Johannes Gutenberg-Universität Mainz, Institut für Organische Chemiem, Duesbergweg 10-14, D-55128 Mainz, Germany.
Chem Soc Rev. 2013 May 21;42(10):4421-42. doi: 10.1039/c3cs35470a. Epub 2013 Feb 25.
Based on important cell-biological and biochemical results concerning the structural difference between membrane glycoproteins of normal epithelial cells and epithelial tumour cells, tumour-associated glycopeptide antigens have been chemically synthesised and structurally confirmed. Glycopeptide structures of the tandem repeat sequence of mucin MUC1 of epithelial tumour cells constitute the most promising tumour-associated antigens. In order to generate a sufficient immunogenicity of these endogenous structures, usually tolerated by the immune system, these synthetic glycopeptide antigens were conjugated to immune stimulating components: in fully synthetic two-component vaccines either with T-cell peptide epitopes or with Toll-like receptor2 lipopeptide ligands or in three-component vaccines with both these stimulants. Alternatively, the synthetic glycopeptide antigens were coupled to immune stimulating carrier proteins. In particular, MUC1 glycopeptide conjugates with Tetanus toxoid proved to be efficient vaccines inducing very strong immune responses in mice. The antibodies elicited with the fully synthetic vaccines showed selective recognition of the tumour-associated glycopeptides as was shown by neutralisation and micro-array binding experiments. After booster immunisations, most of the immune responses showed the installation of an immunological memory. Immunisation with fully synthetic three-component vaccines induced immune reactions with therapeutic effects in terms of reduction of the tumour burden in mice or in killing of tumour cells in culture, while MUC1 glycopeptide-Tetanus toxoid vaccines elicited antibodies in mice which recognised tumour cells in human tumour tissues. The results achieved so far are considered to be promising for the development of an active immunisation against tumours.
基于有关正常上皮细胞和上皮肿瘤细胞的膜糖蛋白结构差异的重要细胞生物学和生物化学结果,已经化学合成并结构确证了肿瘤相关糖肽抗原。上皮肿瘤细胞黏蛋白 MUC1 的串联重复序列的糖肽结构构成了最有前途的肿瘤相关抗原。为了产生这些内源性结构的足够免疫原性,这些通常被免疫系统耐受的合成糖肽抗原被与免疫刺激成分缀合:在完全合成的二组分疫苗中,与 T 细胞肽表位缀合,或与 Toll 样受体 2 脂肽配体缀合,或在三组分疫苗中与这两种刺激物缀合。或者,合成糖肽抗原与免疫刺激载体蛋白偶联。特别是,与破伤风类毒素缀合的 MUC1 糖肽已被证明是有效的疫苗,可在小鼠中诱导非常强烈的免疫反应。用完全合成的疫苗诱导的抗体显示出对肿瘤相关糖肽的选择性识别,如中和和微阵列结合实验所示。在加强免疫后,大多数免疫反应表现出免疫记忆的建立。用完全合成的三组分疫苗进行免疫接种可诱导免疫反应,在减少小鼠肿瘤负担或杀伤培养的肿瘤细胞方面具有治疗效果,而 MUC1 糖肽-破伤风类毒素疫苗在小鼠中诱导的抗体可识别人肿瘤组织中的肿瘤细胞。迄今为止取得的结果被认为是开发针对肿瘤的主动免疫接种的有希望的结果。
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