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Impact of interleukin‐2‐receptor‐targeted cytotoxins on a unique model of murine interleukin‐2‐receptor‐expressing malignancy
Author(s) -
Bacha Patricia A.,
Forte Serene E.,
McCarthy Donna M.,
Estis Leonard,
Yamada Gen,
Nichols Jean C.
Publication year - 1991
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910490118
Subject(s) - in vivo , cytotoxic t cell , receptor , interleukin 2 , diphtheria toxin , fusion protein , immunology , immunotoxin , interleukin , biology , cytotoxicity , cancer research , in vitro , pharmacology , medicine , cytokine , antibody , toxin , recombinant dna , monoclonal antibody , biochemistry , microbiology and biotechnology , gene
DAB 486 IL‐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). DAB 389 IL‐2 is a similarly constructed hybrid protein which is smaller than DAB 486 IL‐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 DAB 486 IL‐2 (10 μg daily for 10 days), beginning 24 hr after administration of CP3 cells, increases mean survival time by approximately 50%. In comparative studies, DAB 389 IL‐2 is more potent in vivo than DAB 486 IL‐2, with approximately 90% of treated animals with no evidence of tumor at 60 days. The mechanism of action of tumor inhibition by DAB 486 IL‐2 is specific, since treatment of animals which have 1L‐2R‐negative EL4 tumors has not resulted in increased survival time. In addition, treatment of such tumors with DA glu53 B 486 IL‐2, a fusion protein which can bind to the IL‐2R but is incapable of inhibiting protein synthesis, is ineffective.