Cytotoxic effects of anti-CD5 radioimmunotoxins on human tumors in vitro and in a nude mouse model.
An immunoconjugate, consisting of both toxin and radionuclide on the same antibody molecule, was synthesized by cross-linking the phytotoxin ricin to the T101 monoclonal antibody recognizing the CD5 cluster expressed on normal and malignant T-cells. The hybrid molecule was then labeled with iodine-125 by an iodine monochloride procedure. This radioimmunotoxin (RIT), which selectively bound to the CD5-positive CEM human leukemia cell line, was selectively inhibitory to antigen-positive cells in protein synthesis inhibition assays. RIT was only 3.0-7.8-fold less toxic and was 1.1-1.6-fold slower than unlabeled immunotoxin in inhibiting protein synthesis. Because of the radionuclide moiety, the RIT also provided information related to biodistribution and pharmacokinetics. Four days following intratumoral injection, more than 125-fold greater activity was found in CEM tumors implanted in nude mice as compared to normal tissues. The mean blood half-life for RIT was 25.7 h and for radiolabeled antibody, 91.3 h. Intratumoral injections of RIT selectively induced regression of established CEM tumors. To our knowledge, these studies are the first to demonstrate that a single immunoconjugate can combine the advantages of both a catalytic toxin and radionuclide for cancer therapy.
Manske
J M
JM
Department of Therapeutic Radiology, University of Minnesota, Minneapolis 55455.
Buchsbaum
D J
DJ
Hanna
D E
DE
Vallera
D A
DA
D000818:Animals; D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation / Q000276:immunology*; D018956:CD5 Antigens; D002470:Cell Survival; D006801:Humans; D000922:Immunotoxins / Q000493:pharmacokinetics / Q000633:toxicity*; D007457:Iodine Radioisotopes; D015458:Leukemia, T-Cell / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D012276:Ricin
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D018956:CD5 Antigens; D000922:Immunotoxins; D007457:Iodine Radioisotopes; D012276:Ricin