Experimental α-particle radioimmunotherapy of breast cancer using 227Th-labeled p-benzyl-DOTA-trastuzumab

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.

In Vitro and In Vivo Efficacy of a Novel CD33-Targeted Thorium-227 Conjugate for the Treatment of Acute Myeloid Leukemia

“…Thorium-227 was purified from an actinium-227 generator as described previously (35). Two hundred and fifty micrograms of CD33 antibody-chelator conjugate were mixed with 227 Th-activities, ranging from 0.2 to 2.5 Mbq and incubated at room temperature for 60 minutes.…”

Molecular Targeted α-Particle Therapy for Oncologic Applications

“…For example, 227 Th has a similarly long half-life (18.7 days) compared with 225 Ac, satisfactory radiochemistry properties, and emits five α-particles per nuclear decay. Investigators have shown the potential of using this α-particle-emitter in preclinical studies when conjugated to trastuzumab or rituximab [92–95]. Although issues regarding the daughter elements need to be further investigated, 227 Th can be generated from a long-term generator and may present a continuous source of radioisotope.…”

Comparative studies on the therapeutic benefit of targeted α-particle radiation therapy for the treatment of disseminated intraperitoneal disease

“…39 For labeling, ascorbic acid (25 μL, 150 mg/mL) was added to the 227 Th contained in HNO 3 (25 μL, 0.1M), and the mixture was neutralized to pH 5.5 with ammonium acetate buffer (5 M, 7.5 μL) before the addition of the immunoconjugate (400 – 500 μg) contained in ammonium acetate solution (0.15 M). The mixture was incubated at 42 °C for 2 h. At the end of incubation, saturated DTPA (10 μL) was added to quench the reaction and the products were purified on a disposable PD-10 column eluted with PBS.…”