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Pharmacokinetics and antineoplastic activity of galectin-1-targeting OTX008 in combination with sunitinib

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Abstract

Purpose

OTX008 is a galectin-1-targeting compound, currently undergoing a phase I clinical trial. This study aimed at investigating OTX008 pharmacokinetics (PK) and antineoplastic activity.

Methods

Pharmacokinetics and activity of OTX008 were analyzed in the human ovarian carcinoma A2780-1A9 and glioblastoma U87MG xenografted in nude mice. In vitro, OTX008 was tested on tumor and endothelial cells.

Results

After 5 mg/kg i.v., OTX008 achieved plasma Cmax of 14.39 μg/mL, distributed rapidly, and was eliminated with a half-life of 31.4 h. Tumor OTX008 Cmax (1.65 μg/g, 1.76 μM), achieved at 0.5 h, remained high at 24 h (0.516 μg/g, 0.55 μM) with AUC of 15.76 μg/g*h. OTX008 accumulated in the tumor after repeated administrations achieving a concentration of 2.3 μM, compatible with the concentrations active in vitro. OTX008 (5 mg/kg i.v., every other day for 3 weeks) inhibited the in vivo growth of A2780-1A9, whereas U87MG was not sensitive. In vitro, OTX008 affected endothelial cell proliferation, motility, invasiveness, and cord formation. Tumor cell proliferation was also inhibited, with differences in sensitivity among cell lines (IC50 from 1 to 190 μM). OTX008 potentiated the activity of the tyrosine kinase inhibitor sunitinib on A2780-1A9 in vivo and in vitro, where the combination showed synergistic (endothelial cells) and additive (A2780-1A9) antiproliferative activity, indicating that the combination targets both the tumor and vascular compartments.

Conclusions

OTX008—alone or in combination with sunitinib—has a favorable PK and antineoplastic activity on selected tumor models through the effects on both endothelial and tumor cells.

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Conflict of interest

E. Cvitkovic and K. Noel are chief officers of OncoEthix SA, and M. D’Incalci is member of the scientific advisory board of OncoEthix SA. This study was supported by a research grant from OncoEthix SA.

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Authors and Affiliations

  1. Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 20156, Milan, Italy

    Massimo Zucchetti, Roberta Frapolli, Federica Sala, Monique Zangarini, Paolo Ubezio, Raffaella Giavazzi & Maurizio D’Incalci

  2. Tumor Angiogenesis Unit, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Parco Scientifico Tecnologico Kilometro Rosso, Via Stezzano, 87, 24126, Bergamo, Italy

    Katiuscia Bonezzi, Patrizia Borsotti, Raffaella Giavazzi & Giulia Taraboletti

  3. OncoEthix SA, 1006, Lausanne, Switzerland

    Esteban Cvitkovic & Kay Noel

Authors
  1. Massimo Zucchetti
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  2. Katiuscia Bonezzi
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  3. Roberta Frapolli
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  4. Federica Sala
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  5. Patrizia Borsotti
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  6. Monique Zangarini
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  7. Esteban Cvitkovic
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  8. Kay Noel
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  9. Paolo Ubezio
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  10. Raffaella Giavazzi
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  11. Maurizio D’Incalci
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  12. Giulia Taraboletti
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Corresponding author

Correspondence to Giulia Taraboletti.

Additional information

Massimo Zucchetti and Katiuscia Bonezzi contributed equally to the work.

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Zucchetti, M., Bonezzi, K., Frapolli, R. et al. Pharmacokinetics and antineoplastic activity of galectin-1-targeting OTX008 in combination with sunitinib. Cancer Chemother Pharmacol 72, 879–887 (2013). https://doi.org/10.1007/s00280-013-2270-2

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  • DOI: https://doi.org/10.1007/s00280-013-2270-2

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