Chemoselective assembly and immunological evaluation of multiepitopic glycoconjugates bearing clustered Tn antigen as synthetic anticancer vaccines
Chemoselective assembly and immunological evaluation of multiepitopic glycoconjugates bearing clustered Tn antigen as synthetic anticancer vaccines
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DOI：
10.1021/bc050010v
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发表时间：
2005-09-01
影响因子：
4.7
通讯作者：
Dumy, P
中科院分区：
文献类型：
--
作者：
Grigalevicius, S;Chierici, S;Dumy, P
在本文中，我们研究了使用区域选择性可寻址功能化模板（RAFT）作为设计抗癌候选疫苗的新支架。我们报道了定义明确的多表位RAFT支架的合成及其免疫学评价。这些偶联物显示成簇的Tn类似物作为肿瘤相关碳水化合物抗原（TACA，B细胞表位）和来自I型脊髓灰质炎病毒的CD4（+）辅助T细胞肽。糖基化和肽表位都是单独合成的，并使用顺序肟键形成策略区域选择性地结合到RAFT核心。在体外和体内研究了候选疫苗的B和T抗原性和免疫原性。这些研究清楚地表明，缀合物的糖基化部分被Tn特异性单克隆抗体识别。此外，通过用我们的候选疫苗免疫小鼠而引发的抗体识别在人肿瘤细胞上表达的天然形式的Tn表位。结合肟连接技术，这些结果表明RAFT支架为工程化有效的合成抗癌疫苗提供了一种有前途的和合适的工具。
In this paper we investigated the use of regioselectively addressable functionalized templates (RAFTs) as new scaffolds for the design of anticancer vaccine candidates. We report the synthesis of well-defined multiepitopic RAFT scaffolds and their immunological evaluation. These conjugates exhibit clustered Tn analogue as tumor-associated carbohydrate antigen (TACA, B-cell epitope) and the CD4(+) helper T-cell peptide from the type I poliovirus. The saccharidic and peptidic epitopes were both synthesized separately and combined regioselectively to the RAFT core using a sequential oxime bond formation strategy. B- and T-antigenicity and immunogenicity of the vaccine candidates were investigated in vitro and in vivo. These studies clearly demonstrate that the saccharidic part of the conjugates is recognized by Tn-specific monoclonal antibodies. Moreover, the antibodies elicited by immunization of mice with our vaccine candidates recognize the native form of Tn epitope expressed on human tumor cells. Together with oxime ligation technique, these results suggest that the RAFT scaffold provides a promising and suitable tool for engineering potent synthetic anticancer vaccine.