Molecular targeting with recombinant cytotoxins of interleukin-13 receptor alpha2-expressing glioma.
A restricted receptor for interleukin 13 (IL-13R alpha2) is over-expressed in high-grade astrocytoma (HGA), but not in normal organs. In order to design and examine new anti-HGA therapies, which are molecularly directed against IL-13R alpha2, we established an IL-13R alpha2-expressing syngeneic immunocompetent murine model of HGA. The model was obtained by transfecting G-26 murine glioma cells with IL-13R alpha2. G-26-IL-13R alpha2(+) cells, but not mock-transfected cells, became susceptible to IL-13 mutant-based cytotoxic proteins that kill human HGA cells. G-26-IL-13R alpha2(+) cells maintained their tumorigenicity in immunocompetent C57BL/J6 mice and preserved their expression of IL-13R alpha2 in vivo. These characteristics of the G-26-IL-13R alpha2(+) tumors allowed us to test molecularly defined anti-glioma passive immunotherapy. A targeted recombinant chimera cytotoxin composed of multiply mutated IL-13 (IL-13.E13Y/R66D/S69D) and a derivative of Pseudomonas exotoxin (PE), PE1E, IL-13.E13Y/R66D/S69D-PE1E, was used in anti-tumor experiments. G-26-IL-13R alpha2(+) cells were killed by IL-13.E13Y/R66D/S69D-PE1E in an IL-4-independent fashion. To test the cytotoxin in vivo, G-26-IL-13R alpha2(+) tumors were established in C57BL/J6 mice and when the tumors reached a size of at least 50 mm3, the mice were treated with IL-13.E13Y/R66D/S69D-PE1E. In the mice treated with the targeted fusion cytotoxin, the tumors regressed and 80% of the animals were cured. This study documents the establishment of an IL-13R alpha2-positive model of HGA in immunocompetent rodents. Furthermore, the effectiveness and safety of the targeted IL-13-based cytotoxin against IL-13R alpha2-expressing tumors in a more clinically relevant in vivo HGA model is promising with regard to the future clinical utility of the cytotoxin.
Mintz
Akiva
A
Department of Neurosurgery/H110, Pennsylvania State University College of Medicine, Hershey, PA 17033-0850, USA.
Gibo
Denise M
DM
Madhankumar
A B
AB
Debinski
Waldemar
W
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D003603:Cytotoxins / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D005098:Exotoxins / Q000235:genetics; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D007116:Immunization, Passive; D000922:Immunotoxins / Q000627:therapeutic use; D018793:Interleukin-13 / Q000235:genetics; D053661:Interleukin-13 Receptor alpha1 Subunit; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011549:Pseudomonas / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D053660:Receptors, Interleukin-13; D011994:Recombinant Proteins / Q000627:therapeutic use; D019076:Transgenes; D016896:Treatment Outcome
D003603:Cytotoxins; D005098:Exotoxins; C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D000922:Immunotoxins; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D011994:Recombinant Proteins