Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, Spain.
Curr Med Chem. 2022;29(7):1258-1270. doi: 10.2174/0929867328666210810152917.
Immunotherapy, alone or in combination with other therapies, is widely used against cancer. Glycoprotein Mucin 1 (MUC1), which is overexpressed and aberrantly glycosylated in tumor cells, is one of the most promising candidates to engineer new cancer vaccines. In this context, the development of stable antigens that can elicit a robust immune response is mandatory. Here, we describe the design and in vivo biological evaluation of three vaccine candidates based on MUC1 glycopeptides that comprise unnatural elements in their structure. By placing the Tn antigen (GalNAcα-O-Ser/Thr) at the center of the design, the chemical modifications include changes to the peptide backbone, glycosidic linkage, and carbohydrate level. Significantly, the three vaccines elicit robust immune responses in mice and produce antibodies that can be recognized by several human cancer cells. In all cases, a link was established between the conformational changes induced by the new elements in the antigen presentation and the immune response induced in mice. According to our data, the development of effective MUC1-based vaccines should use surrogates that mimic the conformational space of aberrantly glycosylated MUC1 glycopeptides found in tumors.
免疫疗法，单独或与其他疗法联合使用，被广泛用于对抗癌症。糖蛋白粘蛋白 1（MUC1）在肿瘤细胞中过度表达和异常糖基化，是工程新癌症疫苗的最有前途的候选物之一。在这种情况下，开发能够引发强大免疫反应的稳定抗原是强制性的。在这里，我们描述了三种基于 MUC1 糖肽的疫苗候选物的设计和体内生物学评价，这些糖肽在其结构中包含非天然元素。通过将 Tn 抗原（GalNAcα-O-Ser/Thr）置于设计的中心，化学修饰包括对肽骨架、糖苷键和糖基水平的改变。重要的是，这三种疫苗在小鼠中引发了强烈的免疫反应，并产生了可以被几种人类癌细胞识别的抗体。在所有情况下，都在抗原呈递中引入的新元素引起的构象变化与在小鼠中诱导的免疫反应之间建立了联系。根据我们的数据，有效的基于 MUC1 的疫苗的开发应该使用模拟在肿瘤中发现的异常糖基化 MUC1 糖肽的构象空间的替代物。
