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 language | English (US) |
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Article number | 1716 |
Journal | Cells |
Volume | 12 |
Issue number | 13 |
DOIs | |
State | Published - 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