Protein- and DNA-Based Active Immunotherapy Targeting Interleukin-13 Receptor Alpha2

Mintz, Akiva; Gibo, Denise M.; Madhankumar, A.B.; Cladel, Nancy M.; Christensen, Neil D.; Debinski, Waldemar

doi:10.1089/cbr.2008.0462

Cited by 16 publications

(12 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An in vitro cell uptake assay was performed on G48 human glioblastoma cells with and without unlabeled Pep-1L as blocking agent to demonstrate the specificity and binding efficiency of [ 64 Cu]Pep-1L. Previously, we reported that this cell line contains about 4,000,000 IL13RA2 binding sites [ 13 , 20 , 26 , 33 ]. [ 64 Cu]Pep-1L bound these IL13RA2-expressing cells, which was significantly inhibited by binding site blockade with unlabeled Pep-1L (Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…In addition to brain cancer, IL13RA2 has also been reported to be highly expressed in other deadly malignancies, including melanoma, head and neck, ovarian and pancreatic cancers [ 22 – 24 ]. We and others have designed and developed a number of molecular targeted therapies based on IL13 and its derivatives that have shown their efficacy in preclinical models of various cancers [ 13 , 19 , 20 , 25 – 29 ]. In fact, our targeted IL13-based agents were recently used as targeting ligand in chimeric antigen receptor (CAR)-engineered T cells that are in clinical trials [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Peptide-based PET imaging of the tumor restricted IL13RA2 biomarker

et al. 2017

Self Cite

View full text Add to dashboard Cite

Peptides that target cancer cell surface receptors are promising platforms to deliver diagnostic and therapeutic payloads specifically to cancer but not normal tissue. IL13RA2 is a tumor-restricted receptor found to be present in several aggressive malignancies, including in the vast majority of high-grade gliomas and malignant melanoma. This receptor has been successfully targeted for diagnostic and therapeutic purposes using modified IL-13 ligand and more recently using a specific peptide, Pep-1L. In the current work, we establish the in vitro and in vivo tumor binding properties of radiolabeled Pep-1L, designed for tumor imaging. We radiolabeled Pep-1L with Copper-64 and demonstrated specific cell uptake in the IL13RA2-over expressing G48 glioblastoma cell line having abundant IL13RA2 expression. [64Cu]Pep-1L binding was blocked by unlabeled ligand, demonstrating specificity. To demonstrate in vivo tumor uptake, we intravenously injected into tumor-bearing mice and demonstrated that [64Cu]Pep-1L specifically bound tumors at 24 hours, which was significantly blocked (3-fold) by pre-injecting unlabeled peptide. To further demonstrate specificity of Pep-1L towards IL13RA2 in vivo, we exploited an IL13RA2-inducible melanoma tumor model that does not express receptor at baseline but expresses abundant receptor after treatment with doxycycline. We injected [64Cu]Pep-1L into mice bearing IL13RA2-inducible melanoma tumors and performed in vivo PET/CT and post-necropsy biodistribution studies and found that tumors that were induced to express IL13RA2 receptor by doxycycline pretreatment bound radiolabeled Pep-1L 3-4 fold greater than uninduced tumors, demonstrating receptor specificity. This work demonstrates that [64Cu]Pep-1L selectively binds hIL13RA2-expressing tumors and validates Pep-1L as an effective platform to deliver diagnostics and therapeutics to IL13RA2-expressing cancers.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Peptide-based PET imaging of the tumor restricted IL13RA2 biomarker

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…IL-13RA2 is highly overexpressed in GBM, with up to 30,000 binding sites per cultured GBM cells [ 61 ]. The GBM cell line G48a expresses about 4,000,000 binding sites for IL-13RA2 per cell [ 74 , 75 , 76 , 77 , 78 , 79 , 80 ]. IL-13 binds to IL-13 receptor A1 (IL-13RA1), forms a more stable heterodimer with IL-4 receptor A (IL-4RA), and then activates downstream signaling pathways [ 62 , 74 , 81 ].…”

Section: Interleukin 13 Receptor Alpha 2 (Il-13ra2) In Glioma Treamentioning

confidence: 99%

Receptor-Targeted Glial Brain Tumor Therapies

Sharma

Debinski

2018

IJMS

Self Cite

View full text Add to dashboard Cite

Among primary brain tumors, malignant gliomas are notably difficult to manage. The higher-grade tumors represent an unmet need in medicine. There have been extensive efforts to implement receptor-targeted therapeutic approaches directed against gliomas. These approaches include immunotherapies, such as vaccines, adoptive immunotherapy, and passive immunotherapy. Targeted cytotoxic radio energy and pro-drug activation have been designed specifically for brain tumors. The field of targeting through receptors progressed significantly with the discovery of an interleukin 13 receptor alpha 2 (IL-13RA2) as a tumor-associated receptor over-expressed in most patients with glioblastoma (GBM) but not in normal brain. IL-13RA2 has been exploited in novel experimental therapies with very encouraging clinical responses. Other receptors are specifically over-expressed in many patients with GBM, such as EphA2 and EphA3 receptors, among others. These findings are important in view of the heterogeneity of GBM tumors and multiple tumor compartments responsible for tumor progression and resistance to therapies. The combined targeting of multiple receptors in different tumor compartments should be a preferred way to design novel receptor-targeted therapeutic approaches in gliomas.

show abstract

“…Expression of IL-13RA2 and EphA2 is partially overlapping; hence, the combined overexpression is ~90% in patients with GBM (31). IL-13RA2 and EphA2 are targets for multiple therapeutic approaches currently in the clinic or under preclinical evaluation (36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52). The first generation of an IL-13-based cytotoxin produced in our laboratory, which nonspecifically targeted IL-13RA2, demonstrated clinical efficacy in patients with recurrent GBM (13,(53)(54)(55).…”

Section: Targeted Cytotoxic Therapy Of Gbmmentioning

confidence: 99%

Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part I: Targeted Cytotoxic Therapy

2017

Self Cite

View full text Add to dashboard Cite

Glioblastoma (GBM), a primary brain tumor, remains an unmet medical need. One of the major obstacles to GBM treatment is the adequate properties of drugs. Complex pathobiology of GBM, including local invasion and intratumoral heterogeneity, represent major challenges to generating effective therapies. We discuss here the design of targeted cytotoxic drugs with an increased access to tumors and pathophysiologically important tumor compartments. Our research and others' have shown that interleukin 13 receptor alpha 2 (IL-13RA2), EphA2, and EphA3 receptors are overexpressed in most patients with GBM, but not in normal brain, and also in spontaneous canine high-grade gliomas like GBM, an excellent translational model of GBM. These receptors and also the EphB2 receptor are overexpressed and are functional in several GBM compartments involved Delivering Cytotoxic Therapies to Glioblastoma 342 in tumor progression and/or resistance to therapies. We pursue the novel idea of targeting all four receptors with one targeted cytotoxic compound (QUAD-CTX). We are constructing a molecularly targeted anti-GBM drug that (i) may not require patient prescreening, (ii) will attack most tumor compartments known to be pathobiologically important, and (iii) performs these functions in one pharmaceutical entity, so it will be suitable for monotherapy. We thus wish to take advantage of a unique opportunity to produce an off-the-shelf, highly specific, molecularly targeted drug candidate suitable to treat perhaps even all patients with GBM. We envision that this "molecular resection" will translate into clear-cut durable responses in patients suffering from this dreadful disease.

show abstract

Protein- and DNA-Based Active Immunotherapy Targeting Interleukin-13 Receptor Alpha2

Abstract: High-grade astrocytoma (HGA) is an invariably fatal malignancy with a mean survival of 14 months de-

Cited by 16 publications

References 27 publications

Peptide-based PET imaging of the tumor restricted IL13RA2 biomarker

Peptide-based PET imaging of the tumor restricted IL13RA2 biomarker

Receptor-Targeted Glial Brain Tumor Therapies

Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part I: Targeted Cytotoxic Therapy

Contact Info

Product

Resources

About