Contributors: Régulation Immunitaire et Vaccinologie; Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur Paris; Chimie des biomolécules; Institut Pasteur Paris -Centre National de la Recherche Scientifique (CNRS); Immunité et cancer (U932); Université Paris Descartes - Paris 5 (UPD5)-Institut Curie Paris -Institut National de la Santé et de la Recherche Médicale (INSERM); Pôle Intégré de Recherche Clinique (PIRC); Institut Pasteur Paris; GSK Vaccines - Belgium; Laboratoire de Mathématiques d'Orsay (LM-Orsay); Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11); The work was funded by the Ligue Nationale Contre le Cancer (Equipe Labellisée 2014), the Banque Privée Européenne, the European Union’s Seventh Framework Programme under Grant Agreement No: 280873 ADITEC and the donors of the MAG-Tn3 program. The authors thank the PIRC (Pôle Integré de Recherche Clinique, Institut Pasteur, Paris, France) for their help in the organization of experiments on cynomolgus monkeys. The authors thank Nancy Dezutter, Valentine Wascotte and David Bouffard for developing the MAG-Tn3 formulation and for discussions; European Project: 280873,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,ADITEC(2011)
نبذة مختصرة : International audience ; Malignant transformations are often associated with aberrant glycosylation processes that lead to the expression of new carbohydrate antigens at the surface of tumor cells. Of these carbohydrate antigens, the Tn antigen is particularly highly expressed in many carcinomas, especially in breast carcinoma. We designed MAG-Tn3, a fully synthetic vaccine based on three consecutive Tn moieties that are O-linked to a CD4+ T cell epitope, to induce anti-Tn antibody responses that could be helpful for therapeutic vaccination against cancer. To ensure broad coverage within the human population, the tetanus toxoid-derived peptide TT830-844 was selected as a T-helper epitope because it can bind to various HLA-DRB molecules. We showed that the MAG-Tn3 vaccine, which was formulated with the GSK proprietary immunostimulant AS15 and designed for human cancer therapy, is able to induce an anti-Tn antibody response in mice of various H-2 haplotypes, and this response correlates with the ability to induce a specific T cell response against the TT830-844 peptide. The universality of the TT830-844 peptide was extended to new H-2 and HLA-DRB molecules that were capable of binding this T cell epitope. Finally, the MAG-Tn3 vaccine was able to induce anti-Tn antibody responses in cynomolgus monkeys, which targeted Tn-expressing tumor cells and mediated tumor cell death both in vitro and in vivo. Thus, MAG-Tn3 is a highly promising anticancer vaccine that is currently under evaluation in a phase I clinical trial.
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