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Vaccination with anti-idiotype antibody ganglidiomab mediates a GD2-specific anti-neuroblastoma immune response

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Abstract

Purpose

Immunotherapy targeting disialoganglioside GD2 emerges as an important treatment option for neuroblastoma, a pediatric malignancy characterized by poor outcome. Here, we report the induction of a GD2-specific immune response with ganglidiomab, a new anti-idiotype antibody to anti-GD2 antibodies of the 14.18 family.

Experimental design and results

Ganglidiomab was generated following immunization of Balb/c mice with 14G2a, and splenocytes were harvested to generate hybridoma cells. Clones were screened by ELISA for mouse antibody binding to hu14.18. One positive clone was selected to purify and characterize the secreted IgG protein (κ, IgG1). This antibody bound to anti-GD2 antibodies 14G2a, ch14.18/CHO, hu14.18, and to immunocytokines ch14.18-IL2 and hu14.18-IL2 as well as to NK-92 cells expressing scFv(ch14.18)-zeta receptor. Binding of these anti-GD2 antibodies to the nominal antigen GD2 as well as GD2-specific lysis of neuroblastoma cells by NK-92-scFv(ch14.18)-zeta cells was competitively inhibited by ganglidiomab, proving GD2 surrogate function and anti-idiotype characteristics. The dissociation constants of ganglidiomab from anti-GD2 antibodies ranged from 10.8 ± 5.01 to 53.5 ± 1.92 nM as determined by Biacore analyses. The sequences of framework and complementarity-determining regions of ganglidiomab were identified. Finally, we demonstrated induction of a GD2-specific humoral immune response after vaccination of mice with ganglidiomab effective in mediating GD2-specific killing of neuroblastoma cells.

Conclusion

We generated and characterized a novel anti-idiotype antibody ganglidiomab and demonstrated activity against neuroblastoma.

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Acknowledgments

We would like to thank Dr. M. Bhattacharya-Chatterjee, University of Kentucky, and Prof. Dr. R. Handgretinger, Center for Pediatric and Adolescence Medicine, University of Tübingen, for providing 1A7 and ch14.18-delta-CH2 for this study. Clinical grade ch14.18/CHO and hu14.18-IL2 were provided by Polymun, Vienna, Austria, and by Apeiron Biologics, Vienna, Austria, respectively. We also thank Prof. Dr. Winfried S. Wels and his group at the Georg-Speyer-Haus, Frankfurt am Main, Germany, for providing the NK-92 cells expressing the scFv(ch14.18)-zeta receptor. We also would like to acknowledge the cooperative group of pediatric oncologists of the SIOPEN-R-NET for the production of ch14.18/CHO antibody carried out by Polymun Scientific, Vienna, Austria, which was financed by charities throughout Europe. We also thank Andrea Plath and Theodor Koepp (University Medicine Greifswald, Pediatric Hematology and Oncology, Greifswald, Germany) for excellent technical assistance. Financial support was provided by the German Federal Ministry of Education and Research (BMBF, NGFNplus, ENGINE, and the Hector Stiftung) (Holger N. Lode), by a Kind-Philipp-Stiftung training grant (Diana Seidel), and by BMBF (FKZ03Z2CN12) within the ZIK-HIKE project (Sven Brandt and Hans-Peter Mueller).

Conflict of interest

There is no conflict of interest to be disclosed.

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Authors and Affiliations

  1. Pediatric Hematology and Oncology, University Medicine Greifswald, Ferdinand-Sauerbruchstrasse 1, 17475, Greifswald, Germany

    Holger N. Lode, Manuela Schmidt, Diana Seidel, Nicole Huebener, Diana Brackrock, Matthias Bleeke, Daniel Reker & Nikolai Siebert

  2. ZIK HIKE, Center for Innovation Competence: Humoral Immune Reactions in Cardiovascular Diseases, University of Greifswald, Greifswald, Germany

    Sven Brandt & Hans-Peter Mueller

  3. Department of Physics, University of Greifswald, Greifswald, Germany

    Christiane Helm

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  1. Holger N. Lode
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  2. Manuela Schmidt
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  3. Diana Seidel
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  4. Nicole Huebener
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Correspondence to Holger N. Lode.

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Lode, H.N., Schmidt, M., Seidel, D. et al. Vaccination with anti-idiotype antibody ganglidiomab mediates a GD2-specific anti-neuroblastoma immune response. Cancer Immunol Immunother 62, 999–1010 (2013). https://doi.org/10.1007/s00262-013-1413-y

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  • DOI: https://doi.org/10.1007/s00262-013-1413-y

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