title: Antitumor activity of liposomal ErbB2/HER2 epitope peptide-based vaccine constructs incorporating TLR agonists and mannose receptor targeting.
abstract: Synthetic and molecularly defined constructs containing the minimal components to mimic and amplify the physiological immune response are able to induce an efficient cytotoxic response. In the current study this approach was applied to the development of highly versatile liposomal constructs to co-deliver peptide epitopes in combination with TLR agonists in order to induce a specific anti-tumor cellular immune response against ErbB2 protein-expressing tumor cells. Liposomes containing ErbB2 p63-71 cytotoxic T lymphocyte (CTL) and HA307-319 T- helper (Th) peptide epitopes associated to innovative synthetic TLR2/1 (Pam(3)CAG) or TLR2/6 agonists (Pam(2)CAG and Pam(2)CGD), were injected in mice bearing ErbB2 protein-expressing tumor cells. Mannosylated ligands were also incorporated into the constructs to target antigen-presenting cells. We showed that the TLR2/6 agonists were more efficient than the TLR2/1 agonists for the eradication of tumors expressing ErbB2 protein. Furthermore, mannose-targeted liposomes displayed higher therapeutic efficiency against tumor allowing treatment with decreased quantities of both TLR ligands and peptide epitopes. Our results validated that antigen-associated mannosylated liposomes combined with efficient TLR ligands are effective vectors for vaccination against tumor. In this study we developed useful tools to evaluate the vaccination efficiency of various adjuvants and/or targeting molecules and their potential synergy.
authors.affiliation: Equipe de Biovectorologie, Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS/Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Thomann
authors.forename: Béatrice
authors.initials: B
authors.lastname: Heurtault
authors.forename: Steffen
authors.initials: S
authors.lastname: Weidner
authors.forename: Mélanie
authors.initials: M
authors.lastname: Brayé
authors.forename: Julien
authors.initials: J
authors.lastname: Beyrath
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fournel
authors.forename: Francis
authors.initials: F
authors.lastname: Schuber
authors.forename: Benoît
authors.initials: B
authors.lastname: Frisch
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry; D000818:Animals; D019496:Cancer Vaccines / Q000627:therapeutic use*; D000939:Epitopes / Q000276:immunology; D005260:Female; D037181:Lectins, C-Type / Q000276:immunology*; D008081:Liposomes / Q000737:chemistry / Q000276:immunology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000276:immunology*; D008422:Materials Testing; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000276:immunology*; D051193:Toll-Like Receptors / Q000819:agonists* / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D000939:Epitopes; D037181:Lectins, C-Type; D008081:Liposomes; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors