant's Abstract) Previous work in the applicant's laboratory has demonstrated that costimulation plays a key role in the induction of an immune response, including one to tumors. This costimulation can be provided by either transfecting a gene encoding a ligand, such as CD80 and/or CD86 into tumor cells, or by transfecting a gene encoding a single chain Fv (scFv) from the appropriate anti-receptor mAb. The scFv approach can have an advantage over the use of natural ligands. For example, CD80 and CD86 bind with high avidity to CTLA-4, which produces a strong negative signal, while the anti-CD28 scFv does not. In addition, scFvs can be used when natural ligands are unknown, such as for CD3-epsilon. In this application, variable region genes from hybridoma antibodies specific for human costimulatory receptors will be expressed as cell surface scFvs to modulate antigen-specific immune responses to tumor cells. Genes encoding scFvs that retain specificity and high binding affinity for CD3-epsilon, CD28, CD2, CD4, CD8, and CD154 have been constructed and expressed as soluble Ig-fusion proteins. Transmembrane domains have been added to some of the scFv gene constructs to direct their expression to the cell surface. These genes will be expressed on the surface of human tumor cell lines to determine their potential for amplification of T cell responses. The applicant hypothesizes that use of antibody derivatives can improve the specificity and potency of cancer gene therapy, and that cell surface expression of scFvs will enhance the immune response to specific antigens when compared with expression of native ligands for T cell surface receptors. He will determine whether expression of scFvs specific for T cell stimulatory and costimulatory molecules on the surface of tumor cells will increase T cell activation, including both CD4+ Th1 responses and CD8+ cytotoxic responses important for tumor rejection.

描述：（申请人摘要）申请人实验室的工作经历