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

Kristen D. Pawlowski, Joseph T. Duffy, Arushi Tiwari, Markella Zannikou, Irina V. Balyasnikova*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish (US)
Article number1716
JournalCells
Volume12
Issue number13
DOIs
StatePublished - Jul 2023

Funding

This research was partly funded by the American Academy of Neurology (AAN) Medical Student Research Scholarship, NINDS R01 NS122395 (I.V.B.) and the Department of Neurological Surgery, Northwestern University, Chicago, IL, USA.

Keywords

  • bi-specific antibody
  • glioblastoma
  • immunotherapy
  • natural killer cells

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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