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Characterization of GD2 Peptide Mimotope DNA Vaccines Effective against Spontaneous Neuroblastoma Metastases

¹ Pediatrics, Experimental Oncology; ² Laboratory of Molecular Libraries, Department of Medical Immunology; ³ Department of Molecular Biology and Bioinformatics, Charité Universitätsmedizin Berlin, Berlin, Germany; Departments of ⁴ Pathophysiology and ⁵ Pediatrics and Juvenile Medicine, Medical University of Vienna, Vienna, Austria; and ⁶ Department of Obstetrics and Gynecology, Yale University, New Haven, Connecticut

Requests for reprints: Holger N. Lode, Experimental Oncology, Charité Universitätsmedizin Berlin, Forum 4, R 2.0407, Augustenburger Platz 1, 13353 Berlin, Germany. Phone: 49-30-450-666233; Fax: 49-30-450-559917; E-mail: holger.lode{at}charite.de.

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. (Cancer Res 2006; 66(21): 10567-75)