Radiolabeled F(ab′)2-cetuximab for theranostic purposes in colorectal and skin tumor-bearing mice models

• P.-S. Bellaye ^[1] ; M. Moreau ^[2] ; O. Raguin ^[3] ; A. Oudot ^[1] ; C. Bernhard ^[2] ; J.-M. Vrigneaud ^[1] ; L. Dumont ^[4] ; D. Vandroux ^[4] ; F. Denat ^[2] ; A. Cochet ^[1] ; F. Brunotte ^[1] ; B. Collin ^[1]
  1. [1] Centre Georges François Leclerc

     Centre Georges François Leclerc

     Arrondissement de Dijon, Francia

     
  2. [2] Institut de Chimie Moléculaire de l’Université de Bourgogne
  3. [3] Oncodesign. Dijon Cedex, France
  4. [4] NVH Medicinal. Dijon, France

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• Localización: Clinical & translational oncology, ISSN 1699-048X, Vol. 20, Nº. 12, 2018, págs. 1557-1570
• Idioma: inglés
• Texto completo no disponible (Saber más ...)
• Resumen

  • Purpose This study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, 111In and 177Lu, respectively.

    Methods We designed F(ab′)2-fragments of cetuximab radiolabeled with 111In and 177Lu. 111In-F(ab′)2-cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of 111In-F(ab′)2-cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on 177Lu-F(ab′)2-cetuximab was evaluated in SWISS nude mice bearing A431 tumors.

    Results Radiolabeling procedure did not change F(ab′)2-cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. 111In-DOTAGA-F(ab′)2-cetuximab exhibited a peak tumor uptake at 24 h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab′)2-cetuximab. SPECT imaging of 111In-DOTAGA-F(ab′)2-cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, 177Lu-DOTAGA-F(ab′)2-cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses.

    Conclusions 111In-DOTAGA-F(ab′)2-cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. 177Lu-DOTAGA-F(ab′)2-cetuximab is an interesting theranostic tool allowing therapy and imaging.