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Anti-L1CAM radioimmunotherapy is more effective with the radiolanthanide terbium-161 compared to lutetium-177 in an ovarian cancer model

  • Jürgen Grünberg
  • Dennis Lindenblatt
  • Holger Dorrer
  • Susan Cohrs
  • Konstantin Zhernosekov
  • Ulli Köster
  • Andreas Türler
  • Eliane Fischer
  • Roger SchibliEmail author
Original Article

Abstract

Purpose

The L1 cell adhesion molecule (L1CAM) is considered a valuable target for therapeutic intervention in different types of cancer. Recent studies have shown that anti-L1CAM radioimmunotherapy (RIT) with 67Cu- and 177Lu-labelled internalising monoclonal antibody (mAb) chCE7 was effective in the treatment of human ovarian cancer xenografts. In this study, we directly compared the therapeutic efficacy of anti-L1CAM RIT against human ovarian cancer under equitoxic conditions with the radiolanthanide 177Lu and the potential alternative 161Tb in an ovarian cancer therapy model.

Methods

Tb was produced by neutron bombardment of enriched 160Gd targets. 161Tb and 177Lu were used for radiolabelling of DOTA-conjugated antibodies. The in vivo behaviour of the radioimmunoconjugates (RICs) was assessed in IGROV1 tumour-bearing nude mice using biodistribution experiments and SPECT/CT imaging. After ascertaining the maximal tolerated doses (MTD) the therapeutic impact of 50 % MTD of 177Lu- and 161Tb-DOTA-chCE7 was evaluated in groups of ten mice by monitoring the tumour size of subcutaneous IGROV1 tumours.

Results

The average number of DOTA ligands per antibody was 2.5 and maximum specific activities of 600 MBq/mg were achieved under identical radiolabelling conditions. RICs were stable in human plasma for at least 48 h. 177Lu- and 161Tb-DOTA-chCE7 showed high tumour uptake (37.8–39.0 %IA/g, 144 h p.i.) with low levels in off-target organs. SPECT/CT images confirmed the biodistribution data. 161Tb-labelled chCE7 revealed a higher radiotoxicity in nude mice (MTD: 10 MBq) than the 177Lu-labelled counterpart (MTD: 12 MBq). In a comparative therapy study with equitoxic doses, tumour growth inhibition was better by 82.6 % for the 161Tb-DOTA-chCE7 than the 177Lu-DOTA-chCE7 RIT.

Conclusions

Our study is the first to show that anti-L1CAM 161Tb RIT is more effective compared to 177Lu RIT in ovarian cancer xenografts. These results suggest that 161Tb is a promising candidate for future clinical applications in combination with internalising antibodies.

Keywords

161Tb 177Lu Radioimmunotherapy Ovarian carcinoma L1CAM mAb chCE7 

Notes

Acknowledgments

This work was supported by the Swiss Cancer Research Foundation (Project No. KFS-2546-02-2010) to Jürgen Grünberg

Conflict of interest

None

Supplementary material

259_2014_2798_MOESM1_ESM.doc (1.4 mb)
ESM 1 (DOC 1391 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Jürgen Grünberg
    • 1
  • Dennis Lindenblatt
    • 1
  • Holger Dorrer
    • 2
  • Susan Cohrs
    • 1
  • Konstantin Zhernosekov
    • 3
  • Ulli Köster
    • 4
  • Andreas Türler
    • 2
    • 5
  • Eliane Fischer
    • 1
  • Roger Schibli
    • 1
    • 6
    Email author
  1. 1.Center for Radiopharmaceutical Sciences ETH-PSI-USZPaul Scherrer InstituteVilligenSwitzerland
  2. 2.Laboratory of Radiochemistry and Environmental ChemistryPaul Scherrer InstituteVilligenSwitzerland
  3. 3.ITG Isotope Technologies Garching GmbHGarchingGermany
  4. 4.Institut Laue-LangevinGrenobleFrance
  5. 5.Department of Chemistry and BiochemistryUniversity of BernBerneSwitzerland
  6. 6.Department of Chemistry and Applied BiosciencesETH ZurichZurichSwitzerland

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