Diseño racional de derivados de mucina como candidatos a vacunas contra el cáncer

Resumo

Currently, one of the most promising approaches to treat cancer is the use of the socalled tumor-associated carbohydrate antigens. Mucin-like glycoproteins and, particularly, mucin 1 (MUC1) is one of the most studied candidates because it is associated with many carcinomas. While in normal tissue, this heavily Oglycosylated membrane glycoprotein carries complex oligosaccharides, in tumors, the expression of MUC1 is usually increased and its carbohydrates are very simple due to incomplete glycosylation. As a result, different antigens that are masked in normal cells are now exposed to the immune system. In this thesis, we have synthesized different representative MUC1 peptides and glycopeptides, containing both natural and unnatural residues, and then studied their binding properties to different anti-MUC1 antibodies. Our study indicates that threonine and serine MUC1-like derivatives display strikingly different binding properties, playing the methyl group of the threonine a crucial role in the recognition process. The sugar moiety linked to threonine fixes the presentation of the proper bioactive conformation. In addition, to the best of our knowledge, this is the first time that a mechanism is proposed, at atomic resolution, to explain the role that the carbohydrate plays in the molecular recognition by anti- MUC-1 antibodies. All these results may have implications for rational therapeutic and diagnostic antigen-antibody engineering. Interestingly, during the conduct of the pre-doctoral stay in the Complex Carbohydrate Center at the University of Georgia (USA), under the supervision of Professor Geert-Jan Boons, we were able synthesize a three component vaccine candidate which contained the unnatural amino acid ?-methylserine. This novel vaccine breaks tolerance and induces immune response against the tumor-associated glycoprotein MUC1 in mice.