Synthesis of Glycopeptide-Based Cancer Antigen Vaccines

描述(申请人提供)：肿瘤相关碳水化合物抗原(TACA)是在癌细胞上表现出高度限制性表达的糖和寡糖。由于TACAs是癌细胞所特有的，因此产生针对TACAs的主动免疫反应作为一种减少癌症转移或复发的手段引起了人们的极大兴趣。TACA也是评估癌症侵袭性的有用生物标志物。在主动免疫治疗中使用TACA的两个主要挑战是它们的抗原性差，以及通过化学手段合成寡糖和相关糖偶联物的固有困难。本申请旨在合成和研究TACA糖偶联物的抗原性。该提案的一个关键方面是研究与TACA无关的异种碳水化合物介导的疫苗抗原性增强。异种碳水化合物被认为是通过抗碳水化合物抗体介导的机制来增强抗原性。这一建议利用了受过有机化学和免疫学培训的PI之间的协作交互作用，因此所有疫苗的抗原性将在小鼠身上得到很好的表征。 公共卫生相关性：该项目将开发和评估疫苗在小鼠身上的细胞和体液免疫反应，这将作为人类抗癌疫苗的先导。将开发化学方法，以帮助产生用于癌症治疗的诊断和治疗试剂。

DESCRIPTION (provided by applicant): Tumor-associated carbohydrate antigens (TACAs) are saccharides and oligosaccharides which show highly restricted expression on cancer cells. Since TACAs are unique to cancer cells, there is a great interest in generating an active immune response against TACAs as a means of reducing cancer metastasis or recurrence. TACAs are also useful biomarkers for evaluating the aggressiveness of the cancer. Two major challenges to using TACAs in active immunotherapy are their poor antigenicity and the inherent difficulty of synthesizing oligosaccharides and related glycoconjugates by chemical means. This application proposes to synthesize and study the antigenicity of TACA glycoconjugates. A key aspect of the proposal is the study of increased vaccine antigenicity mediated by xenobiotic carbohydrates unrelated to the TACAs. The xenobiotic carbohydrates are proposed to enhance antigenicity through anti- carbohydrate antibody-mediated mechanisms. This proposal takes advantage of a collaborative interaction between PIs trained in organic chemistry and immunology so that the antigenicity of all vaccines will be well characterized in mice. PUBLIC HEALTH RELEVANCE: This project will develop and evaluate the cellular and humor immune response of vaccines in mice that will serve as leads for human anti-cancer vaccines. Chemical approaches will be developed that will aid in generating diagnostic and therapeutic agents for the treatment of cancer.