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.

Détails

Ressource 1Télécharger: Delage_Pharmaceutics-13-00096.pdf (3085.94 [Ko])
Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_28C0A40301A0
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
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.
Périodique
Pharmaceutics
Auteur(s)
Delage J.A., Faivre-Chauvet A., Barbet J., Fierle J.K., Schaefer N., Coukos G., Viertl D., Dunn S.M., Gnesin S., Prior J.O.
ISSN
1999-4923 (Print)
ISSN-L
1999-4923
Statut éditorial
Publié
Date de publication
13/01/2021
Peer-reviewed
Oui
Volume
13
Numéro
1
Pages
96
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Résumé
1C1m-Fc, an anti-tumor endothelial marker 1 (TEM-1) scFv-Fc fusion protein antibody, was previously successfully radiolabeled with <sup>177</sup> 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 [ <sup>177</sup> Lu]Lu-1C1m-Fc in patients.
Mots-clé
177Lu radiolabeling, DOTA conjugation, TEM-1, biodistribution, fusion protein antibody, theranostic, tumor/liver ratio
Pubmed
Web of science
Open Access
Oui
Création de la notice
25/01/2021 13:59
Dernière modification de la notice
08/05/2021 6:32
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