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Cellular Processing of Copper-67-labeled Monoclonal Antibody chCE7 by Human Neuroblastoma Cells

Radiopharmacy Division, Paul Scherrer Institute, CH-5232 Villigen-PSI [I. N-H., R. S., K. Z., P. A. S.] University Hospital, Department of Nuclear Medicine, CH-4031 Basel [H. R. M.]; and Central Laboratory of the Blood Transfusion Service of the Swiss Red Cross, CH-3014 Bern [H. P. A., J-J. M.], Switzerland

Monoclonal antibody chCE7, an internalizing neuroblastoma-specific chimeric antibody, was derivatized with the macrocyclic amine ligand 4-[(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl] benzoic acid tetrahydrochloride and labeled with the potential therapeutic nuclide ⁶⁷Cu. Using pulse labeling and an acid elution endocytosis assay, ⁶⁷Cu-chCE7 was found to be internalized into human neuroblastoma (SKN-AS) cells at a similar rate and to a similar extent as ¹²⁵I-labeled chCE7. Uptake of ⁶⁷Cu-chCE7 and ¹²⁵I-chCE7 into the acid stable (intracellular) pool proceeded with similar kinetics during the first 2 h of internalization. However, in contrast to ¹²⁵I-chCE7-loaded cells, at later times intracellular radioactivity kept increasing in the case of ⁶⁷Cu-chCE7-loaded cells. It was shown that this effect is due to the intracellular accumulation of a low M_r degradation product consisting of the ⁶⁷Cu-4[(1,4,8,11-tetraazacy-clotetradec-1-yl)-methyl] benzoic acid complex, possibly with a short peptide attached to it. Degradation of both ¹²⁵I-chCE7 and ⁶⁷Cu-chCE7 was inhibited by chloroquine, indicating endosomal or lysosomal degradation, and a 43,000 M_r fragment was found to be the major high M_r degradation product in both cases. Although at times between 4 and 6 h of internalization intracellular breakdown of ⁶⁷Cu-chCE7 was found to proceed more slowly, the major difference between the two immunoconjugates resides in the prolonged cellular retention of the ⁶⁷Cu-chCE7 metabolite.

¹ To whom requests for reprints should be addressed.

Received 7/18/94. Accepted 10/31/94.

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