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Pretargeting with Labeled Bivalent Peptides Allowing the Use of Four Radionuclides

¹¹¹In, ¹³¹I, ^99mTc, and ¹⁸⁸Re¹

University Medical Center Nijmegen, Nijmegen, the Netherlands [F. G. v. S., E. O., A. C. S., W. J. G. O., F. H. M. C., O. C. B.], and Immunomedics, Inc., Morris Plains, New Jersey 07950 [W. J. M., G. L. G., D. M. G.]

Purpose: The therapeutic effect of directly labeled antibodies in solid tumors is limited, mainly due to the relatively low uptake of the radiolabeled antibody in tumors as compared with their blood level. In previous studies, we have shown that renal cell carcinoma (RCC) can be targeted very effectively with the ¹¹¹In-labeled bivalent peptide di-diethylenetriamminepentaacetic acid diDTPA-FKYK, after pretargeting the tumor with a bispecific antibody. In this study, we further developed this pretargeting approach for radioimmunotherapy of renal cell cancer.

Experimental Design: Pretargeting with the biologically produced anti-RCC x anti-DTPA bispecific monoclonal antibody (bsMAb G250xDTIn1) was tested in mice with SK-RC-52 RCC tumors. Tumors were pretargeted with 15 µg of bispecific monoclonal antibody G250xDTIn1, and 24 h later, mice received 6 ng of the radiolabeled bivalent peptide. Two different peptides were used: (a) diDTPA-FKYK labeled with ¹¹¹In or ¹³¹I; and (b) thiosemicarbonylglyoxylcysteinyl-diDTPA(In)-KYKK labeled with ^99mTc or ¹⁸⁸Re. Mice were killed 6, 24, 48, and 72 h postinjection (p.i.), and biodistribution of the radiolabel was determined.

Results: The ¹¹¹In-labeled peptide showed excellent tumor uptake [42.6 ± 7.3% injected dose/gram (ID/g) at 6 h p.i. and 25.6 ± 7.7% ID/g at 72 h p.i.] and tumor:blood ratios (700 at 72 h p.i.). The specific tumor targeting of ¹⁸⁸Re- and ^99mTc-labeled peptides was similar (20–25% ID/g, 6 h p.i.). However, the uptake and the retention in the tumor of the ^99mTc- and ¹⁸⁸Re-labeled peptide were significantly lower than those of the ¹¹¹In-labeled peptide. Tumor uptake of the ¹³¹I-labeled peptide was significantly lower as compared with the other three radiolabeled peptides; furthermore, an almost complete washout of the radiolabel from the tumor over time was observed (14.5 ± 4.9% ID/g at 6 h p.i. and 0.33 ± 0.15% ID/g at 72 h p.i.).

Conclusions: Using a newly developed bivalent peptide, this pretargeting approach can now be used for targeting with the matched pair ¹⁸⁸Re and ^99mTc.

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				F. G. van Schaijk, E. Oosterwijk, A. C. Soede, M. Broekema, C. Frielink, W. J. McBride, D. M. Goldenberg, F. H.M. Corstens, and O. C. Boerman Pretargeting of Carcinoembryonic Antigen-Expressing Tumors with a Biologically Produced Bispecific Anticarcinoembryonic Antigen x Anti-Indium-Labeled Diethylenetriaminepentaacetic Acid Antibody Clin. Cancer Res., October 1, 2005; 11(19): 7130s - 7136s. [Abstract] [Full Text] [PDF]