Synthesis of a Liposomal MUC1 Glycopeptide-Based Immunotherapeutic and Evaluation of the Effect of l-Rhamnose Targeting on Cellular Immune Responses.
Synthesis of a Liposomal MUC1 Glycopeptide-Based Immunotherapeutic and Evaluation of the Effect of l-Rhamnose Targeting on Cellular Immune Responses.
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DOI：
10.1021/acs.bioconjchem.5b00528
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发表时间：
2016-01-20
影响因子：
4.7
通讯作者：
Sucheck SJ
中科院分区：
文献类型：
--
作者：
Karmakar P;Lee K;Sarkar S;Wall KA;Sucheck SJ
对细胞外抗原的CD 8+应答的产生需要抗原呈递细胞（APC）对抗原的加工和通过MHC I类分子交叉呈递至CD 8 + T细胞受体。交叉呈递通过有效的抗原摄取以及随后的免疫复合物介导的APC成熟来促进。我们假设，通过将含有CD 8 + T细胞表位的糖肽序列递送到修饰有免疫复合物靶向配体（L-鼠李糖（Rha）表位）的脂质体表面上，可以实现对含有CD 8 + T细胞表位的糖肽序列的抗原摄取的改善。我们从肿瘤标志物MUC 1的可变数目串联重复区合成了一个20个氨基酸的糖肽TSAPDT（GalNAc）RPAPGSTAPPAHGV，该序列在免疫原性DTR基序处含有N-末端叠氮基和肿瘤相关的α-N-乙酰半乳糖胺（GalNAc）。MUC 1抗原通过铜（I）催化的叠氮基-炔环加成（CuAAc）化学连接至Toll样受体-2配体Pam 3Cys。在C57 BL/6小鼠组中评价Rh修饰的脂质体Pam 3Cys-MUC 1-Tn 4疫苗。一些组预先免疫以产生抗Rha抗体。与对照组相比，接受Rha脂质体疫苗的表达抗Rha抗体的小鼠显示出更高的细胞免疫原性，同时保持强的体液应答。
Generation of a CD8+ response to extracellular antigen requires processing of the antigen by antigen presenting cells (APC) and cross-presentation to CD8+ T cell receptors via MHC class I molecules. Cross-presentation is facilitated by efficient antigen uptake followed by immune-complex-mediated maturation of the APCs. We hypothesize that improved antigen uptake of a glycopeptide sequence containing a CD8+ T cell epitope could be achieved by delivering it on a liposome surface decorated with an immune complex-targeting ligand, an L-Rhamnose (Rha) epitope. We synthesized a 20 amino acid glycopeptide TSAPDT(GalNAc)RPAPGSTAPPAHGV from the variable number tandem repeat region of the tumor marker MUC1 containing an N-terminal azido moiety and a tumor-associated α-N-acetyl galactosamine (GalNAc) at the immunogenic DTR motif. The MUC1 antigen was attached to Pam3Cys, a Toll-like receptor-2 ligand via copper (I)-catalyzed azido-alkyne cycloaddtion (CuAAc) chemistry. The Rha-decorated liposomal Pam3Cys-MUC1-Tn 4 vaccine was evaluated in groups of C57BL/6 mice. Some groups were previously immunized to generate anti-Rha antibodies. Anti-Rha antibody expressing mice that received the Rha liposomal vaccine showed higher cellular immunogenicity compared to the control group while maintaining a strong humoral response.