A fully synthetic carbohydrate-based cancer vaccine

肿瘤的进展与肿瘤上异常碳水化合物的出现密切相关。 细胞表面。大量的临床前和临床研究自然证明了这一点。 获得、被动注射或主动诱导的针对这些碳水化合物相关抗体的抗体 肿瘤抗原能够消灭肿瘤细胞。以碳水化合物为基础的癌症疫苗开发， 然而，由于大多数患者难以产生高滴度的免疫球蛋白抗体，这一问题变得更加复杂。这个 成功开发基于碳水化合物的癌症疫苗需要一种新的策略来获得更多 有效地将肿瘤相关碳水化合物表位呈现给免疫系统，导致更多 高效的职业转换为免疫球蛋白抗体。 我们已经证明了由一种与肿瘤相关的全合成疫苗候选 糖类抗原、杂合肽T辅助表位和脂肽佐剂S-[(R)-2，3- Dipalmitoyloxy-propyl]-N-palmitoyl-(R)-cysteine(Pam3Cys)能成功地诱导高滴度的免疫球蛋白 抗体。该应用程序的目标是详细地研究三个- 组份癌症--可激发强烈相关的抗肿瘤免疫反应的疫苗。此外， TLR配体(佐剂)在极化免疫反应中的作用将被研究。因此，三个- 将合成在B表位和T表位、TLR配体和拓扑结构上不同的成分癌症疫苗 合成化合物的抗原性及其抗血清对肿瘤的识别和中和能力 牢房将被确定。最后，合成疫苗候选者诱导一系列细胞因子的能力 与适应性免疫反应相关的课程将会被研究。 在我们的研究完成后，我们将能够将 糖脂肽与先天和获得性免疫反应以及抗血清识别和 消灭癌细胞。这些相关性将为小鼠肿瘤挑战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.