Impact of DOTA Conjugation on Pharmacokinetics and Immunoreactivity of [<sup>177</sup>Lu]Lu-1C1m-Fc, an Anti TEM-1 Fusion Protein Antibody in a TEM-1 Positive Tumor Mouse Model
Judith Anna Delage,
Alain Faivre-Chauvet,
Jacques Barbet,
Julie Katrin Fierle,
Niklaus Schaefer,
George Coukos,
David Viertl,
Steven Mark Dunn,
Silvano Gnesin,
John O. Prior
Affiliations
Judith Anna Delage
Radiopharmacy Unit, Department of Pharmacy, Lausanne University Hospital and University of Lausanne, CH-1011 Lausanne, Switzerland
Alain Faivre-Chauvet
CRCINA, INSERM 1232-CNRS ERL 6001, University of Angers, University of Nantes, 44000 Nantes, France
Jacques Barbet
Groupement d’Intérêt Public Arronax, F-44800 Saint-Herblain, France
Julie Katrin Fierle
LAbCore, Ludwig Institute for Cancer Research, Lausanne University Hospital and University of Lausanne, CH-1066 Epalinges, Switzerland
Niklaus Schaefer
Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital and University of Lausanne, CH-1011 Lausanne, Switzerland
George Coukos
Ludwig Institute for Cancer Research and Department of Oncology, Lausanne University Hospital and University of Lausanne, CH-1011 Lausanne, Switzerland
David Viertl
Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital and University of Lausanne, CH-1011 Lausanne, Switzerland
Steven Mark Dunn
LAbCore, Ludwig Institute for Cancer Research, Lausanne University Hospital and University of Lausanne, CH-1066 Epalinges, Switzerland
Silvano Gnesin
Institute of Radiation Physics, Lausanne University Hospital and University of Lausanne, CH-1011 Lausanne, Switzerland
John O. Prior
Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital and University of Lausanne, CH-1011 Lausanne, Switzerland
1C1m-Fc, an anti-tumor endothelial marker 1 (TEM-1) scFv-Fc fusion protein antibody, was previously successfully radiolabeled with 177Lu. 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 [177Lu]Lu-1C1m-Fc in patients.
