Characterization of GD2 peptide mimotope DNA vaccines effective against spontaneous neuroblastoma metastases.
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.
Fest
Stefan
S
Pediatrics, Experimental Oncology, Charité Universitätsmedizin Berlin, Germany.
Huebener
Nicole
N
Weixler
Silke
S
Bleeke
Matthias
M
Zeng
Yan
Y
Strandsby
Anne
A
Volkmer-Engert
Rudolf
R
Landgraf
Christiane
C
Gaedicke
Gerhard
G
Riemer
Angelika B
AB
Michalsky
Elke
E
Jaeger
Ines S
IS
Preissner
Robert
R
Förster-Wald
Elisabeth
E
Jensen-Jarolim
Erika
E
Lode
Holger N
HN
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*
D019496:Cancer Vaccines; D005732:Gangliosides; D019444:Vaccines, DNA; C019403:ganglioside, GD2; D007371:Interferon-gamma