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Biodistribution and Radiation Dose Estimates for Yttrium- and Iodine-labeled Monoclonal Antibody IgG and Fragments in Nude Mice Bearing Human Colonic Tumor Xenografts¹

Center for Molecular Medicine and Immunology [R. M. S., C. M-H., D. P., D. M. G.], University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, and Temple University Hospital [J. A. S.], Philadelphia, Pennsylvania 19140

An anti-carcinoembryonic antigen murine monoclonal antibody designated NP-4, and its F(ab')₂ and Fab' fragments, were coupled to the 1/1 mixture of 1-isothiocyanato-benzyl-3-methyl- and 1-methyl-3-isothiocyanato-benzyl-diethylenetriaminepentaacetic acid chelate and labeled with ¹¹¹In or ⁸⁸Y. Biodistribution studies in nude mice bearing a human colonic tumor xenograft were performed with these labeled conjugates, and comparisons were made to unconjugated NP-4 IgG and fragments labeled with ¹³¹I. Regardless of the labeling method, higher tumor uptake was found with the intact IgG than with the fragments, but due to faster blood clearance, tumor/blood ratios were higher for the fragments than for the IgG. Tumor uptake for the radiometal-labeled NP-4 was generally higher than the ¹³¹I-labeled NP-4. Tumor/nontumor ratios for the liver, kidney, and spleen were higher for the ¹¹¹In- and ⁸⁸Y-labeled NP-4 IgG than the respective radiometal-labeled fragments, but tumor/nontumor ratios for the ¹³¹I-NP-4 fragments were higher than the ¹³¹I-NP-4 IgG. Radiometal uptake in the kidney was approximately 8 and 150 times higher than the ¹³¹I-NP-4 F(ab')₂ and Fab', respectively, and the clearance of radiometal activity in the kidneys was approximately 10 times slower than the radioiodine. Quantitation of ⁸⁸Y or ¹¹¹In activity in the femur showed 3–5%/g for the IgG and F(ab')₂ and only 1–2%/g for the Fab'. The amount of radioactivity in the femur remained constant over time, and between 60 and 100% of the ⁸⁸Y activity remained after flushing the core of the femur with saline, whereas 50–70% of the ¹¹¹In and only 25–30% of the ¹³¹I activity remained after washing. Radiation dose estimates derived from these studies suggest that at the maximal tolerated dose ¹³¹I-NP-4 IgG would deliver 5.9 times the dose to the tumor as ⁹⁰Y-labeled NP-4 IgG. ⁹⁰Y-labeled fragments would not be useful due to higher doses to the kidneys than to the tumor. However, with ¹³¹I-labeled IgG and fragments there is greater flexibility to permit tumoricidal doses without excessive toxicity to the normal tissues.

¹ Supported in part by USPHS Grants CA 39841 and BRSG RR-05903 from the NIH. Presented in part at the Second Conference on Radioimmunodetection and Radioimmunotherapy of Cancer, Princeton, NJ, 1988.

² To whom requests for reprints should be addressed, at Center for Molecular Medicine and Immunology, 1 Bruce Street, Newark, NJ 07103.

Received 8/18/89. Revised 1/ 8/90.

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