IL13RA2 targeted alpha particle therapy against glioblastomas

Abstract

Glioblastoma (GBM) is the most aggressive primary malignant brain cancer that invariably results in a dismal prognosis. Chemotherapy and radiotherapy have not been completely effective as standard treatment options for patients due to recurrent disease. We and others have therefore developed molecular strategies to specifically target interleukin 13 receptor alpha 2 (IL13RA2), a GBM restricted receptor expressed abundantly on over 75% of GBM patients. In this work, we evaluated the potential of Pep-1L, a novel IL13RA2 targeted peptide, as a platform to deliver targeted lethal therapies to GBM. To demonstrate GBM-specificity, we radiolabeled Pep-1L with Copper-64 and performed in vitro cell binding studies, which demonstrated specific binding that was blocked by unlabeled Pep-1L. Furthermore, we demonstrated real-time GBM localization of [64Cu]Pep-1L to orthotopic GBMs using small animal PET imaging. Based on these targeting data, we performed an initial in vivo safety and therapeutic study using Pep-1L conjugated to Actinium-225, an alpha particle emitter that has been shown to potently and irreversibly kill targeted cells. We infused [225Ac]Pep-1L into orthotopic GBMs using convection-enhanced delivery and found no significant adverse events at injected doses. Furthermore, our initial data also demonstrated significantly greater overall, median and mean survival in treated mice when compared to those in control groups (p < 0.05). GBM tissue extracted from mice treated with [225Ac]Pep-1L showed double stranded DNA breaks, lower Ki67 expression and greater propidium iodide internalization, indicating anti-GBM therapeutic effects of [225Ac]Pep-1L. Based on our results, Pep-1L warrants further investigation as a potential targeted platform to deliver anti-cancer agents.

A novel interleukin‐13 receptor alpha 2‐targeted hybrid peptide for effective glioblastoma therapy

“…However, it has been suggested that there is still an advantage to using the hybrid peptide for GB therapy in convection-enhanced delivery (CED), for which several clinical trials have been performed recently for the treatment of brain tumors (Mehta, Sonabend, & Bruce, 2017). One study reported on the efficacy of IL-13Rα2-targeted alpha therapy against GB using the Pep-1L peptide (Sattiraju et al, 2017), which was shown to target IL-13Rα2 by another group (Pandya, Gibo, Garg, Kridel, & Debinski, 2012). Several reports recently also showed evidence of cell-penetrating peptides crossing the blood-brain barrier (Gallo, Defaus, & Andreu, 2019;Stalmans et al, 2015).…”

“…The monomeric receptor interleukin‐13 receptor alpha 2 (IL‐13Rα2), which has a higher affinity to interleukin‐13 (IL‐13) than that of IL‐13Rα1 (Andrews, Holloway, Puddicombe, Holgate, & Davies, ), has significant roles in GB cells and can be used as a decoy receptor (Newman et al., ; Rahaman et al., ). Thus, several groups have reported the potency of targeting IL‐13Rα2 for GB therapy (Brown et al., ; Joshi, Husain, & Puri, ; Sattiraju et al., ; Sengupta, Thaci, Crawford, & Sampath, ; Thaci et al., ). We also reported the efficacy of targeting IL‐13Rα2 in GB cells with an immunotoxin, such as the cytotoxin IL‐13, in which receptor‐targeted human IL‐13 was fused with a mutated form of a Pseudomonas exotoxin (Kawakami, Kawakami, Liu, & Puri, ; Kawakami, Kawakami, & Puri, ; Kawakami, Kioi, Liu, Kawakami, & Puri, ).…”

[18F]DCP, First Generation PET Radiotracer for Diagnosis of Radiation Resistant Head and Neck Cancer

“…These mice received 10 mg/kg 100 µL of the non-radioactive [ 19 F]DCP, 30 min prior to the injection of radiotracer. The images were reconstructed using TriFoil attenuation correction and Fourier rebinning parameters (56,66). The reconstructed CT and PET images were co-registered and analyzed using the TriFoil filtered backprojection 3D-OSEM algorithm.…”

Delivery of GalNAc-conjugated splice-switching ASOs to non-hepatic cells through ectopic expression of asialoglycoprotein receptor

“…18 Cancer-specific receptors, such as the IL-13Rα2 or EGFRvIII receptors, which are specifically expressed or amplified glioblastomas, are already being tested for targeted therapies using ligand and aptamers, but are not yet widely available. [19][20][21] Here we aimed to adopt the hepatic ASGP-R/GN3 receptor/ligand system for targeted delivery of GN3conjugated ASOs to non-hepatic cancer cell lines, by ectopically expressing ASGP-R. Early work characterizing receptors in mouse fibroblasts, and more recent work in HEK293T cells, showed that ASGP-R is functional when expressed ectopically.…”