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Pretargeting of Carcinoembryonic Antigen–Expressing Tumors with a Biologically Produced Bispecific Anticarcinoembryonic Antigen x Anti-Indium–Labeled Diethylenetriaminepentaacetic Acid Antibody

Authors' Affiliations: Departments of ¹ Nuclear Medicine and ² Urology, Radboud University Nijmegen Medical Center, Nijmegen, ³ Ludwig Institute for Cancer Research, ⁴ University Medical Center Utrecht, Utrecht, the Netherlands, ⁵ Immunomedics, Inc., Morris Plains, and ⁶ Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey

Requests for reprints: Frank G. van Schaijk, Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands. Phone: 31-24-361-9097; Fax: 31-24-361-8942; E-mail: F.vanSchaijk{at}hetnet.nl.

Purpose: The aim of these studies was to develop a pretargeting strategy for CEA-expressing cancers using biologically produced bispecific monoclonal antibodies (bsMAb). The bsMAbs used in this system have affinity for the carcinoembryonic antigen on the one hand, and for indium-labeled diethylenetriaminepentaacetic acid (DTPA), on the other.

Experimental Design: Stable quadroma clones producing bsMAb MN-14xDTIn-1 were isolated. LS174T tumor–bearing mice were injected with 1 to 100 µg of bsMAb followed by 1 to 60 ng of an ¹¹¹In-labeled bivalent peptide [Ac-Phe-Lys(DTPA)-Tyr-Lys(DTPA)-NH₂]. Mice were killed at 24 hours postinjection and the biodistribution of the radiolabel was determined. The biodistribution of diDTPA labeled with four different radionuclides (¹¹¹In, ^99mTc, nonresidualizing ¹²⁵I, and residualizing ¹²⁵I) was determined at various time points postinjection following pretargeting of LS174T tumors with bsMAb MN-14xDTIn-1.

Results: Optimal tumor targeting was observed when tumors were pretargeted with 10 µg of bsMAb MN-14xDTIn-1 and when 6 ng of a radiolabeled peptide was given 72 hours later. The uptake of the four radiolabels in LS174T tumors at 4 hours postinjection was similar. However, at later time points, the ¹¹¹In-label and residualizing ¹²⁵I-label were better retained in the tumor than the nonresidualizing ¹²⁵I label. Although the absolute uptake in the tumor (in terms of percentage of injected dose per gram of tissue) was 5-fold lower than the uptake obtained with directly labeled MN-14, the pretargeting strategy revealed much higher tumor-to-blood ratios due to the rapid clearance of the radiolabel from the circulation as compared with ¹¹¹In-MN-14 (445 ± 90 and 5.3 ± 1.1, respectively, at 72 hours postinjection).

Conclusions: Effective targeting of carcinoembryonic antigen-expressing tumors was achieved with a newly produced bispecific antibody. The ¹¹¹In-labeled L-amino acid peptide and ¹²⁵I-D-amino acid peptide were better retained in the tumor than the ^99mTc- and ¹²⁵I-L-amino acid peptide. Very high tumor-to-blood ratios were obtained due to rapid background clearance.