The pharmacokinetics, normal tissue toxicity and anti-tumor effects of [111]In-NLS-trastuzumab in mice bearing HER2-overexpressing breast cancer xenografts

Objectives The objective of this study was to examine the pharmacokinetics and normal tissue toxicity of ¹¹¹In-trastuzumab harboring nuclear localization sequences (NLS), and to assess its efficacy in mice implanted with breast cancer xenografts expressing increasing levels of HER2.

Methods Blood pharmacokinetics of ¹¹¹In-NLS-trastuzumab was measured in non-tumor bearing mice. Toxicity was assessed by histopathologic examination of tissues and by determination of hematology and clinical biochemistry parameters. For radioimmunotherapy, MDA-MB-361 or MDA-MB-231 tumor-bearing mice were injected with a single dose of ¹¹¹In-NLS-trastuzumab. Control groups were administered saline, trastuzumab, ¹¹¹In-trastuzumab, or an ¹¹¹In-labeled non-specific antibody.

Results The blood t_1/2 of ¹¹¹In-NLS-trastuzumab was 23-34 h, and the maximum tolerable dose (MTD) was 9.2-18.5 MBq; doses >18.5 MBq caused decreased leukocyte and platelet counts. There was no evidence of damage to the liver, kidneys or heart. ¹¹¹In-NLS-trastuzumab exhibited strong anti-tumor effects against MDA-MB-361 xenografts, decreasing their growth rate 4-fold compared with that in saline-treated mice. ¹¹¹In-NLS-trastuzumab had no effect on the growth of HER2-negative MDA-MB-231 xenografts.

Conclusions ¹¹¹In-NLS-trastuzumab was well tolerated at the MTD, and exhibited strong anti-tumor effects against HER2-overexpressing MDA-MB-361 xenografts. These studies warrant further exploration of the radiopharmaceutical in the treatment of breast cancer metastases with HER2 overexpression.