Abstract
BackgroundThe 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.MethodsBiodistribution 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.ResultsThe 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.ConclusionInternalizing 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.
Highlights
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
There was a large difference between the amount of activity in tumor and in normal organs for 227Th-trastuzumab
The uptake of non-tumor binding 227Th-rituximab (Figure 1b) in tumor was significantly lower than the uptake of 227Th-trastuzumab (Figure 1a)
Summary
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. The human epidermal growth factor receptor-2 (HER-2/neu) is a transmembrane receptor tyrosine kinase that is over-expressed in 25% to 30% of metastatic breast cancers and associated with more aggressive disease [2]. No alpha-emitting radioimmunoconjugate (RIC) has reached phase III clinical trial yet due to poor physical or chemical characteristics, supply limitations, and high production costs for the most promising alpha emitters [4]. We have suggested 227Th as a novel radionuclide for alpha-particle radioimmunotherapy (RIT), as this radionuclide can be produced in clinically relevant amounts from b-decay of the long-term generator 227Ac [5,6]. The yield of 227Ac after purification is relatively high and 226Ra is highly available, making the process cost efficient. 227Ac has a half-life of 21.8 years and would serve as a generator nuclide for 227Th production for decades [7]
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