Robust immune responses elicited by a fully synthetic three-component vaccine
Robust immune responses elicited by a fully synthetic three-component vaccine
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DOI：
10.1038/nchembio.2007.25
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发表时间：
2007-10-01
影响因子：
14.8
通讯作者：
Boons, Geert-Jan
中科院分区：
文献类型：
--
作者：
Ingale, Sampat;AWolfert, Margreet;Boons, Geert-Jan
Globo-H、Lewis(Y) 和 Tn 抗原等糖类的过度表达是致癌转化细胞的共同特征。利用这种异常糖基化来开发癌症疫苗的努力因难以引发针对肿瘤相关碳水化合物与载体蛋白的经典缀合物的高滴度 IgG 抗体而变得复杂。我们设计、化学合成和免疫学评估了许多完全合成的候选疫苗，以制定克服肿瘤相关碳水化合物和糖肽免疫原性差的策略。我们发现，由 TLR2 激动剂、混杂肽 T 辅助表位和肿瘤相关糖肽组成的三组分疫苗可以在小鼠体内引发异常高滴度的 IgG 抗体，该抗体可以识别表达肿瘤相关碳水化合物的癌细胞。该候选疫苗的优异特性归因于细胞因子的局部产生、共刺激蛋白的上调、巨噬细胞和树突状细胞的摄取增强以及避免表位抑制。
The overexpression of saccharides such as Globo- H, Lewis(Y) and Tn antigen is a common feature of oncogenic transformed cells. Endeavors to exploit this aberrant glycosylation for cancer vaccine development have been complicated by difficulties in eliciting high titers of IgG antibodies against classical conjugates of tumor- associated carbohydrates to carrier proteins. We have designed, chemically synthesized and immunologically evaluated a number of fully synthetic vaccine candidates to establish strategies to overcome the poor immunogenicity of tumor- associated carbohydrates and glycopeptides. We have found that a three- component vaccine composed of a TLR2 agonist, a promiscuous peptide T- helper epitope and a tumor- associated glycopeptide can elicit in mice exceptionally high titers of IgG antibodies that can recognize cancer cells expressing the tumor- associated carbohydrate. The superior properties of the vaccine candidate are attributed to the local production of cytokines, upregulation of costimulatory proteins, enhanced uptake by macrophages and dendritic cells and avoidance of epitope suppression.