Comparing high LET 227Th- and low LET 177Lu-trastuzumab in mice with HER-2 positive SKBR-3 xenografts

Curr Radiopharm. 2013 Jun 6;6(2):78-86. doi: 10.2174/18744710113069990017.

Abstract

The aim of the present study was to compare the biodistribution, normal tissue toxicity and therapeutic effect of the alpha-particle emitting 227Th-trastuzumab and the beta-particle emitting 177Lu-trastuzumab in mice with HER2- expressing SKBR-3 breast cancer xenografts.

Methods: Biodistributions of the two radioimmunoconjugates were determined at different time points after i.v. injection. Inhibition of tumor growth was measured after single injection of 227Th-trastuzumab (200, 400, 600 or 1000 kBq/kg), 177Lu-trastuzumab (40 or 200 MBq/kg) or saline. The toxicity profiles were compared by measurements of body weight,clinical chemistry and hematological parameters, as well as histological examination of tissue specimens.

Results: 400 kBq/kg of 227Th-trastuzumab and 40 MBq/kg of 177Lu-trastuzumab both resulted in an absorbed radiation dose to tumor of approximately 3 Gy. A significant anti-tumor effect and increased survival were observed at injected dosages of 400-1000 kBq/kg of 227Th-trastuzumab and 200 MBq/kg of 177Lu-trastuzumab as compared to the saline control. When compared at the same therapeutic effect level (100% prolonged growth delay as compared to control) the absorbed radiation dose of 227Th-trastuzumab was 3 times lower than with 177Lu-trastuzumab, indicating a relative biological effect (RBE) of 2.8 for 227Th-trastuzumab. In contrast, when compared at the same temporary decrease of WBC count (50% decrease in number of white blood cells as compared to control), the growth delay was 3 times longer with 177Lutrastuzumab than with 227Th-trastuzumab, which indicates that the therapeutic index was three times higher for 177Lutrastuzumab than for 227Th-trastuzumab.

Conclusion: In this xenograft model the RBE was higher for 227Th-trastuzumab than for 177Lu-trastuzumab, while the therapeutic index of 177Lu-trastuzumab was superior to that of 227Th-trastuzumab.

Publication types

  • Comparative Study

MeSH terms

  • Alpha Particles / therapeutic use
  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacokinetics*
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Beta Particles / therapeutic use
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Female
  • Immunoconjugates / pharmacokinetics*
  • Immunoconjugates / therapeutic use
  • Leukocyte Count
  • Mammary Neoplasms, Experimental / drug therapy
  • Mammary Neoplasms, Experimental / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Organometallic Compounds / pharmacokinetics*
  • Organometallic Compounds / therapeutic use
  • Radioimmunotherapy / methods
  • Radiopharmaceuticals / pharmacokinetics*
  • Radiopharmaceuticals / therapeutic use
  • Receptor, ErbB-2
  • Tissue Distribution
  • Trastuzumab
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal, Humanized
  • Immunoconjugates
  • Organometallic Compounds
  • Radiopharmaceuticals
  • thorium-227DOTA-p-benzyl-trastuzumab
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab