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

Authors
  • Bellaye, P.-S.1
  • Moreau, M.2
  • Raguin, O.3
  • Oudot, A.1
  • Bernhard, C.2
  • Vrigneaud, J.-M.1
  • Dumont, L.4
  • Vandroux, D.4
  • Denat, F.2
  • Cochet, A.1
  • Brunotte, F.1
  • Collin, B.1, 2
  • 1 Centre Georges-François Leclerc, Service de médecine nucléaire, 1 rue du professeur Marion, Dijon, 21000, France , Dijon (France)
  • 2 Université de Bourgogne Franche-Comté, Institut de Chimie Moléculaire de l’Université de Bourgogne, UMR CNRS 6302, Dijon Cedex, 21078, France , Dijon Cedex (France)
  • 3 Oncodesign, Dijon Cedex, 21076, France , Dijon Cedex (France)
  • 4 NVH Medicinal, 64 rue Sully, Dijon, 21000, France , Dijon (France)
Type
Published Article
Journal
Clinical & Translational Oncology
Publisher
Springer-Verlag
Publication Date
May 17, 2018
Volume
20
Issue
12
Pages
1557–1570
Identifiers
DOI: 10.1007/s12094-018-1886-4
Source
Springer Nature
Keywords
License
Green

Abstract

PurposeThis 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.MethodsWe 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.ResultsRadiolabeling 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.Conclusions111In-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.

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