Comparison of the tolerability of terbium-161 and lutetium-177 in combination with somatostatin analogues in the preclinical setting
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Purpose
[ 177 Lu]Lu-DOTATATE, a somatostatin receptor (SSTR) agonist, is clinically established for the treatment of metastasized neuroendocrine neoplasms, while the SSTR antagonist [ 177 Lu]Lu- DOTA-LM3 has not been routinely used in clinics yet. In studies performed with tumor-bearing mice, terbium-161 showed better therapeutic efficacy than lutetium-177 particularly in combination with DOTA-LM3. The present study aimed at investigating adverse events in mice after treatment with 161 Tb- and 177 Lu-based DOTA-LM3 and DOTATATE.
Methods
Dosimetry calculations were performed based on biodistribution data of the radiopeptides in immunocompetent mice. Treatment effects on blood cell counts were assessed on Days 10, 28 and 56 after application of [ 161 Tb]Tb-DOTA-LM3 or [ 161 Tb]Tb-DOTATATE applied at 20 MBq per mouse. In an additional study, these radiopeptides were applied at 100 MBq per mouse and the effects compared to those observed after application of the 177 Lu-labeled counterparts. Bone marrow smears, blood plasma parameters and organ histology were assessed on Day 56 which was defined as the study end.
Results
The absorbed organ dose was commonly higher for the SSTR antagonist than for the SSTR agonist and application of terbium-161 delivered more dose than lutetium-177. Application of 20 MBq [ 161 Tb]Tb-DOTA-LM3 and [ 161 Tb]Tb-DOTATATE was well tolerated without major hematological changes observed. The injection of 100 MBq of these radiopeptides and the 177 Lu- labeled counterparts affected the blood cell counts, but mostly only transiently. Irrespective of the employed radionuclide, the lymphocytes were 40-50% lower in treated mice compared to the untreated controls on Day 10 ( p <0.05), while at the same timepoint, erythrocyte counts dropped by ∼10% but only after application of the antagonist ( p <0.05). Similarly, more pronounced decrease in thrombocyte counts was measured in mice administered with the antagonist than in those treated with the agonist on Day 10. All blood cell counts recovered by Day 56. Histological analyses revealed minimal abnormalities in the kidneys, liver and spleen of treated mice. No correlation was observed between the organ dose and frequency of the occurrence of abnormalities.
Conclusion
Hematologic changes were more pronounced in mice treated with the SSTR antagonist than in those treated with the agonist. The increased absorbed dose following the application of terbium-161 instead of lutetium-177 did not result in more critical adverse effects. The observed hematological changes recovered over time, hence, the application of [ 161 Tb]Tb-DOTA-LM3 and [ 161 Tb]Tb-DOTATATE should be safe at activity levels that are recommended for the 177 Lu-based analogues.
