Targeting glioblastoma multiforme with an IL-13/diphtheria toxin fusion protein in vitro and in vivo in nude mice.
Fusion proteins composed of tumor binding agents and potent catalytic toxins show promise for intracranial therapy of brain cancer and an advantage over systemic therapy. Glioblastoma multiforme (GBM) is the most common form of brain cancer and overexpresses IL-13R. Thus, we developed an interleukin-13 receptor targeting fusion protein, DT(390)IL13, composed of human interleukin-13 and the first 389 amino acids of diphtheria toxin. To measure its ability to inhibit GBM, DT(390)IL13 was tested in vitro and found to inhibit selectively the U373 MG GBM cell line with an IC(50) around 12 pmol/l. Cytotoxicity was neutralized by anti-human-interleukin-13 antibody, but not by control antibodies. In vivo, small U373 MG glioblastoma xenografts in nude mice completely regressed in most animals after five intratumoral injections of 1 microg of DT(390)IL13 q.o.d., but not by the control fusion protein DT(390)IL-2. DT(390)IL13 was also tested against primary explant GBM cells of a patient's excised tumor and the IC(50) was similar to that measured for U373 MG. Further studies showed a therapeutic window for DT(390)IL13 of 1-30 microg/injection and histology studies and enzyme measurements showed that the maximum tolerated dose of DT(390)IL13 had little effect on kidney, liver, spleen, lung and heart in non-tumor-bearing immunocompetent mice. Together, these data suggest that DT(390)IL13 may provide an important, alternative therapy for brain cancer.
Li
Chunbin
C
Department of Therapeutic Radiology-Radiation Oncology, Section on Experimental Cancer Immunology, University of Minnesota Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Hall
Walter A
WA
Jin
Ni
N
Todhunter
Deborah A
DA
Panoskaltsis-Mortari
Angela
A
Vallera
Daniel A
DA
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D004167:Diphtheria Toxin / Q000008:administration & dosage* / Q000627:therapeutic use; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D066298:In Vitro Techniques; D018793:Interleukin-13 / Q000008:administration & dosage* / Q000627:therapeutic use; D053661:Interleukin-13 Receptor alpha1 Subunit; D007700:Kinetics; D020714:Maximum Tolerated Dose; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018123:Receptors, Interleukin / Q000378:metabolism; D053660:Receptors, Interleukin-13; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage
D000970:Antineoplastic Agents; D004167:Diphtheria Toxin; C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D011993:Recombinant Fusion Proteins