Bi-Specific Killer Cell Engager Enhances NK Cell Activity against Interleukin-13 Receptor Alpha-2 Positive Gliomas.

Abstract

Glioblastoma (GBM) is a lethal brain tumor with limited therapeutic options. Bi-specific killer cell engagers (BiKEs) are novel immunotherapies designed to engage natural killer (NK) cells against cancer. We designed a BiKE molecule consisting of a single-domain CD16 antibody, an interleukin-15 linker, and a single-chain variable antibody against the glioma-associated antigen interleukin 13 receptor alpha 2 (IL13Rα2). Recombinant BiKE protein was expressed in HEK cells and purified. Flow cytometric analysis of co-cultures of peripheral blood-derived NK cells with GBM6 and GBM39 patient-derived xenograft lines revealed significantly increased activation of NK cells (CD25+CD69+) and increased glioma cell killing following BiKE treatment compared to controls (n = 4, p < 0.01). Glioma cell killing was also confirmed via immunofluorescence staining for cleaved caspase-3 (p < 0.05). In vivo, intracranial delivery of NK cells with BiKE extended median survival in mice bearing GBM6 (p < 0.01) and GBM12 (p < 0.01) tumors compared to controls. Finally, histological analysis of brain tissues revealed a higher frequency of peritumoral NK cells in mice treated with BiKE than with NK cells alone (p < 0.05). In conclusion, we demonstrate that a BiKE generated in a mammalian expression system is functional in augmenting NK cell targeting of IL13Rα2-positive gliomas.

• Authors: Kristen D Pawlowski, Joseph T Duffy, Arushi Tiwari, Markella Zannikou, Irina V Balyasnikova
• Journal: Cells (Cells) Vol. 12 Issue 13 (Jun 25 2023) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 37443750 (Publication Type: Journal Article)

Chemical References

• Interleukin-13 Receptor alpha2 Subunit

Topics

• Humans
• Animals
• Mice
• Interleukin-13 Receptor alpha2 Subunit (metabolism)
• Killer Cells, Natural
• Immunotherapy
• Brain Neoplasms (metabolism)
• Glioblastoma (metabolism)
• Mammals