Enhancing HER2-Positive Breast Cancer Therapy with 225Ac-Labeled Trastuzumab in NRG Mice: A Radioimmunotherapy Approach

The study aimed to enhance the therapeutic index of HER2-positive breast cancer treatment in mice by examining the efficacy and toxicity of trastuzumab conjugated with the α-particle emitter, Ac-225. The research involved administering different forms of trastuzumab modified with DOTA to mice and assessing their impact on body weight, complete blood cell counts, and liver and kidney function. The tumor growth index and survival rates were also measured.

The results indicated that the trastuzumab F(ab')2 and Fab fragments, when associated with Ac-225, did not affect the complete blood cell counts or liver and kidney function, unlike the IgG form which caused a significant decrease in white blood cells, platelets, red blood cells, and hematocrit. Tumor growth was inhibited by all forms of trastuzumab modified with Ac-225, with the F(ab')2 fragment showing the most promising results in terms of tumor growth inhibition and increased survival rate. The median survival time for mice treated with Ac-225-DOTA-trastuzumab F(ab')2 was notably higher compared to the other forms and the control groups.

Furthermore, the tumor uptake of Ac-225-DOTA-trastuzumab IgG and F(ab')2 was higher than that of the Fab fragment, and the elimination from the bloodstream was slowest for the IgG form. The spleen and liver uptake were highest for the IgG form, while the kidney uptake was highest for the Fab form.

In conclusion, Ac-225-DOTA-trastuzumab F(ab')2 demonstrated the most favorable therapeutic index by effectively inhibiting tumor growth and extending survival with minimal toxicity, suggesting its potential as a superior treatment option for HER2-positive breast cancer compared to standard trastuzumab therapy.