Preparation of Polyvalent Anticancer Vaccines for T-cell activation

用于T细胞激活的多价抗癌疫苗的制备

• 批准号: 7612646
• 负责人: Pavel Nagorny
• 金额: $ 4.68万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-20 至 2010-08-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612646
• 关键词: Affinity; American; Antibodies; Antigen-Presenting Cells; B-Lymphocytes; Binding; Biological; Carbohydrates; Development; Epitopes; Evaluation; Failure; Generations; Glycosides; Goals; Human; Immune response; Immune system; Immunoglobulin G; Immunologist; Laboratories; Life; Lymphocyte; Lymphocyte Activation; Lysosomes; Malignant Neoplasms; Metabolic; Metabolism; Modification; Neoplasm Metastasis; Peptide Fragments; Peptides; Polyvalent Vaccine; Preparation; Production; Property; Public Health; Research; Research Proposals; Scheme; Site; Structure; T-Cell Activation; T-Lymphocyte; Vaccines; Vertebral column; Work; base; cancer cell; chemical synthesis; chemotherapy; fighting; immunogenic; immunogenicity; improved; prevent; response; tool; tumor

DESCRIPTION (provided by applicant): The discovery of a potent carbohydrate-based anticancer vaccine has been a long-standing goal for tumor immunologists. Its use harnesses the power of the human immune system to fight cancer. Such an approach is complementary to chemotherapy, and is especially promising for the treatment of cancer metastasis. By conducting the proposed research, we plan to develop a modified carbohydrate-based vaccine that will be able to induce a long-lasting immune system response to different types of cancer cells. We propose to achieve the superior immunogenic properties by modification of the currently available polyvalent anticancer vaccine that has been synthesized in Danishefsky's laboratories. The currently available polyvalent vaccine is only capable of B-lymphocyte activation. This activation results in a short- term immunogenic response; in order to induce a long-lasting immune response against the cancer cells, the activation of T-cell lymphocytes should be targeted. One of the reasons for the current vaccine's failure to interact with T-lymphocytes is its instability to cellular metabolism. We propose to increase the stability by modifying the glycosidic linkages holding carbohydrate units and attaching the carbohydrate epitopes to the vaccine backbone. It is known that the corresponding S-glycosides are more stable to enzymatic degradation as well as to the acidic medium inside lysosomes. Furthermore, S-glycosides have similar to O-glycosides conformational properties such that the immunogenicity of the vaccine is not significantly influenced by these modifications. We also propose to increase the affinity of the vaccine by incorporating a YAF peptide fragment to the vaccine backbone. Recently, it has been shown that the YAF peptide promotes delivery of carbohydrate epitope to a T-cell by binding to a MHC-II site. Thus, the objective of this proposal is to introduce S-glycosidic linkages and the YAF peptide into the currently existing polyvalent anticancer vacccine and to develop a consise chemical synthesis of the modified vaccine in order to deliver material for biological evaluation. We believe that the proposed work is very important for public health because every year cancer takes the lives of more than five hundred thousands Americans. The development of a potent anticancer vaccine would provide a new valuable tool to fight and prevent cancer using the power of human immune system.

描述（由申请人提供）：发现一种有效的基于碳水化合物的抗癌疫苗一直是肿瘤免疫学家的长期目标。它的使用利用人体免疫系统的力量来对抗癌症。这种方法是化疗的补充，对于治疗癌症转移特别有希望。通过进行拟议的研究，我们计划开发一种改良的基于碳水化合物的疫苗，该疫苗将能够诱导针对不同类型癌细胞的持久免疫系统反应。我们建议通过修改目前可用的多价抗癌疫苗（该疫苗已在达尼塞夫斯基实验室合成）来实现卓越的免疫原性。目前可用的多价疫苗只能激活B淋巴细胞。这种激活会导致短期免疫原性反应；为了诱导针对癌细胞的持久免疫反应，应针对T细胞淋巴细胞的激活。目前的疫苗无法与T淋巴细胞相互作用的原因之一是其对细胞代谢的不稳定性。我们建议通过修改持有碳水化合物单元的糖苷键并将碳水化合物表位连接到疫苗主链来提高稳定性。众所周知，相应的 S-糖苷对酶促降解以及溶酶体内的酸性介质更稳定。此外，S-糖苷具有与O-糖苷相似的构象特性，使得疫苗的免疫原性不会受到这些修饰的显着影响。我们还建议通过将 YAF 肽片段整合到疫苗骨架中来增加疫苗的亲和力。最近，研究表明，YAF 肽通过与 MHC-II 位点结合，促进碳水化合物表位向 T 细胞的递送。因此，本提案的目的是将S-糖苷键和YAF肽引入现有的多价抗癌疫苗中，并开发改良疫苗的简洁化学合成方法，以便为生物学评价提供材料。我们相信，拟议的工作对公共健康非常重要，因为癌症每年夺走超过五十万美国人的生命。有效抗癌疫苗的开发将为利用人体免疫系统的力量对抗和预防癌症提供新的有价值的工具。