A bifunctional HBED-derivative for labeling of antibodies with 67Ga, 111In and 59Fe. Comparative biodistribution with 111In-DPTA and 131I-labeled antibodies in mice bearing antibody internalizing and non-internalizing tumors.
To investigate whether bifunctional ligands containing chelating structures other than EDTA and DTPA and metallic radiotracers other than 111In will reduce the non-specific radioactivity uptake in the liver during immunoscintigraphy, we synthetized an isothiocyanato-substituted phenolic polyaminocarboxylic acid (HBED-CI) for labeling of MAbs with 67Ga, 111In and 59Fe. Biodistribution of HBED-CI-labeled MAbs was compared to that of 131I and 111In-DTPA labeled MAbs in nude mice bearing tumors, which differ with regard to intracellular internalization and catabolism of the corresponding MAb-antigen complex. In the liver a continuous radioactivity excretion for 67Ga-HBED-CI-labeled MAbs was observed with kinetics that parallel 131I clearance after administration of 131I-MAbs, while 111In-HBED-CI-labeling led to a constant 111In liver level quite similar to that of 111In-DTPA-MAbs. In tumors, 67Ga-HBED-CI-MAb uptake again paralleled that of 131I-MAbs, showing continuous accumulation in tumor tissues when internalization of the MAb-antigen complex was not involved. A much lower uptake, which peaked between 24 and 48 h, was found in the case of MAb-antigen internalization. 111In of 111In-HBED-CI- and 111In-DTPA-labeled MAbs continuously accumulated in both types of tumors. Compared with 111In-DTPA-MAbs, an improvement in tumor-to-liver ratios, due to the reduced liver radioactivity associated with 67Ga-HBED-CI-labeled MAbs, could only be obtained with non-internalizing tumors. The time course of radioactivity distribution in the liver and in MAb-internalizing tumors after administration of 67Ga-HBED-CI-, 111In-HBED-CI- and 111In-DTPA-labeled MAbs further indicates a dominating influence of the metallic radiotracer rather than the ligand on retention or excretion of radioactivity in MAb-catabolizing tissues.
Schuhmacher
J
J
Institute of Radiology and Pathophysiology, German Cancer Research Center, Heidelberg.
Klivényi
G
G
Hull
W E
WE
Matys
R
R
Hauser
H
H
Kalthoff
H
H
Schmiegel
W H
WH
Maier-Borst
W
W
Matzku
S
S
D000818:Animals; D000911:Antibodies, Monoclonal; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005710:Gallium Radioisotopes; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D007504:Iron Radioisotopes; D007553:Isotope Labeling / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009374:Neoplasms, Experimental / Q000378:metabolism*; D004369:Pentetic Acid / Q000493:pharmacokinetics*
D000911:Antibodies, Monoclonal; D005710:Gallium Radioisotopes; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D007504:Iron Radioisotopes; C037740:N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid; D004369:Pentetic Acid; D004492:Edetic Acid