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. 2011 Aug 24;1(1):18.
doi: 10.1186/2191-219X-1-18.

Experimental α-Particle Radioimmunotherapy of Breast Cancer Using 227Th-labeled p-benzyl-DOTA-trastuzumab

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Free PMC article

Experimental α-Particle Radioimmunotherapy of Breast Cancer Using 227Th-labeled p-benzyl-DOTA-trastuzumab

Nasir Abbas et al. EJNMMI Res. .
Free PMC article

Abstract

Background: The aim of the present study was to explore the biodistribution, normal tissue toxicity, and therapeutic efficacy of the internalizing low-dose rate alpha-particle-emitting radioimmunoconjugate 227Th-trastuzumab in mice with HER2-expressing breast cancer xenografts.

Methods: Biodistribution of 227Th-trastuzumab and 227Th-rituximab in nude mice bearing SKBR-3 xenografts were determined at different time points after injection. Tumor growth was measured after administration of 227Th-trastuzumab, 227Th-rituximab, cold trastuzumab, and saline. The toxicity of 227Th-trastuzumab was evaluated by measurements of body weight, blood cell, and clinical chemistry parameters, as well as histological examination of tissue specimens.

Results: The tumor uptake reached peak levels of 34% ID/g (4.6 kBq/g) 3 days after injection of 400 kBq/kg of 227Th-trastuzumab. The absorbed radiation dose to tumor was 2.9 Gy, while it was 2.4 Gy to femur due to uptake of the daughter nuclide 223Ra in bone; the latter already explored in clinical phases I and II trials without serious toxicity. A significant dose-dependent antitumor effect was observed for dosages of 200, 400, and 600 kBq/kg of 227Th-trastuzumab but no effect of 400 and 600 kBq/kg 227Th-rituximab (non-tumor binding). No serious delayed bone marrow or normal organ toxicity was observed, but there was a statistical significant reduction in blood cell parameters for the highest-dose group of 227Th-trastuzumab treatment.

Conclusion: Internalizing 227Th-trastuzumab therapy was well tolerated and resulted in a dose-dependent inhibition of breast cancer xenograft growth. These results warrant further preclinical studies aiming at a clinical trial in breast cancer patients with metastases to bone.

Figures

Figure 1
Figure 1
Biodistribution of 227Th-conjugates and 223Ra in mice with SKBR-3 xenografts. Biodistribution profile of 227Th-trastuzumab (a) and daughter nuclide 223 Ra (c) after administration of 227Th-trastuzumab, and biodistribution of 227Th-rituximab (b) and daughter nuclide 223 Ra (d) after administration 227Th-rituximab, in mice bearing SKBR-3 xenografts. The measured 227Th activities were normalized to an injection of 400 kBq/kg bodyweight. Values are mean ± SD. N = 6 for each time point except at day 3, where N = 5.
Figure 2
Figure 2
Absorbed radiation doses to normal tissues and tumor xenografts. Absorbed radiation dose in tumor and normal organs of mice injected with 227Th-trastuzumab (a) or 227Th-rituximab (b). Cumulated activities were calculated from biodistribution curves and multiplied with the mean energy of α-particles from 227Th, 223Ra, and daughters. Biodistribution data of 227Th-trastuzumab and 227 Th-rituximab were normalized to 400 kBq/kg bodyweight.
Figure 3
Figure 3
Effects of 227Th-based RIT on growth of individual SKBR-3 tumor xenografts. Individual tumor growth after treatment with NaCl (a); 20, 100, and 250 μg cold trastuzumab (b); 227Th-rituximab at dosage of 400 and 600 kBq/kg (c); 200 kBq/kg (d); 400 kBq/kg (e) and 600 kBq/kg (f) of 227Th-trastuzumab. N = 9 to 19.
Figure 4
Figure 4
Effects of 227Th-based RIT on survival of mice with SKBR-3 tumor xenografts. Survival of mice after intravenous injection of NaCl, 20,100, and 250 μg cold trastuzumab, and 200, 400, and 600 kBq/kg 227Th-trastuzumab (a), or 400 and 600 kBq/kg 227Th-rituximab (b).
Figure 5
Figure 5
Blood cell counts after 227Th-trastuzumab therapy. Assessment of bone marrow toxicity estimated by white blood cell counts (a) and platelet counts (b) as a function of time after administration of NaCl, cold trastuzumab, and 200, 400, and 600 kBq/kg of 227Th-trastuzumab. Line graphs shows means of each treatment group.
Figure 6
Figure 6
Assessment of liver and kidney functions after 227Th-trastuzumab therapy. Measurement of urea (a), ALT (b), ALP (c), and AST (d) concentration in blood of mice with time after administration of NaCl, cold trastuzumab, 200, 400, and 600 kBq/kg of 227Th-trastuzumab.
Figure 7
Figure 7
Histological examination of bone marrow after 227Th-trastuzumab therapy. Histological microscopy images of bone marrow in femur of mice after administration of NaCl (a) or 600 kBq/kg 227Th-trastuzumab (b) showing islands of haemopoetic cells composed of blood cells in various stages of maturation (arrow a), a great population of nucleated blood cells (arrow b), and blood vessels (arrow c).
Figure 8
Figure 8
Autoradiography images after 227Th-trastuzumab therapy. Autoradiography images of the radioactivity distribution in 5-μm-thick frozen tissue sections from four different SKBR-3 human tumor xenografts in athymic nude mice following injection of 600 kBq/kg of 227Th-trastuzumab. Tumors in mages (a) and (b) were resected 4 days post injection, while (c) and (d) were removed 8 days post injection. N = 4.

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