A bispecific immunotoxin (DTAT13) targeting human IL-13 receptor (IL-13R) and urokinase-type plasminogen activator receptor (uPAR) in a mouse xenograft model.
A bispecific immunotoxin (IT) called DTAT13 was synthesized in order to target simultaneously the urokinase-type plasminogen activator receptor (uPAR)-expressing tumor neovasculature and IL-13 receptor expressing glioblastoma cells with the goal of intratumoral administration for brain tumors. The recombinant hybrid was created using the non-internalizing N-terminal fragment (ATF) of uPA and the IL-13 molecule for binding plus the catalytic and translocation portion of diphtheria toxin (DT) for killing. The 71 kDa protein was highly selective for human glioblastoma in vitro showing no loss on binding compared with DTAT and DTIL13 controls. In vivo, DTAT13 caused the regression of small tumors when administered at 10 micro g/day given on a five-dose schedule every other day. DTAT13 was able to target both overexpressed uPAR and the vasculature, as demonstrated by its ability to kill HUVEC cells. Also, mortality studies indicated that DTAT13 was less toxic than DTAT or DTIL13. These findings indicate that bispecific IT may allow treatment of a broader subset of antigenically diverse patients while simultaneously reducing the exposure to toxin required than if two separate agents were employed.
Todhunter
Deborah A
DA
Department of Neurosurgery, University of Minnesota Cancer Center, Minneapolis 55455, USA.
Hall
Walter A
WA
Rustamzadeh
Edward
E
Shu
Yanqun
Y
Doumbia
Sekou O
SO
Vallera
Daniel A
DA
D000818:Animals; D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy; D006801:Humans; D000922:Immunotoxins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D053661:Interleukin-13 Receptor alpha1 Subunit; D007668:Kidney / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism*; D053660:Receptors, Interleukin-13; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification / Q000494:pharmacology; D018675:Toxicity Tests; D023041:Xenograft Model Antitumor Assays
D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; C512526:DTAT13 protein; C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D000922:Immunotoxins; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D015514:Oncogene Proteins, Fusion; C524898:PLAUR protein, human; D010446:Peptide Fragments; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C471586:diphtheria toxin-urokinase fusion protein, human