1. Anti-L1CAM radioimmunotherapy is more effective with the radiolanthanide terbium-161 compared to lutetium-177 in an ovarian cancer model.
- Author
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Grünberg, Jürgen, Lindenblatt, Dennis, Dorrer, Holger, Cohrs, Susan, Zhernosekov, Konstantin, Köster, Ulli, Türler, Andreas, Fischer, Eliane, and Schibli, Roger
- Subjects
CELL adhesion molecules ,RADIOIMMUNOTHERAPY ,OVARIAN cancer patients ,OVARIAN cancer treatment ,XENOGRAFTS - 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 Cu- and Lu-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 Lu and the potential alternative Tb in an ovarian cancer therapy model. Methods: Tb was produced by neutron bombardment of enriched Gd targets. Tb and Lu 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 Lu- and Tb-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. Lu- and Tb-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. Tb-labelled chCE7 revealed a higher radiotoxicity in nude mice (MTD: 10 MBq) than the Lu-labelled counterpart (MTD: 12 MBq). In a comparative therapy study with equitoxic doses, tumour growth inhibition was better by 82.6 % for the Tb-DOTA-chCE7 than the Lu-DOTA-chCE7 RIT. Conclusions: Our study is the first to show that anti-L1CAM Tb RIT is more effective compared to Lu RIT in ovarian cancer xenografts. These results suggest that Tb is a promising candidate for future clinical applications in combination with internalising antibodies. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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