title: The fully synthetic MAG-Tn3 therapeutic vaccine containing the tetanus toxoid-derived TT830-844 universal epitope provides anti-tumor immunity.
abstract: 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.
authors: Unité de Régulation Immunitaire et Vaccinologie, Equipe Labellisée Ligue Contre le Cancer, Institut Pasteur, 25 rue du Docteur Roux, 75015, Paris, France.|Institut National de la Santé et de la Recherche Médicale U1041, Paris, France.
authors: Daphné
authors: D
authors: Laubreton
authors: Unité de Chimie des Biomolécules, Institut Pasteur, Paris, France.|Centre National de la Recherche Scientifique UMR3523, Paris, France.
authors: Sylvie
authors: S
authors: Bay
authors: Institut Curie, Paris Sciences et Lettres Research University, Paris, France.|Institut National de la Santé et de la Recherche Médicale U932, Paris, France.
authors: Christine
authors: C
authors: Sedlik
authors: Pôle Intégré de Recherche Clinique, Institut Pasteur, Paris, France.
authors: Cécile
authors: C
authors: Artaud
authors: Unité de Chimie des Biomolécules, Institut Pasteur, Paris, France.|Centre National de la Recherche Scientifique UMR3523, Paris, France.
authors: Christelle
authors: C
authors: Ganneau
authors: Unité de Régulation Immunitaire et Vaccinologie, Equipe Labellisée Ligue Contre le Cancer, Institut Pasteur, 25 rue du Docteur Roux, 75015, Paris, France.|Institut National de la Santé et de la Recherche Médicale U1041, Paris, France.
authors: Edith
authors: E
authors: Dériaud
authors: Institut Curie, Paris Sciences et Lettres Research University, Paris, France.|Institut National de la Santé et de la Recherche Médicale U932, Paris, France.
authors: Sophie
authors: S
authors: Viel
authors: GSK Vaccines, Rixensart, Belgium.
authors: Anne-Laure
authors: AL
authors: Puaux
authors: Institut Curie, Paris Sciences et Lettres Research University, Paris, France.|Institut National de la Santé et de la Recherche Médicale U932, Paris, France.
authors: Sebastian
authors: S
authors: Amigorena
authors: GSK Vaccines, Rixensart, Belgium.
authors: Catherine
authors: C
authors: Gérard
authors: Unité de Régulation Immunitaire et Vaccinologie, Equipe Labellisée Ligue Contre le Cancer, Institut Pasteur, 25 rue du Docteur Roux, 75015, Paris, France.|Institut National de la Santé et de la Recherche Médicale U1041, Paris, France.
authors: Richard
authors: R
authors: Lo-Man
authors: Unité de Régulation Immunitaire et Vaccinologie, Equipe Labellisée Ligue Contre le Cancer, Institut Pasteur, 25 rue du Docteur Roux, 75015, Paris, France. claude.leclerc@pasteur.fr.|Institut National de la Santé et de la Recherche Médicale U1041, Paris, France. claude.leclerc@pasteur.fr.
authors: Claude
authors: C
authors: Leclerc
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D006183:H-2 Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D018992:Myelin-Associated Glycoprotein / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D013745:Tetanus Toxoid / Q000276:immunology*; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000276:immunology
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D059811:HLA-DRB1 Chains; C115082:MAG protein, human; D018992:Myelin-Associated Glycoprotein; D010446:Peptide Fragments; D013745:Tetanus Toxoid; C040286:Tn antigen; D014614:Vaccines, Synthetic
keywords: Antibody response; Anticancer vaccine; MAG-Tn3; TT830-844; Universal epitope