Comparing High LET 227Th- and Low LET 177Lu-trastuzumab in Mice with HER-2 Positive SKBR-3 Xenografts

Nasir      Abbas; Helen      Heyerdahl; Oyvind   S.   Bruland; Ellen   Mengshoel   Brevik; Jostein      Dahle

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.

Keywords: Alpha radiation; beta radiation; 227Th; 177Lu; trastuzumab; radioimmunotherapy; RBE, SKBR-3.

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