IMMUNOGENIC TUMOR ASSOCIATED MUCIN PEPTIDES

某些粘蛋白表位与肿瘤相关，并被检测到 在人粘蛋白糖蛋白MUC1的串联重复核心内，从恶性 细胞，但不是正常细胞。已知的大多数抗MUC1抗体(Abs) 用串联重复核心的APDTRPAPG区域识别表位，这是 被称为MUC1的免疫显性(ID)区域。一种新的结构模型 这个ID区是基于核磁共振数据提出的。DTR中的Thr残留量 串联重复序列的基序在体内是O糖基化的。一些抗MUC1抗体已经显示出 当Thr与核心型糖基化时，对DTR基序的亲和力更高 多聚糖。多肽表位与C末端效应区的结合 人类C5a过敏性毒素已被证明可以改善这些物质的传递 并同时刺激免疫反应。基于这些 发现具有增强肿瘤选择性的新的MUC1样免疫原肽 将被开发作为肿瘤疫苗的免疫原，并用于生产 选择性提高的免疫诊断试剂。结构模型将 用于设计、合成和测试构象受限的类MUC1 具有增强免疫原性的多肽和多肽模拟物。结构性的 中国人肿瘤相关表位(肽和碳水化合物)的特征 MUC1串联重复核心的ID区域将通过光学(ECD， FTIR、VCD)和核磁共振波谱，以及分子模拟方法。为了增强 对MUC1样肽的表位特异性抗体和/或细胞反应， 包括多肽和免疫佐剂部分的分子结构将是 设计和合成。C-末端效应区的有效类似物 人类C5a，YSFKPMPLaR，将被用作分子佐剂。这个 MUC1表位的免疫原性将在体外和体内进行评估。它 最近发现人类癌细胞含有另一种序列 突变(天冬氨酸被Glu取代)在PDTR片段中出现的频率很高。 MUC1ID区突变的起源和发生率 这些突变对病毒结构、抗原性和免疫原性的影响 将对串联重复多肽进行研究。肿瘤相关疾病的存在 序列变异增加了将它们用作免疫原的可能性 肿瘤程度较高的免疫诊断试剂的研制 选择性及其在治疗中的应用更具特异性和有效性 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.