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Radioimmunotherapy of Human Colorectal Carcinoma Xenografts Using ⁹⁰Y-labeled Monoclonal Antibody CO17-1A Prepared by Two Bifunctional Chelate Techniques¹

Medical Sciences Division, Oak Ridge Associated Universities, Oak Ridge, Tennessee 37831-0117 [Y-C. C. L., L. C. W., T. T. H. S., B. L., J. E. C., E. C. H.], and The Wistar Institute, Philadelphia, Pennsylvania 19104-4268 [Z. S.]

Monoclonal antibody CO17-1A, which has specificity for colorectal and pancreatic carcinomas, was radiolabeled with the pure ß emitter, ⁹⁰Y, by either the cyclic diethylenetriaminepentaacetic acid (DTPA) anhydride technique or by a site-specific bifunctional chelate technique using 1-(p-aminobenzyl)DTPA (p-NH₂-Bz-DTPA). Female nude mice bearing SW 948 human colorectal carcinoma xenografts were given injections i.v. of ⁹⁰Y-labeled monoclonal antibody CO17-1A at dosages of 100, 150, and 200 µCi/25 g body weight. Unlabeled CO17-1A (100 µg/25 g body weight) was coadministered.

In animals receiving ⁹⁰Y-CO17-1A prepared by the cyclic DTPA anhydride technique, tumor volume was unchanged from base line at a dose of 200 µCi/25 g. As the dosage of ⁹⁰Y-CO17-1A increased, the rate of tumor growth decreased, but all experimental animals in this group died between 14 and 21 days. In contrast, CO17-1A radiolabeled with ⁹⁰Y by the site-specific p-NH₂-Bz-DTPA bifunctional chelate technique produced a maximum tumor volume reduction of 87% in the 200 µCi/25 g group by day 15, and no deaths were noted in any of the ⁹⁰Y-CO17-1A-treated groups for 71 days. Dose-response curves again showed increased tumoricidal effects with increased dosages of ⁹⁰Y-CO17-1A.

S-2-(3-Aminopropylamino)ethylphosphorothioic acid, commonly known as WR-2721, is a radioprotective drug which has been shown to protect against bone marrow depression in irradiated humans. No protection was observed when WR-2721 was used as an adjunct to treatment with ⁹⁰Y-CO17-1A prepared by either the cyclic DTPA anhydride technique or the site-specific p-NH₂-Bz-DTPA technique. When the site-specific p-NH₂-Bz-DTPA technique was used, the reduction in WBC and hemoglobin levels correlated with increasing bone marrow toxicity at higher doses. We conclude that CO17-1A labeled with ⁹⁰Y via the site-specific p-NH₂-Bz-DTPA technique has potential for radioimmunotherapy of human colorectal carcinoma.

¹ This article is based on work supported by Contract DE-AC05-76OR00033 between the United States Department of Energy and Oak Ridge Associated Universities (ORAU), NIH Grant 5-RO1-CA39706-05.

² To whom requests for reprints should be addressed, at Medical Sciences Division, Oak Ridge Associated University, Oak Ridge, TN 37831-0117.

Received 11/17/89. Revised 4/16/90.

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