Development of Targeted lmmuno-PET Imaging Agents for Breast Cancer Brain Metastasis (BCBM)

摘要

Transforming growth factor-beta (TGF-beta) is a cytokine that acts as a tumor promoter in breast cancer brain metastasis. It is tumor promoting by activating immunosuppression and enhancing breast cancer cells' ability to metastasize. Since TGF-beta is overexpressed and plays a role in breast cancer brain metastasis progression, it can be exploited as a biomarker for immuno-PET imaging through radiolabelling of fresolimumab, a monoclonal antibody (mAb) that inhibits all active isoforms of TGF-beta. Methods: An immuno-PET imaging agent was synthesized in the form of an 89Zr-DFO-fresolimumab targeting vector to investigate a breast cancer brain adapted mouse model. The number of DFO chelate sites per antibody were determined. Additionally, immunoreactivity experiments were done to ensure that the integrity of the antibody was maintained after radiolabeling. Lastly, the imaging probe was tested in-vivo in a mouse model to determine characteristics of the probe's distribution. Results: DFO was chelated to the antibody fresolimumab. The number of DFOs per fresolimumab was determined to be 3.8 +/- 0.8. The imaging probe, 89 Zr-DFO-fresolimumab was prepared with high radiochemical purity (> 95%) and with good radiochemical yield (∼70%). Immunoreactivity was maintained, the radiolabeling process did not affect the properties of fresolimumab's ability to bind to TGF-beta. muPET/CT imaging was done to determine the distribution of the radiotracer. The targeting vector was able to cross the blood brain barrier in a specialized mouse model and be localized with adequate signal in the brain tumor. Conclusion: Results from this study showed the targeting vector's ability to cross the compromised blood brain barrier and enough signal was seen to characterize the brain tumor. The tumor progression was imaged with high quality using diffusion weighted MRI. This study can be used to provide the baseline untreated model to be compared against mice with brain tumors after receiving treatment in future studies. These initial studies for 89Zr-DFO-Fresolimumab are promising however, further work is needed to assess the tracer characteristics.