Journal
PHARMACEUTICS
Volume 13, Issue 1, Pages -Publisher
MDPI
DOI: 10.3390/pharmaceutics13010096
Keywords
TEM-1; fusion protein antibody; DOTA conjugation; Lu-177 radiolabeling; biodistribution; tumor; liver ratio; theranostic
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Funding
- Alfred and Annemarie von Sick Grant (Zurich, Switzerland)
- Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital (Lausanne, Switzerland)
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The study confirmed the increase of liver uptake and loss of immunoreactivity with high DOTA per 1C1m-Fc ratio, while also identifying one DOTA per 1C1m-Fc as the optimal choice for future translation of [Lu-177]Lu-1C1m-Fc in patients.
1C1m-Fc, an anti-tumor endothelial marker 1 (TEM-1) scFv-Fc fusion protein antibody, was previously successfully radiolabeled with Lu-177. TEM-1 specific tumor uptake was observed together with a non-saturation dependent liver uptake that could be related to the number of dodecane tetraacetic acid (DOTA) chelator per 1C1m-Fc. The objective of this study was to verify this hypothesis and to find the best DOTA per 1C1m-Fc ratio for theranostic applications. 1C1m-Fc was conjugated with six concentrations of DOTA. High-pressure liquid chromatography, mass spectrometry, immunoreactivity assessment, and biodistribution studies in mice bearing TEM-1 positive tumors were performed. A multi-compartment pharmacokinetic model was used to fit the data and a global pharmacokinetic model was developed to illustrate the effect of liver capture and immunoreactivity loss. Organ absorbed doses in mice were calculated from biodistribution results. A loss of immunoreactivity was observed with the highest DOTA per 1C1m-Fc ratio. Except for the spleen and bone, an increase of DOTA per 1C1m-Fc ratio resulted in an increase of liver uptake and absorbed dose and a decrease of uptake in tumor and other tissues. Pharmacokinetic models correlated these results. The number of DOTA per antibody played a determining role in tumor targeting. One DOTA per 1C1m-Fc gave the best pharmacokinetic behavior for a future translation of [Lu-177]Lu-1C1m-Fc in patients.
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