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Preclinical Assessments of ⁹⁰Y-labeled C110 Anti-Carcinoembryonic Antigen Immunotoxin: A Therapeutic Immunoconjugate for Human Colon Cancer¹

Department of Nuclear Medicine [T. I., A. B. B.] and Division of Oncology, Department of Medicine [H. Q., J. A. C., T. W. G.], University of Massachusetts Medical Center, Worcester, Massachusetts 01655, and Abbott Laboratories, Abbott Park, Illinois 60064 [D. K. J.]

We have synthesized ⁹⁰Y-labeled immunotoxin (IT) containing ricin A chain and C110 anti-carcinoembryonic antigen monoclonal antibody (MAb) to produce a therapeutic immunoconjugate for human colon cancer. The C110 IT was labeled with ⁹⁰Y via a benzylisothiocyanate derivative of diethylenetriaminepentaacetic acid. The efficiency of ⁹⁰Y labeling was consistently 90 to 98%, with a specific activity of about 1 µCi/µg. In in vitro stability studies, more than 80% of ⁹⁰Y remained bound to the C110 IT for up to 5 days after incubation. The percentage of binding of ⁹⁰Y-labeled C110 IT to carcinoembryonic antigen-coated microbeads was 86%, indicating good retention of the initial immuno-reactivity of the C110 MAb. In in vitro protein synthesis inhibition assays, ⁹⁰Y-labeled C110 IT was approximately 3.7-fold more toxic to the LS174T human colon carcinoma cell line than unmodified C110 IT and 1380-fold more toxic than ⁹⁰Y-labeled C110 MAb. Biodistribution studies of ⁹⁰Y-labeled C110 IT in LS174T tumor-bearing mice showed that, at 24 h following i.p. injection, high accumulation of radioactivity was seen in the i.p. tumor and liver and, thereafter, high accumulation in these tissues remained almost unchanged until up to 168 h, with percentage of injected dose/g ranging from 15 to 18% in the tumor and 10 to 15% in the liver. The radioactivity in the spleen and bone gradually increased with time and reached their highest levels (approximately 8% of injected dose/g) at 168 h. Estimation of absorbed radiation doses to the tissues showed that i.p. tumor would have received an approximately 1.5 to 7 times higher radiation dose than normal organs. In in vivo therapeutic trials, ⁹⁰Y-labeled C110 IT provided survival prolongation of LS174T tumor-bearing mice superior to that with either unmodified C110 IT or ⁹⁰Y-labeled C110 MAb (4 < 0.01; Mann-Whitney U test).

These results indicate that ⁹⁰Y-labeled C110 anti-carcinoembryonic antigen IT may be a potent therapeutic immunoconjugate for human colon cancer and that it may have direct relevance for i.p. treatment of peritoneal carcinomatosis from colon cancers.

¹ Supported in part by Grant R01-CA-39748 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Division of Oncology, Department of Medicine, University of Massachusetts Medical Center, 55 Lake Avenue North, Worcester, MA 01655.

Received 2/12/90. Accepted 9/25/90.