A fully synthetic carbohydrate-based cancer vaccine

肿瘤进展与肿瘤细胞表面异常碳水化合物的出现密切相关。 细胞的表面。广泛和不断扩大的临床前和临床研究表明， 针对这些碳水化合物相关的获得性、被动施用或主动诱导的抗体 肿瘤抗原能够消除肿瘤细胞。碳水化合物为基础的癌症疫苗的发展， 然而，由于在大多数患者中难以引发高滴度的IgG抗体而变得复杂。的 成功开发基于碳水化合物的癌症疫苗需要一种新的策略， 肿瘤相关碳水化合物表位向免疫系统的有效呈递， 有效的类别转换为IgG抗体。 我们已经证明，由肿瘤相关的 碳水化合物抗原、混杂肽T辅助表位和脂肽佐剂S-[（R）-2，3- 二棕榈酰氧基丙基]-N-棕榈酰-（R）-半胱氨酸（Pam3Cys）可成功地诱导高滴度的IgG 抗体的本申请的目的是详细研究三层结构的最佳结构， 用于引发强的和相关的抗肿瘤免疫应答的组分癌症疫苗。而且 将研究TLR配体（佐剂）抑制免疫应答的作用。因此，三- 将合成在B和T表位、TLR配体和拓扑结构方面不同的癌症疫苗成分 合成化合物的抗原性和抗血清识别和中和癌症的能力 细胞将被确定。最后，合成疫苗候选物诱导一系列细胞因子的能力 与适应性免疫应答相关的研究。 在我们的研究完成后，我们将能够使建筑之间的相互关系， 糖脂肽与先天性和适应性免疫应答以及抗血清识别和 消灭癌细胞这些相关性将为小鼠肿瘤攻击提供坚实的科学基础 研究或I期临床试验。

Tumor progression is intimately associated with the appearance of unusual carbohydrates on the surface of cells. A broad and expanding body of preclinical and clinical studies demonstrates that naturally acquired, passively administered or actively induced antibodies against these carbohydrate-associated tumor antigens are able to eliminate tumor cells. Carbohydrate-based cancer vaccine developmenthas, however, been complicated by the difficulty of eliciting high titers of IgG antibodies in most patients. The successful development of a carbohydrate-based cancer vaccine requires a novel strategy for a more efficient presentation of tumor associated carbohydrate epitopes to the immune system resulting in a more efficient class switch to IgG antibodies. We have shown that a full-synthetic vaccine candidate composed of a tumor-associated carbohydrate-antigen, a promiscuous peptide T-helper epitope and the lipopeptide adjuvant S-[(R)-2,3- dipalmitoyloxy-propyl]-N-palmitoyl-(R)-cysteine (Pam3Cys) can successfully elicit high titers of IgG antibodies. The objective of this application is to investigate in detail the optimum architecture of a three- component cancer-vaccine for eliciting a strong and relevant anti-tumor immune response. Furthermore, the role of the TLR ligand (adjuvant) to polarize the immune response will be investigated. Thus, three- component cancer vaccines will be synthesized that differ in B- and T-epitopes, TLR ligands and topology The antigenicity of the synthetic compounds and ability of the antisera to recognize and neutralize cancer cells will be determined. Finally, the ability of the synthetic vaccine candidates to induce a range of cytokines relevant to adaptive immune response will be examined. At the completion of our studies, we will be able to make correlations between the architecture of the glycolipopeptides and innate and adaptive immune responses and the ability of antisera to recognize and eliminate cancer cells. These correlations will provide a firm scientific foundation for murine tumor-challenge studies or a phase I clinical trial.