title: Anti-L1CAM radioimmunotherapy is more effective with the radiolanthanide terbium-161 compared to lutetium-177 in an ovarian cancer model.
abstract: OBJECTIVE
  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.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232, Villigen, Switzerland.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Grünberg
authors.forename: Dennis
authors.initials: D
authors.lastname: Lindenblatt
authors.forename: Holger
authors.initials: H
authors.lastname: Dorrer
authors.forename: Susan
authors.initials: S
authors.lastname: Cohrs
authors.forename: Konstantin
authors.initials: K
authors.lastname: Zhernosekov
authors.forename: Ulli
authors.initials: U
authors.lastname: Köster
authors.forename: Andreas
authors.initials: A
authors.lastname: Türler
authors.forename: Eliane
authors.initials: E
authors.lastname: Fischer
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008187:Lutetium / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D039842:Neural Cell Adhesion Molecule L1 / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000532:radiotherapy*; D016499:Radioimmunotherapy; D011868:Radioisotopes / Q000627:therapeutic use*; D013725:Terbium / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D000911:Antibodies, Monoclonal; D039842:Neural Cell Adhesion Molecule L1; D011868:Radioisotopes; D013725:Terbium; D008187:Lutetium