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

Authors
  • Pawlowski, Kristen D1, 2
  • Duffy, Joseph T1
  • Tiwari, Arushi1
  • Zannikou, Markella1
  • Balyasnikova, Irina V1
  • 1 Department of Neurological Surgery, Northwestern University, Chicago, IL 60611, USA.
  • 2 Rush Medical College, Rush University Medical Center, Chicago, IL 60612, USA.
Type
Published Article
Journal
Cells
Publisher
MDPI AG
Publication Date
Jun 25, 2023
Volume
12
Issue
13
Identifiers
DOI: 10.3390/cells12131716
PMID: 37443750
Source
Medline
Keywords
Language
English
License
Unknown

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.

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