Targeted therapy of breast cancer with low dose rate alpha-particle-emitting 227Th-trastuzumab

Objectives The purpose of this study was to explore the potential of a low dose rate alpha-particle emitting radioimmunoconjugate; ²²⁷Th-trastuzumab (Herceptin), as a novel treatment of metastatic breast cancer.

Methods Two HER2-expressing breast cancer cell lines, BT-474 and SKBR-3, as well as the HER2-negative cell line MCF-7 were incubated with 0-20 kBq/ml of ²²⁷Th-Herceptin and cell bound activity was measured. Cell survival, growth rate and induction of apoptosis were studied. Mice with subcutaneous SKBR-3 tumor xenografts were treated with 200, 400 and 600 kBq/kg of intravenously injected ²²⁷Th-trastuzumab, non-specific ²²⁷Th-rituximab or cold trastuzumab and the growth of the tumors were followed for up to 4 months. The toxicity of the treatment was evaluated by monitoring blood cell counts.

Results The therapeutic effect on cells in culture depended both on differences in growth rate of the cell lines and on differences in binding of ²²⁷Th-trastuzumab. High in vitro growth-rate correlated with weaker therapeutic effect. Single injection of 200 kBq/kg ²²⁷Th-trastuzumab resulted in a growth delay of 54 or 51 days in growing to 500 mm³ as compared with untreated mice or mice treated with cold Herceptin, respectively. There was a dosage dependent increase in therapeutic effect. Hematological toxicity to blood was modest and temporary.

Conclusions This study shows a therapeutic effect of low dose-rate alpha-particle radioimmunotherapy against breast cancer cells and warrants further in vivo studies with repeated dosing.

Research Support This work was supported by The Norwegian Research Council, The Norwegian Cancer Society, Helse SørØst and Algeta ASA.