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

• Published in: Pharmaceutics Vol. 13; no. 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: Journal Article
• Language: English
• Published: Switzerland MDPI AG 13.01.2021; MDPI
• 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; United States > US; Germany; 177Lu radiolabeling; TEM-1; biodistribution; tumor/liver ratio; fusion protein antibody; DOTA conjugation; theranostic; 177 Lu radiolabeling
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics13010096

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.