Impact of interleukin-2-receptor-targeted cytotoxins on a unique model of murine interleukin-2-receptor-expressing malignancy.
DAB486IL-2 is a genetically engineered fusion protein consisting of a portion of diphtheria toxin fused to human IL-2. It is specifically cytotoxic for tumor cells which bear high-affinity IL-2 receptors (IL-2R). DAB389IL-2 is a similarly constructed hybrid protein which is smaller than DAB486IL-2 and is slightly more potent in vitro. We have developed a murine model of IL-2R-expressing malignancy to study the in vivo efficacy of these genetically engineered cytotoxins. Following intravenous administration of CP3 cells, C57BL/6 mice develop tumors which are lymphatic in distribution. When mice are injected i.v. with 10(6) CP3 cells, 90% of the animals show signs of observable tumor by day 10 to 20; death occurs in 50% of untreated animals by day 30. Intravenous treatment of mice with DAB486IL-2 (10 micrograms daily for 10 days), beginning 24 hr after administration of CP3 cells, increases mean survival time by approximately 50%. In comparative studies, DAB389IL-2 is more potent in vivo than DAB486IL-2, with approximately 90% of treated animals with no evidence of tumor at 60 days. The mechanism of action of tumor inhibition by DAB486IL-2 is specific, since treatment of animals which have IL-2R-negative EL4 tumors has not resulted in increased survival time. In addition, treatment of such tumors with DAglu53B486IL-2, a fusion protein which can bind to the IL-2R but is incapable of inhibiting protein synthesis, is ineffective.
Bacha
P A
PA
Seragen, Inc., Hopkinton, MA 01748.
Forte
S E
SE
McCarthy
D M
DM
Estis
L
L
Yamada
G
G
Nichols
J C
JC
D000818:Animals; D003603:Cytotoxins / Q000008:administration & dosage*; D004167:Diphtheria Toxin / Q000008:administration & dosage* / Q000737:chemistry; D007376:Interleukin-2 / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D016019:Survival Analysis
D003603:Cytotoxins; D004167:Diphtheria Toxin; D007376:Interleukin-2; D015375:Receptors, Interleukin-2