Structure-guided Cancer Vaccines based on Glycopeptides Supported on Diverse Nanoparticles stars

Abstract

Cancer is a worldwide problem and various cancer therapies are emerging as potential solutions. Among these cancer therapies, a very attractive strategy is that of therapeutic cancer vaccines, which can use tumor-associated peptide fragments that can induce an immune response. In this thesis, we focus on the peptide sequence of MUC1, a glycoprotein presents on the surface of epithelial cells, which leaves simple carbohydrates, and the backbone of the peptide exposed in cancer cells due to aberrant glycosylation. In nature, this exposure to the immune system doesn't trigger a sufficient immune response, due to elusive mechanisms of the cancer cells. For this reason, the core of the present work is to design MUC1-based peptide vaccines modifying the backbone with non-natural mimetics or using different carrier systems to present the antigen to the immune system. In this thesis are presented two vaccines conjugated that have been shown to elicit high immune response utilizing in one case β-amino acid substitutions in the peptide backbone and utilizing as carrier gold nanoparticles, and a second one utilizing an epitope of the MUC1 along with a T helper epitope conjugated to silica nanoparticles. We also present in this work the synthesis of different MUC1 glycopeptides with modifications in the Arg residue and their comparison in terms of affinity towards the SM3 anti-MUC1 monoclonal antibody to select a vaccine candidate among them.