Metabolic Engineering of Cancer for Immunotargeting

用于免疫靶向的癌症代谢工程

• 批准号: 6622918
• 负责人: Zhongwu Guo
• 金额: $ 21.8万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6622918
• 关键词: amines; antitumor antibody; chemical conjugate; chemical synthesis; laboratory mouse; mannose; melanoma; monoclonal antibody; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; nonhuman therapy evaluation; sialate; synthetic vaccines; tetanus toxoid; tumor antigens; vaccine development

DESCRIPTION: (provided by applicant) Oncogenic transformations are closely correlated with the change of glycosylation patterns of cell surfaces, and the aberrant carbohydrates expressed on tumors, which are called tumor-associated carbohydrate antigens (TACAs), are important targets for the development of cancer vaccines that can be used for cancer diagnosis and therapy. However, the problem of immunotolerance to TACAs has severely hindered further progress in the area. To solve this problem and to develop new, effective cancer vaccines, this project will exploit a new strategy that is based on modified TACAs and metabolic engineering of cancers. First, a TACA on cancer cells will be metabolically modified by treating them with an artificial derivative of a monosaccharide that can be taken as a precursor by cancer cells to biosynthesize a neoantigen - an artificially modified analog of the TACA. The metabolic engineering of cancer takes the advantage of the remarkable flexibility of carbohydrate biosynthetic machineries. Then, specific monoclonal antibodies (mAbs) will be used to selectively target tumor cells labeled by the neoantigen. The mAbs in return can be prepared with a synthetic vaccine made of the neoantigen. As vaccines made of artificial carbohydrates are potentially more immunogenic than those made of the natural TACAs and the metabolic engineering can specifically mark cancer cells, effective vaccines may be easily composed from modified TACAs and the new strategy will potentially solve the problem of immunotolerance to TACAs. The metabolic modifying targets of this project are sialyl TACAs. Melanoma is employed as the tumor model, and GD3 and GM3 on its cells are the specific targets. The N-modified analogs of mannosamine and sialic acid will be used as the precursors, and the neoantigens expressed on melanoma will then be the N-modified derivatives of GD3 and GM3. The aims of this project are: 1)to find the effective precursors for metabolic engineering of melanoma via studying the bioavailability of various precursors to the enzymes involved in the biosynthesis of sialyl TACAs and to melanoma cells; 2) to find the effective vaccines that can provoke specific immune responses to the neoantigens via studying the conjugates of various N-modified GD3 and GM3; 3) to illustrate the new strategy through specific immunotargeting of metabolically engineered melanoma. This research will eventually establish a proper combination of the precursor and vaccine. As the overexpression of sialic acid is found in various tumors and sialic acid is a shared feature of many TACAs, the principles established herein may be of wide applicability.

描述：（由申请人提供）致癌转化是紧密的 与细胞表面的糖基化模式的变化相关， 在肿瘤上表达的异常碳水化合物，称为肿瘤相关 碳水化合物抗原（TACA）是发展的重要目标 可用于癌症诊断和治疗的癌症疫苗。但是， 对塔卡斯的免疫耐受性问题严重阻碍了进一步的进展 该区域。 为了解决这个问题并开发新的有效的癌症疫苗， 项目将利用基于修改的塔卡斯的新策略和 癌症的代谢工程。首先，癌细胞上的TACA将是 通过用A的人工导数对其进行代谢修饰 单糖可以作为癌细胞作为先驱 生物合成新抗原 - 一种人为修改的TACA类似物。这 癌症的代谢工程具有非凡的优势 碳水化合物生物合成机器的灵活性。然后，特定的单克隆 抗体（mAb）将用于选择性地靶向由 新抗原。可以用由由由 新抗原。由于人造碳水化合物制成的疫苗可能是 比天然塔卡斯和代谢更具免疫原性 工程可以专门标记癌细胞，有效的疫苗可能是 轻松由改良的塔卡斯（Tacas）组成，新策略将有可能解决 对塔卡斯的免疫耐受性的问题。代谢修饰目标 这个项目是Siallyl Tacas。 黑色素瘤被用作肿瘤模型，其细胞上的GD3和GM3是 特定目标。甘露糖胺和唾液酸的N修饰类似物将是 用作前体，在黑色素瘤上表达的新抗原将是 GD3和GM3的N修饰衍生物。该项目的目的是：1） 找到黑色素瘤代谢工程的有效前体 研究各种前体的生物利用度 siallyl塔卡斯和黑色素瘤细胞的生物合成； 2）找到 有效的疫苗可以引起对疫苗的特定免疫反应 通过研究各种N修饰GD3和GM3的偶联物，新抗原； 3） 通过特定的免疫目标来说明新策略 代谢设计的黑色素瘤。这项研究最终将建立一个 前体和疫苗的正确组合。作为过表达 在各种肿瘤中发现唾液酸，唾液酸是 许多塔卡斯（Tacas），本文建立的原则可能具有广泛的适用性。