Impact of DOTA Conjugation on Pharmacokinetics and Immunoreactivity of [ 177 Lu]Lu-1C1m-Fc, an Anti TEM-1 Fusion Protein Antibody in a TEM-1 Positive Tumor Mouse Model

1C1m-Fc, an anti-tumor endothelial marker 1 (TEM-1) scFv-Fc fusion protein antibody, was previously successfully radiolabeled with Lu. 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...

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Bibliographic Details
Published in:Pharmaceutics 2021-01, Vol.13 (1), p.96
Main Authors: Delage, Judith Anna, Faivre-Chauvet, Alain, Barbet, Jacques, Fierle, Julie Katrin, Schaefer, Niklaus, Coukos, George, Viertl, David, Dunn, Steven Mark, Gnesin, Silvano, Prior, John O
Format: Article
Language:English
Subjects:
177Lu radiolabeling
Antibodies
Antigens
biodistribution
Cancer
Cell adhesion & migration
Chromatography
DOTA conjugation
fusion protein antibody
Laboratory animals
Life Sciences
Mass spectrometry
Pharmacokinetics
Proteins
Ratios
Scientific imaging
TEM-1
tumor/liver ratio
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Summary:1C1m-Fc, an anti-tumor endothelial marker 1 (TEM-1) scFv-Fc fusion protein antibody, was previously successfully radiolabeled with Lu. 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]Lu-1C1m-Fc in patients.
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics13010096