Impact of DOTA Conjugation on Pharmacokinetics and Immunoreactivity of [177Lu]Lu-1C1m-Fc, an Anti TEM-1 Fusion Protein Antibody in a TEM-1 Positive Tumor Mouse Model - Archive ouverte HAL Access content directly
Journal Articles Pharmaceutics Year : 2021

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

(1, 2) , (3) , (4) , (1, 2) , (1, 2) , (1, 2) , (1, 2) , (1, 2) , (1, 2) , (1, 2)
1
2
3
4

Abstract

1C1m-Fc, an anti-tumor endothelial marker 1 (TEM-1) scFv-Fc fusion protein antibody, was previously successfully radiolabeled with 177 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 [ 177 Lu]Lu-1C1m-Fc in patients.
Fichier principal
Vignette du fichier
pharmaceutics-13-00096Eq13.pdf (581.41 Ko) Télécharger le fichier
Origin : Publication funded by an institution

Dates and versions

inserm-03109836 , version 1 (14-01-2021)

Identifiers

Cite

Judith Anna Delage, Alain Faivre-Chauvet, Jacques Barbet, Julie Katrin Fierle, Niklaus Schaefer, et al.. Impact of DOTA Conjugation on Pharmacokinetics and Immunoreactivity of [177Lu]Lu-1C1m-Fc, an Anti TEM-1 Fusion Protein Antibody in a TEM-1 Positive Tumor Mouse Model. Pharmaceutics, 2021, 13 (96), Online ahead of print. ⟨10.3390/pharmaceutics13010096⟩. ⟨inserm-03109836⟩
74 View
34 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More