IMMUNOGENIC TUMOR ASSOCIATED MUCIN PEPTIDES

某些粘蛋白表位与肿瘤相关， 在人粘蛋白糖蛋白MUC 1的串联重复核心内， 细胞，而不是正常细胞。大多数已知的抗MUC 1抗体（Abs） 识别具有串联重复核心的APDTRPAPG区域的表位， 称为MUC 1的免疫显性（ID）区域。一种新的结构模型， 该ID区域是基于NMR数据提出的。DTR中的Thr残基 串联重复序列的基序在体内被O-糖基化。MUC 1的一些Abs已经显示出 当Thr被核心型糖基化时，对DTR基序的亲和力更高 聚糖。肽表位与C-末端效应区的连接 已经显示，人C5 a过敏毒素的释放 抗原，同时刺激免疫反应。基于这些 新的MUC 1样免疫原性肽具有增强的肿瘤选择性 将被开发用作肿瘤疫苗的免疫原， 具有改进的选择性的免疫诊断试剂。结构模型将 用于设计、合成和测试构象受限的MUC 1样 具有增强的免疫原性的肽和肽模拟物。结构性 癌相关表位（肽和碳水化合物）的特征， MUC 1串联重复核心的ID区将通过光学（ECD， FTIR，VCD）和NMR光谱和分子模拟方法。加强 表位特异性Ab和/或对MUC 1样肽的细胞应答， 包括肽和免疫佐剂部分的分子构建体将 设计合成C-末端效应区的有效类似物， 人C5 a，YSFKPMPLaR，将用作分子佐剂。的 将在体外和体内评价MUC 1表位的免疫原性。它 最近发现，人类癌细胞含有一种替代序列， 在PDTR片段中以高发生率存在突变（Glu取代Asp）。 MUC 1 ID区突变的起源和发生率，以及MUC 1和MUC 2基因突变的发生率。 这些突变对结构、抗原性和免疫原性的影响 将研究串联重复肽。存在肿瘤相关的 序列变体提高了它们用作免疫原的可能性， 生成具有更高肿瘤程度的免疫诊断试剂 选择性及其在治疗中的应用， 疫苗。

Certain mucin epitopes are associated with tumors and are detected within the tandem repeat core of human mucin glycoprotein, MUC1, from malignant cells but not normal cells. Most of the known anti-MUC1 antibodies (Abs) recognize epitopes with the APDTRPAPG region of tandem repeat core, which is known as an immunodominant (ID) region of the MUC1. A new structural model of this ID-region is proposed based on NMR data. The Thr residue within the DTR motif of tandem repeat is O-glycosylated in vivo. Some Abs to MUC1 have shown a higher affinity to the DTR motif when Thr is glycosylated with core-type glycans. The attachment of peptide epitopes to the C-terminal effector region of the human C5a anaphylatoxin has been shown to improve the delivery of these antigens and simultaneously stimulate an immune response. Based on these findings, new MUC1-like immunogenic peptides with enhanced tumor selectivity will be developed to be used as immunogens for tumor vaccines and for producing immunodiagnostic reagents with improved selectivity. The structural model will be used to design, synthesize, and test conformationally constrained MUC1-like peptides and peptidomimetics with enhanced immunogenicity. The structural features of the carcinoma-associated epitopes (peptide and carbohydrate) in the ID-region of the MUC1 tandem repeat core will be evaluated by optical (ECD, FTIR, VCD) and NMR spectroscopy and by molecular modeling methods. To enhance epitope-specific Ab and/or cellular responses to the MUC1-like peptides, molecular constructs that include peptide and immunoadjuvant moieties will be designed and synthesized. A potent analog of the C-terminal effector region of the human C5a, YSFKPMPLaR, will be used as a molecular adjuvant. The immunogenecity of the MUC1 epitopes will be evaluated in vitro and in vivo. It was shown recently that human carcinoma cells contain an alternative sequence variant (substitutions of Asp by Glu) at a high incidence in the PDTR fragment. The origin and incidence of mutations in the ID-region of the MUC1 and the effects of these mutations on structure, antigenicity, and immunogenicity of tandem repeat peptides will be investigated. The existence of tumor-associated sequence variants raises the possibility for their use as immunogens for the generation of immunodiagnostic reagents with a higher degree of tumor selectivity and their application to therapy as more specific and efficient vaccines.