Grigalevicius Saulius, Chierici Sabine, Renaudet Olivier, Lo-Man Richard, Dériaud Edith, Leclerc Claude, Dumy Pascal
LEDSS UMR 5616 and ICMG-FR2607, Université Joseph Fourier, BP 53, 38041 Grenoble Cedex 9, France.
Bioconjug Chem. 2005 Sep-Oct;16(5):1149-59. doi: 10.1021/bc050010v.
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 1 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.
在本文中,我们研究了区域选择性可寻址功能化模板(RAFTs)作为设计抗癌疫苗候选物的新型支架的用途。我们报告了明确的多表位RAFT支架的合成及其免疫学评估。这些缀合物展示了聚集的Tn类似物作为肿瘤相关碳水化合物抗原(TACA,B细胞表位)以及来自1型脊髓灰质炎病毒的CD4+辅助性T细胞肽。糖基和肽表位均分别合成,并使用顺序肟键形成策略区域选择性地与RAFT核心结合。在体外和体内研究了候选疫苗的B抗原性和T抗原性以及免疫原性。这些研究清楚地表明,缀合物的糖基部分被Tn特异性单克隆抗体识别。此外,用我们的候选疫苗免疫小鼠所引发的抗体识别在人肿瘤细胞上表达的Tn表位的天然形式。连同肟连接技术,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景且合适的工具。