Search

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.

Introduction: We assessed the suitability of the radiolanthanide (155)Tb (t1/2=5.32 days, Eγ=87 keV (32%), 105keV (25%)) in combination with variable tumor targeted biomolecules using preclinical SPECT imaging., Methods: (155)Tb was produced at ISOLDE (CERN, Geneva, Switzerland) by high-energy (~1.4 GeV) proton irradiation of a tantalum target followed by ionization and on-line mass separation. (155)Tb was separated from isobar and pseudo-isobar impurities by cation exchange chromatography. Four tumor targeting molecules - a somatostatin analog (DOTATATE), a minigastrin analog (MD), a folate derivative (cm09) and an anti-L1-CAM antibody (chCE7) - were radiolabeled with (155)Tb. Imaging studies were performed in nude mice bearing AR42J, cholecystokinin-2 receptor expressing A431, KB, IGROV-1 and SKOV-3ip tumor xenografts using a dedicated small-animal SPECT/CT scanner., Results: The total yield of the two-step separation process of (155)Tb was 86%. (155)Tb was obtained in a physiological l-lactate solution suitable for direct labeling processes. The (155)Tb-labeled tumor targeted biomolecules were obtained at a reasonable specific activity and high purity (>95%). (155)Tb gave high quality, high resolution tomographic images. SPECT/CT experiments allowed excellent visualization of AR42J and CCK-2 receptor-expressing A431 tumors xenografts in mice after injection of (155)Tb-DOTATATE and (155)Tb-MD, respectively. The relatively long physical half-life of (155)Tb matched in particular the biological half-lives of (155)Tb-cm09 and (155)Tb-DTPA-chCE7 allowing SPECT imaging of KB tumors, IGROV-1 and SKOV-3ip tumors even several days after administration., Conclusions: The radiolanthanide (155)Tb may be of particular interest for low-dose SPECT prior to therapy with a therapeutic match such as the β(-)-emitting radiolanthanides (177)Lu, (161)Tb, (166)Ho, and the pseudo-radiolanthanide (90)Y., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Terbium-149 is among the most interesting therapeutic nuclides for medical applications. It decays by emission of short-range α-particles (Eα = 3.967 MeV) with a half-life of 4.12 h. The goal of this study was to investigate the anticancer efficacy of a 149Tb-labeled DOTA-folate conjugate (cm09) using folate receptor (FR)-positive cancer cells in vitro and in tumor-bearing mice. 149Tb was produced at the ISOLDE facility at CERN. Radiolabeling of cm09 with purified 149Tb resulted in a specific activity of ~1.2 MBq/nmol. In vitro assays performed with 149Tb-cm09 revealed a reduced KB cell viability in a FR-specific and activity concentration-dependent manner. Tumor-bearing mice were injected with saline only (group A) or with 149Tb-cm09 (group B: 2.2 MBq; group C: 3.0 MBq). A significant tumor growth delay was found in treated animals resulting in an increased average survival time of mice which received 149Tb-cm09 (B: 30.5 d; C: 43 d) compared to untreated controls (A: 21 d). Analysis of blood parameters revealed no signs of acute toxicity to the kidneys or liver in treated mice over the time of investigation. These results demonstrated the potential of folate-based α-radionuclide therapy in tumor-bearing mice.

Purpose: The radiolanthanide (161)Tb (T 1/2 = 6.90 days, Eβ(-) av = 154 keV) was recently proposed as a potential alternative to (177)Lu (T 1/2 = 6.71 days, Eβ(-) av = 134 keV) due to similar physical decay characteristics but additional conversion and Auger electrons that may enhance the therapeutic efficacy. The goal of this study was to compare (161)Tb and (177)Lu in vitro and in vivo using a tumour-targeted DOTA-folate conjugate (cm09)., Methods: (161)Tb-cm09 and (177)Lu-cm09 were tested in vitro on folate receptor (FR)-positive KB and IGROV-1 cancer cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay. In vivo (161)Tb-cm09 and (177)Lu-cm09 (10 MBq, 0.5 nmol) were investigated in two different tumour mouse models with regard to the biodistribution, the possibility for single photon emission computed tomography (SPECT) imaging and the antitumour efficacy. Potentially undesired side effects were monitored over 6 months by determination of plasma parameters and examination of kidney function with quantitative SPECT using (99m)Tc-dimercaptosuccinic acid (DMSA)., Results: To obtain half-maximal inhibition of tumour cell viability a 4.5-fold (KB) and 1.7-fold (IGROV-1) lower radioactivity concentration was required for (161)Tb-cm09 (IC50 ~0.014 MBq/ml and ~2.53 MBq/ml) compared to (177)Lu-cm09 (IC50 ~0.063 MBq/ml and ~4.52 MBq/ml). SPECT imaging visualized tumours of mice with both radioconjugates. However, in therapy studies (161)Tb-cm09 reduced tumour growth more efficiently than (177)Lu-cm09. These findings were in line with the higher absorbed tumour dose for (161)Tb-cm09 (3.3 Gy/MBq) compared to (177)Lu-cm09 (2.4 Gy/MBq). None of the monitored parameters indicated signs of impaired kidney function over the whole time period of investigation after injection of the radiofolates., Conclusion: Compared to (177)Lu-cm09 we demonstrated equal imaging features for (161)Tb-cm09 but an increased therapeutic efficacy for (161)Tb-cm09 in both tumour cell lines in vitro and in vivo. Further preclinical studies using other tumour-targeting radioconjugates are clearly necessary to draw final conclusions about the future clinical perspectives of (161)Tb.

Unlabelled: Terbium offers 4 clinically interesting radioisotopes with complementary physical decay characteristics: (149)Tb, (152)Tb, (155)Tb, and (161)Tb. The identical chemical characteristics of these radioisotopes allow the preparation of radiopharmaceuticals with identical pharmacokinetics useful for PET ((152)Tb) and SPECT diagnosis ((155)Tb) and for α- ((149)Tb) and β(-)-particle ((161)Tb) therapy. The goal of this proof-of-concept study was to produce all 4 terbium radioisotopes and assess their diagnostic and therapeutic features in vivo when labeled with a folate-based targeting agent., Methods: (161)Tb was produced by irradiation of (160)Gd targets with neutrons at Paul Scherrer Institute or Institut Laue-Langevin. After neutron capture, the short-lived (161)Gd decays to (161)Tb. (149)Tb, (152)Tb, and (155)Tb were produced by proton-induced spallation of tantalum targets, followed by an online isotope separation process at ISOLDE/CERN. The isotopes were purified by means of cation exchange chromatography. For the in vivo studies, we used the DOTA-folate conjugate cm09, which binds to folate receptor (FR)-positive KB tumor cells. Therapy experiments with (149)Tb-cm09 and (161)Tb-cm09 were performed in KB tumor-bearing nude mice. Diagnostic PET/CT ((152)Tb-cm09) and SPECT/CT ((155)Tb-cm09 and (161)Tb-cm09) studies were performed in the same tumor mouse model., Results: Carrier-free terbium radioisotopes were obtained after purification, with activities ranging from approximately 6 MBq (for (149)Tb) to approximately 15 MBq (for (161)Tb). The radiolabeling of cm09 was achieved in a greater than 96% radiochemical yield for all terbium radioisotopes. Biodistribution studies showed high and specific uptake in FR-positive tumor xenografts (23.8% ± 2.5% at 4 h after injection, 22.0% ± 4.4% at 24 h after injection, and 18.4% ± 1.8% at 48 h after injection). Excellent tumor-to-background ratios at 24 h after injection (tumor to blood, ≈ 15; tumor to liver, ≈ 5.9; and tumor to kidney, ≈ 0.8) allowed the visualization of tumors in mice using PET ((152)Tb-cm09) and SPECT ((155)Tb-cm09 and (161)Tb-cm09). Compared with no therapy, α- ((149)Tb-cm09) and β(-)-particle therapy ((161)Tb-cm09) resulted in a marked delay in tumor growth or even complete remission (33% for (149)Tb-cm09 and 80% for (161)Tb-cm09) and a significantly increased survival., Conclusion: For the first time, to our knowledge, 4 terbium radionuclides have been tested in parallel with tumor-bearing mice using an FR targeting agent. Along with excellent tumor visualization enabled by (152)Tb PET and (155)Tb SPECT, we demonstrated the therapeutic efficacy of the α-emitter (149)Tb and β(-)-emitter (161)Tb.