A fully synthetic vaccine consisting of a tumor-associated glycopeptide antigen and a T-Cell epitope for the induction of a highly specific humoral immune response
A fully synthetic vaccine consisting of a tumor-associated glycopeptide antigen and a T-Cell epitope for the induction of a highly specific humoral immune response
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DOI：
10.1002/anie.200501594
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发表时间：
2005-01-01
影响因子：
16.6
通讯作者：
Kunz, H
中科院分区：
文献类型：
--
作者：
Dziadek, S;Hobel, A;Kunz, H
7630 2005 Wiley-VCH Verlag GmbH & Co. KGaA，魏因海姆Angew. Chem.Int.Ed.2005，44，7630-7635幼稚B细胞增殖并分化成分泌抗体的浆细胞。需要激活的CD 4 + T辅助细胞的额外刺激。反过来，当TH细胞的受体（TCR）结合到由细胞表面上的主要组织相容性复合体（MHC II）呈递的T细胞肽抗原时，TH细胞被激活。[4]我们在此描述了构建抗肿瘤疫苗1的概念，其中来自MUC 1串联重复区的肿瘤相关唾液酸-Tn糖肽抗原通过极性、非免疫原性氨基酸间隔区连接至来自卵清蛋白（OVA 323 -339）的TH细胞肽表位[5]（图1a）。这种合成疫苗应该被抗原呈递细胞（APC）吸收。构建体1加工后，卵清蛋白T细胞表位[5]应该由APC上的MHC II复合物呈递并被T细胞受体（TCR）识别。这导致初始T细胞的活化和分化。活化的TH细胞然后刺激那些也呈递相应T细胞表位的B细胞。根据上述机制，（图1b），B细胞的免疫球蛋白受体对1中的肿瘤相关MUC 1糖肽抗原的识别以及随后在相同的B细胞中对构建体1的加工与另外的共刺激信号结合将引发针对MUC 1糖肽抗原的特异性抗体的强烈产生。表位缀合物1通过固相上的片段缩合来构建。选择作为靶结构的序列GVT* SAPDTRPAP的MUC 1糖肽抗原含有免疫显性基序PDTRP，[6]其在正常细胞上的MUC 1中被大聚糖侧链掩蔽。在乳腺癌、胃癌和结肠癌中鉴定出的唾液酸-Tn抗原[7-9]作为肿瘤相关糖组分掺入Thr 3处的肽序列中。对肿瘤细胞中粘蛋白的异常糖基化的检查[10，11]揭示了唾液酸-Tn抗原可能不是最丰富的，但就肿瘤选择性而言肯定是非常重要的结构。
7630 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2005, 44, 7630–7635 naive Bcell to proliferate and to differentiate into an antibody-secreting plasma cell. Additional stimulation by activated CD4+ T helper cells is required. In turn, the TH cells are activated when their receptor (TCR) binds to a T-cell peptide antigen presented by the major histocompatibility complex (MHC II) on the surface of a cell.[4] We describe herein a concept for the construction of antitumor vaccines 1 in which a tumor-associated sialyl-Tn glycopeptide antigen from the tandem repeat region of MUC1 is connected to a TH-cell peptide epitope from ovalbumin (OVA323–339)[5] through a polar, nonimmunogenic amino acid spacer (Figure1a). Such a synthetic vaccine should be taken up by antigen-presenting cells (APCs). After processing of construct 1, the ovalbumin T-cell epitope [5] should be presented by MHC II complexes on APCs and recognized by the T-cell receptor (TCR). This results in the activation and differentiation of naive T cells. The activated TH cells then stimulate those B cells that also present the corresponding T-cell epitope. It is anticipated that, according to the mechanism illustrated above (Figure 1b), recognition of the tumor-associated MUC1 glycopeptide antigen in 1 by the immunoglobulin receptor of a Bcell and subsequent processing of construct 1 in the same B cell combined with additional co-stimulatory signals will initiate a strong production of specific antibodies directed against the MUC1 glycopeptide antigen.The glycopeptide–T-cell-epitope conjugate 1 was constructed by fragment condensation on a solid phase. The MUC1 glycopeptide antigen of the sequence GVT* SAPDTRPAP chosen as the target structure contains the immunodominant motif PDTRP,[6] which is masked in MUC1 on normal cells by the large glycan side chains. The sialyl-Tn antigen, which has been identified in mammary, stomach, and colon carcinomas,[7–9] was incorporated into the peptide sequence at Thr3 as the tumor-associated saccharide component. Examination of the aberrant glycosylation of mucines in tumor cells [10, 11] reveals that the sialyl-Tn antigen may not be the most abundant, but is certainly a highly important structure in terms of tumor selectivity.