IL2-PE664Glu, a new chimeric protein cytotoxic to human-activated T lymphocytes.
To produce a molecule that will kill activated T cells as well as lymphomas and leukemias expressing interleukin 2 (IL2) receptors, we have created a recombinant chimeric protein in which IL2 is attached in peptide linkage to a truncated mutant form of Pseudomonas exotoxin (PE) (Lorberboum-Galski, H., FitzGerald, D.J.P., Chandhary, V.K., Adhya, S., and Pastan, I. (1988) Proc. Natl. Acad. Sci. U.S.A. 85, 1922-1926). Although this molecule was very active on rodent cells, it had lower activity on some human cell types. A new chimeric protein termed IL2-PE664Glu has been constructed that is extremely toxic to both phytohemagglutinin blasts and mixed leukocyte reaction blasts prepared from monkey and human lymphocytes. The chimeric gene encoding this protein was constructed by fusing a cDNA clone for human interleukin 2 to the 5' end of a mutated cDNA encoding a full-length PE molecule. Four amino acids in domain I of PE were changed thus decreasing its nonspecific toxicity. IL2-PE664Glu is a much more active cytotoxic molecule for primate and human-activated T cells than IL2-PE40 which is a chimeric protein that was found to be an effective immunosuppressive agent in rodent models. Our results indicate that IL2-PE664Glu should be evaluated as an immunosuppressive agent for the treatment of human immune disorders in which activated T cells expressing the IL2 receptor are prominent.
Lorberboum-Galski
H
H
Division of Cancer Biology and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Garsia
R J
RJ
Gately
M
M
Brown
P S
PS
Clark
R E
RE
Waldmann
T A
TA
Chaudhary
V K
VK
FitzGerald
D J
DJ
Pastan
I
I
D036002:ADP Ribose Transferases; D000818:Animals; D001427:Bacterial Toxins; D001483:Base Sequence; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002678:Chimera; D005098:Exotoxins / Q000235:genetics / Q000494:pharmacology* / Q000633:toxicity; D005971:Glutamates; D018698:Glutamic Acid; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000494:pharmacology* / Q000633:toxicity; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D015345:Oligonucleotide Probes; D011550:Pseudomonas aeruginosa / Q000235:genetics; D051381:Rats; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000502:physiology; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins / Q000494:pharmacology / Q000633:toxicity; D013045:Species Specificity; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D005971:Glutamates; D018698:Glutamic Acid; D007376:Interleukin-2; D015345:Oligonucleotide Probes; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C065698:interleukin 2-PE66(4Glu) protein, recombinant