Targeting IL-13Rα2 for effective treatment of malignant peripheral nerve sheath tumors in mouse models

Abstract

OBJECTIVEMalignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that harbor a high potential for metastasis and have a devastating prognosis. Combination chemoradiation aids in tumor control and decreases tumor recurrence but causes deleterious side effects and does not extend long-term survival. An effective treatment with limited toxicity and enhanced efficacy is critical for patients suffering from MPNSTs.METHODSThe authors recently identified that interleukin-13 receptor alpha 2 (IL-13Rα2) is overexpressed on MPNSTs and could serve as a precision-based target for delivery of chemotherapeutic agents. In the work reported here, a recombinant fusion molecule consisting of a mutant human IL-13 targeting moiety and a point mutant variant of Pseudomonas exotoxin A (IL-13.E13 K-PE4E) was utilized to treat MPNST in vitro in cell culture and in an in vivo murine model.RESULTSIL-13.E13 K-PE4E had a potent cytotoxic effect on MPNST cells in vitro. Furthermore, intratumoral administration of IL-13.E13 K-PE4E to orthotopically implanted MPNSTs decreased tumor burden 6-fold and 11-fold in late-stage and early-stage MPNST models, respectively. IL-13.E13 K-PE4E treatment also increased survival by 23 days in the early-stage MPNST model.CONCLUSIONSThe current MPNST treatment paradigm consists of 3 prongs: surgery, chemotherapy, and radiation, none of which, either singly or in combination, are curative or extend survival to a clinically meaningful degree. The results presented here provide the possibility of intratumoral therapy with a potent and highly tumor-specific cytotoxin as a fourth treatment prong with the potential to yield improved outcomes in patients with MPNSTs.

IL-13Rα2 Status Predicts GB-13 (IL13.E13K-PE4E) Efficacy in High-Grade Glioma

“…The foundational efforts of Puri and colleagues in developing cintredekin besudotox have demonstrated the feasibility of creating such a molecule for killing of IL-13Rα2-expressing cells by linking a truncated form of PE to human IL-13 [ 66 ]. GB-13 is essentially the successor of cintredekin besudotox, featuring refinements to both the targeting moiety and the payload domain [ 24 ]. We observed favorable potency with GB-13 compared to previous reports of cintredekin besudotox in IL-13Rα2-upregulated HGG cell lines [ 42 , 66 , 67 , 68 , 69 ].…”

“…First, high-dose CED infusion into the brainstem of HGG-bearing mice was associated with profound toxicity, which indicates a narrow therapeutic window for this agent when delivered directly into eloquent brain regions. This is especially notable since a previous in vivo study of intra-tumoral GB-13 in a murine model of malignant peripheral nerve sheath tumor did not find dose-limiting toxicities [ 24 ]. Furthermore, observed toxicities in a phase I clinical trial of cintredekin besudotox delivered by CED into the brainstem of DIPG patients were limited to transient cranial nerve deficits and lethargy after infusion [ 72 ].…”

“…IL-13Rα2 is expressed almost exclusively on cancer cells and is a clinically validated target for biologic therapeutics. Malignant diseases with known IL-13Rα2 upregulation include but are not limited to HGG [ 16 , 21 , 22 , 23 ], malignant peripheral nerve sheath tumors [ 24 ], colon cancer [ 25 ], pancreatic cancer [ 26 ], ovarian cancer [ 27 ], and melanoma [ 28 ]. Recent studies suggest that overexpression of IL-13Rα2 is detected in up to 83% of malignant pediatric brain tumors, including DMG, and up to 78% of adult GBM [ 23 , 29 , 30 , 31 ].…”

“…GB-13 consists of an N-terminal IL-13-targeting moiety with a single engineered point mutation, the C-terminus of which is linked to the N-terminus of a full-length PE molecule containing four point mutations. These modifications greatly enhance the selectivity and affinity for IL-13Ra2 and reduce toxicity to non-malignant cells [ 24 , 38 , 39 ]. The IL-13 moiety attaches to IL-13Ra2 at the cell surface of malignant target cells and facilitates the internalization of the toxin, which irreversibly disables eukaryotic elongation factor 2 (eEF2) by adenosine diphosphate (ADP)-ribosylation using oxidized nicotinamide adenine dinucleotide (NAD+), causing arrest of protein synthesis and eventual Bak- and caspase-mediated apoptosis [ 40 , 41 , 42 ].…”

Targeting interleukin-13 receptor α2 (IL-13Rα2) for glioblastoma therapy with surface functionalized nanocarriers

“…During scrutiny of such process, high affinity mutants were investigated based on above-mentioned mutations. Moreover, in comparison to native IL-13, the shuffling of Lys to the position of Arg at location 105 resulted in 17 folds high affinity for receptor while replacement of Arg with Lys at location 109 mimicked the receptor affinity by 27 folds (Mrowczynski et al., 2019 ). Overall, this discussion concludes that it is possible to produce mutants that have low affinity for binding with IL13Rα1 and high affinity for IL13Rα2.…”