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A newly human developed diabody against CD99 delivers a lethal signal through p53 pathway reactivation in Ewing sarcoma cells and synergistically acts with doxorubicin

Authors:

Katia Scotlandi ,

Rizzoli Institute, Bologna, Italy
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Clara Guerzoni,

Rizzoli Institute, Bologna, Italy
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Valentina Fiori,

Rizzoli Institute, Bologna, Italy
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Cristina Manara,

Rizzoli Institute, Bologna, Italy
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Michela Pasello,

Rizzoli Institute, Bologna, Italy
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Diego Moricoli,

Rizzoli Institute, Bologna, Italy
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Mara Gellini,

Rizzoli Institute, Bologna, Italy
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Maurizio Cianfriglia,

Rizzoli Institute, Bologna, Italy
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Mauro Magnani

Rizzoli Institute, Bologna, Italy
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Abstract

Ewing sarcoma is the second most frequent primary tumor of bone, preferentially occurring in children and adolescents. Despite significant improvements have been achieved in localized tumors thanks to dose intensification of chemotherapy, outcome of patients with metastasis at diagnosis remains grim. In addition, even in the most favorable situations, patients must face with important side effects which significantly impact their quality of life. Either scientific and patient communities are now very sensitive on the need of new drugs,which may reduce chemotherapy toxicity while maintaining effectiveness of current regimens. We present here a new engeneered human bivalent single chain fragment variable diabody (C7 scFv diabody) directed against CD99, a transmembrane protein whose high expression characterizes Ewing sarcoma. The triggering of CD99 with C7scFv diabody induces rapid and massive Ewing sarcoma cell death through MDM2 ubiquitination and p53 reactivation. Accordingly, the most CD99-responsive Ewing sarcoma cells have transcriptional active p53 and greatly benefit from MDM2 degradation. CD99 triggering also potentiates the cytotoxic effect of doxorubicin in vitro and in vivo and reactivates p53 to a much greater degree, which in turn markedly increased expression of pro-apoptosis genes. Evaluation of Ki-67 labelling and apoptosis rate by TUNEL confirms the efficacy of the treatment in xenografts. In contrast, mesenchymal stem cells, though expressing high levels of CD99, show no p53 activation and escape death induced by CD99 C7scFv diabody. No sign of toxicity was observed in mice treated with anti-CD99 scFV C7 diabody. Overall, our data provide the rationale for the use of this newly developed anti-CD99 diabody in the treatment of patients with Ewing sarcoma.
How to Cite: Scotlandi, K., Guerzoni, C., Fiori, V., Manara, C., Pasello, M., Moricoli, D., Gellini, M., Cianfriglia, M. and Magnani, M., 2015. A newly human developed diabody against CD99 delivers a lethal signal through p53 pathway reactivation in Ewing sarcoma cells and synergistically acts with doxorubicin. European Journal of Molecular & Clinical Medicine, 2(2), p.57. DOI: http://doi.org/10.1016/j.nhtm.2014.11.010
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Published on 07 Feb 2015.
Peer Reviewed

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