title: Characterization of GD2 peptide mimotope DNA vaccines effective against spontaneous neuroblastoma metastases.
abstract: Disialoganglioside GD2 is an established target for immunotherapy in neuroblastoma. We tested the hypothesis that active immunization against the glycolipid GD2 using DNA vaccines encoding for cyclic GD2-mimicking decapeptides (i.e., GD2 mimotopes) is effective against neuroblastoma. For this purpose, two GD2 peptide mimotopes (MA and MD) were selected based on docking experiments to anti-GD2 antibody ch14.18 (binding free energy: -41.23 kJ/mol for MA and -48.06 kJ/mol for MD) and Biacore analysis (K(d) = 12.3 x 10(-5) mol/L for MA and 5.3 x 10(-5) mol/L for MD), showing a higher affinity of MD over MA. These sequences were selected for DNA vaccine design based on pSecTag2-A (pSA) also including a T-cell helper epitope. GD2 mimicry was shown following transfection of CHO-1 cells with pSA-MA and pSA-MD DNA vaccines, with twice-higher signal intensity for cells expressing MD over MA. Finally, these DNA vaccines were tested for induction of tumor protective immunity in a syngeneic neuroblastoma model following oral DNA vaccine delivery with attenuated Salmonella typhimurium (SL 7207). Only mice receiving the DNA vaccines revealed a reduction of spontaneous liver metastases. The highest anti-GD2 humoral immune response and natural killer cell activation was observed in mice immunized with the pSA-MD, a finding consistent with superior calculated binding free energy, dissociation constant, and GD2 mimicry potential for GD2 mimotope MD over MA. In summary, we show that DNA immunization with pSA-MD may provide a useful strategy for active immunization against neuroblastoma.
authors.affiliation: Pediatrics, Experimental Oncology, Charité Universitätsmedizin Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fest
authors.forename: Nicole
authors.initials: N
authors.lastname: Huebener
authors.forename: Silke
authors.initials: S
authors.lastname: Weixler
authors.forename: Matthias
authors.initials: M
authors.lastname: Bleeke
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.forename: Anne
authors.initials: A
authors.lastname: Strandsby
authors.forename: Rudolf
authors.initials: R
authors.lastname: Volkmer-Engert
authors.forename: Christiane
authors.initials: C
authors.lastname: Landgraf
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gaedicke
authors.forename: Angelika B
authors.initials: AB
authors.lastname: Riemer
authors.forename: Elke
authors.initials: E
authors.lastname: Michalsky
authors.forename: Ines S
authors.initials: IS
authors.lastname: Jaeger
authors.forename: Robert
authors.initials: R
authors.lastname: Preissner
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Förster-Wald
authors.forename: Erika
authors.initials: E
authors.lastname: Jensen-Jarolim
authors.forename: Holger N
authors.initials: HN
authors.lastname: Lode
mesh_terms: D000818:Animals; D016466:CHO Cells; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D006224:Cricetinae; D005732:Gangliosides / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009447:Neuroblastoma / Q000276:immunology / Q000517:prevention & control / Q000556:secondary*; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D005732:Gangliosides; D019444:Vaccines, DNA; C019403:ganglioside, GD2; D007371:Interferon-gamma