Analysis of Biodistribution of Intracranially Infused Radiolabeled Interleukin-13 Receptor–Targeted Immunotoxin IL-13PE by SPECT/CT in an Orthotopic Mouse Model of Human Glioma

Abstract

Interleukin-13 Pseudomonas exotoxin (IL-13PE), a targeted agent for interleukin-13 receptor α2 (IL-13Rα2)-expressing tumors, has been administered intracranially by convection-enhanced delivery (CED) for glioma therapy in several clinical trials including a randomized phase 3 clinical trial. However, its intracranial distribution was not optimally evaluated. We investigated the intracranial distribution of radiolabeled IL-13PE after CED in a murine model of glioblastoma multiforme. Methods: IL-13PE was radiolabeled with Na 125 I and evaluated for its activity in vitro in receptor-positive U251 or -negative T98G human glioma cell lines. Gliomas were grown in nude mice after intracranial implantation with U251 cells, and 125 I-IL-13PE was stereotactically administered by bolus or CED for 3 d, followed by micro-SPECT/CT imaging. SPECT images were evaluated quantitatively and compared with histology and autoradiography results. Results: The radioiodination technique resulted in a specific and biologically active 125 I-IL-13PE, which bound and was cytotoxic to IL-13Rα2-positive but not to IL-13Rα2-negative tumor cells. Both the binding and the cytotoxic activities were blocked by a 100-fold excess of IL-13, which indicated the specificity of binding and cytotoxicity. SPECT/CT imaging revealed retention of 125 I-IL-13PE administered by CED in U251 tumors and showed significantly higher volumes of distribution and maintained detectable drug levels for a longer period of time than the bolus route. These results were confirmed by autoradiography. Conclusion: IL-13PE can be radioiodinated without the loss of specificity, binding, or cytotoxic activity. Intracranial CED administration produces a higher volume of distribution for a longer period of time than the bolus route. Thus, CED of IL-13PE is superior to bolus injection in delivering the drug to the entire tumor.

Targeting of IL-4 and IL-13 receptors for cancer therapy

“…To assess the bio-distribution of IL-13PE, we developed a biologically active and highly specific radioiodinated IL-13PE for administration into the brain parenchyma, and intratumorally in an orthotopic glioma mouse model [121]. We observed better 125 I-IL-13PE distribution by CED than by bolus administration, as assessed by micro-SPECT/CT.…”

“…Intracranial CED administration produced a higher volume of distribution for a longer period of time than did the bolus route. Based on these studies, it is recommended that future trials with CED of IL-13PE should incorporate detailed analysis of drug distribution to determine if delivery of the drug is adequate and covers the expected area [120,121].…”

IL-13 receptor α2 is a negative prognostic factor in human lung cancer and stimulates lung cancer growth in mice

“…IL13Rα2 has been shown to be highly expressed in many tumor types, such as colon, glioblastoma, ovarian, head and neck, kidney, and mesothelioma, but not by most normal cells such as immune cells or endothelial cells [ 4 – 9 ]. IL13Rα2 is also associated with poor prognosis in human cancers and a target for cancer therapy [ 10 – 11 ]. IL-13 binding to IL13Rα2 increased tumor migration and invasion.…”

GrB-TWEAK: A Potential Novel Biologic for NSCLC Therapy

“…88 Accordingly, efforts are underway to optimize the CED approach, including the use of real-time imaging techniques to assess the best catheter positioning and infusion parmeters for effective drug distribution. [90][91][92][93] In summary, for both systemic and local drug delivery methods, the limited penetration of therapeutic agents into tumor cell-infiltrated normal brain tissue remains a key hurdle to increasing the survival of GB patients.…”