Preclinical assessments of 90Y-labeled C110 anti-carcinoembryonic antigen immunotoxin: a therapeutic immunoconjugate for human colon cancer.
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 microCi/microgram. 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 immunoreactivity 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 less than 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.
Ito
T
T
Department of Nuclear Medicine, University of Massachusetts Medical Center, Worcester 01655.
Qiu
H
H
Collins
J A
JA
Brill
A B
AB
Johnson
D K
DK
Griffin
T W
TW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D001345:Autoradiography; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D004307:Dose-Response Relationship, Radiation; D000922:Immunotoxins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000628:therapy*; D012276:Ricin / Q000008:administration & dosage; D016019:Survival Analysis; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000008:administration & dosage*
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D000922:Immunotoxins; D015021:Yttrium Radioisotopes; D012276:Ricin