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

Abstract

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.