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Recombinant immunotoxins containing anti-Tac(Fv) and derivatives of
Pseudomonas exotoxin produce complete regression in mice of an
interleukin-2 receptor-expressing human carcinoma
RJ Kreitman, P Bailon, VK Chaudhary, DJ FitzGerald and I Pastan
Division of Cancer Biology and Diagnosis, National Cancer Institute,
National Institutes of Health, Bethesda, MD 20892.
Anti-Tac(Fv)-PE40 is a recombinant single-chain immunotoxin composed of the
variable domains of the monoclonal antibody anti-Tac, which binds to the
p55 subunit of the interleukin-2 receptor (IL-2R), and a truncated form of
Pseudomonas exotoxin (PE), which does not bind to the PE receptor
(Chaudhary et al, Nature 339:394, 1989). Whereas its cytotoxic activity
toward autoimmune and malignant target cells has been established, its
efficacy in vivo remains unknown. To establish an animal model, we produced
ATAC-4 cells by transfecting the gene encoding the low-affinity IL-2R (p55)
into A431 epidermoid carcinoma cells. ATAC-4 cells contained low-affinity
IL-2Rs (2 x 10(5)/cell) and formed tumors in nude mice. In tissue culture,
protein synthesis in ATAC-4 cells was inhibited 50% (IC50) at 0.06 ng/mL
(0.9 pmol/L) of anti-Tac(Fv)-PE40. IC50s for the derivatives
anti-Tac(Fv)-PE38, which is missing PE amino acids 365-380, and
anti-Tac(Fv)-PE38KDEL, which contains the same deletion plus the KDEL
carboxyl terminus, were 0.04 and 0.025 ng/mL, respectively. All the agents
produced complete tumor regressions in ATAC-4 tumor-bearing mice and
anti-Tac(Fv)-PE38KDEL had significant antitumor activity at 1% of the LD50.
The dose limiting toxicity of anti-Tac(Fv)-PE38KDEL was from hemorrhagic
liver necrosis, which was observed at approximately 55% of the LD50.
Volume 83,
Issue 2,
pp. 426-434,
01/15/1994
Copyright © 1994 by The American Society of Hematology
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