Retargeting interleukin 13 for radioimmunodetection and radioimmunotherapy of human high-grade gliomas.
A vast majority of patients with glioblastoma multiforme (GBM), a high-grade glioma, overexpress abundant amounts of a receptor for interleukin (IL)-13 in situ. This receptor is more restrictive because it is IL-4-independent and therefore differs from the IL-13/4 signaling receptor of normal tissue that is shared with IL-4. We previously identified one of the sites on the human IL (hIL)-13 molecule that is important for its interaction with the IL-13/4 receptor, a residue of glutamic acid at position 13. In this study, we mutated the cytokine and produced hIL-13.E13Y, in which the glutamic acid was substituted by tyrosine. This additional tyrosine residue was therefore strategically located within the region of IL-13 interaction with the signaling physiological receptor. hIL-13.E13Y did not transduce signals through the IL-13/4 receptor, whereas its interaction with the more restrictive, GBM-associated receptor remained intact. The mutated hIL-13 could be readily radiolabeled. Radiolabeled hIL-13.E13Y produced specific autoradiographic images of human GBM specimens. We demonstrate an effective way to redirect hIL-13 to its more restrictive receptor found in high-grade gliomas by mutagenizing the cytokine, and, concomitantly, we equipped hIL-13 with an additional tyrosine residue for higher specific activity radiolabeling.
Debinski
W
W
Department of Surgery, Pennsylvania State University, College of Medicine, Hershey 17033-0850, USA. wdebinski@psghs.edu
Thompson
J P
JP
D000595:Amino Acid Sequence; D000818:Animals; D005910:Glioma / Q000000981:diagnostic imaging* / Q000532:radiotherapy*; D006801:Humans; D018793:Interleukin-13 / Q000737:chemistry / Q000627:therapeutic use*; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D016719:Radioimmunodetection; D016499:Radioimmunotherapy
D018793:Interleukin-13; D007457:Iodine Radioisotopes