A fully synthetic carbohydrate-based cancer vaccine

描述（由申请人提供）：肿瘤进展与细胞表面上异常碳水化合物的出现密切相关。广泛和不断扩大的临床前和临床研究表明，天然获得的、被动给予的或主动诱导的针对这些碳水化合物相关肿瘤抗原的抗体能够消除肿瘤细胞。然而，基于碳水化合物的癌症疫苗开发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。基于碳水化合物的癌症疫苗的成功开发需要一种新的策略，用于将肿瘤相关的碳水化合物表位更有效地呈递给免疫系统，从而导致更有效地向IgG抗体的类别转换。我们已经表明，由肿瘤相关碳水化合物抗原、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（Pam 3Cys）组成的全合成疫苗候选物可以成功地引发高滴度的IgG抗体。本申请的目的是详细研究3组分癌症疫苗的最佳结构，以引发强烈且相关的抗肿瘤免疫反应。此外，将研究TLR配体（佐剂）抑制免疫应答的作用。因此，将合成在B-和T-表位、TLR配体和拓扑结构上不同的3组分癌症疫苗。将测定合成化合物的抗原性和抗血清识别和中和癌细胞的能力。最后，将检查合成疫苗候选物诱导与适应性免疫应答相关的一系列细胞因子的能力。在我们的研究完成后，我们将能够使糖脂肽的结构和先天性和适应性免疫反应以及抗血清识别和消除癌细胞的能力之间的相关性。这些相关性将为小鼠肿瘤攻击研究或I期临床试验提供坚实的科学基础。

DESCRIPTION (provided by applicant): 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 development has, 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 3-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, 3-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.