Title:Comparing High LET 227Th- and Low LET 177Lu-trastuzumab in Mice with HER-2 Positive SKBR-3 Xenografts
Volume: 6
Issue: 2
Author(s): Nasir Abbas, Helen Heyerdahl, Oyvind S. Bruland, Ellen Mengshoel Brevik and Jostein Dahle
Affiliation:
Keywords:
Alpha radiation; beta radiation; 227Th; 177Lu; trastuzumab; radioimmunotherapy; RBE, SKBR-3.
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.
