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

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 (67)Cu- and (177)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 (177)Lu and the potential alternative (161)Tb in an ovarian cancer therapy model.

METHODS:

Tb was produced by neutron bombardment of enriched (160)Gd targets. (161)Tb and (177)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 (177)Lu- and (161)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. (177)Lu- and (161)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. (161)Tb-labelled chCE7 revealed a higher radiotoxicity in nude mice (MTD: 10 MBq) than the (177)Lu-labelled counterpart (MTD: 12 MBq). In a comparative therapy study with equitoxic doses, tumour growth inhibition was better by 82.6 % for the (161)Tb-DOTA-chCE7 than the (177)Lu-DOTA-chCE7 RIT.

CONCLUSIONS:

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

• Authors: Jürgen Grünberg, Dennis Lindenblatt, Holger Dorrer, Susan Cohrs, Konstantin Zhernosekov, Ulli Köster, Andreas Türler, Eliane Fischer, Roger Schibli
• Journal: European journal of nuclear medicine and molecular imaging (Eur J Nucl Med Mol Imaging) Vol. 41 Issue 10 Pg. 1907-15 (Oct 2014) ISSN: 1619-7089 [Electronic] Germany
• PMID: 24859811 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Neural Cell Adhesion Molecule L1
• Radioisotopes
• Terbium
• Lutetium

Topics

• Animals
• Antibodies, Monoclonal (pharmacokinetics, therapeutic use)
• Cell Line, Tumor
• Female
• Humans
• Lutetium (pharmacokinetics, therapeutic use)
• Mice
• Neural Cell Adhesion Molecule L1 (immunology)
• Ovarian Neoplasms (radiotherapy)
• Radioimmunotherapy
• Radioisotopes (therapeutic use)
• Terbium (pharmacokinetics, therapeutic use)
• Tissue Distribution
• Tomography, Emission-Computed, Single-Photon