Bispecific immune cell engager enhances the anticancer activity of CD16+ NK cells and macrophages in vitro, and eliminates cancer metastasis in NK humanized NOG mice.
| Autor: | Khoshtinat Nikkhoi S; Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA., Yang G; Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA., Owji H; Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA., Grizotte-Lake M; Taconic Biosciences Inc, Germantown, New York, USA., Cohen RI; Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA., Gil Gonzalez L; St Michael's Hospital Keenan Research Centre for Biomedical Science, Toronto, Ontario, Canada., Massumi M; Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA., Hatefi A; Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA ahatefi@pharmacy.rutgers.edu.; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA. |
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| Jazyk: | angličtina |
| Zdroj: | Journal for immunotherapy of cancer [J Immunother Cancer] 2024 Mar 15; Vol. 12 (3). Date of Electronic Publication: 2024 Mar 15. |
| DOI: | 10.1136/jitc-2023-008295 |
| Abstrakt: | Background: In a prior report, we detailed the isolation and engineering of a bispecific killer cell engager, referred to as BiKE:E5C1. The BiKE:E5C1 exhibits high affinity/specificity for the CD16a activating receptor on natural killer (NK) cells and human epidermal growth factor receptor 2 (HER2) on cancer cells. In vitro studies have demonstrated that BiKE:E5C1 can activate the NK cells and induce the killing of HER2+ ovarian and breast cancer cells, surpassing the performance of the best-in-class monoclonal antibody, Trazimera (trastuzumab). To advance this BiKE technology toward clinical application, the objective of this research was to demonstrate the ability of BiKE:E5C1 to activate CD16+ immune cells such as NK cells and macrophages to kill cancer cells, and eradicate metastatic HER2+ tumors in NK humanized NOG mice. Methods: We assessed BiKE:E5C1's potential to activate CD16-expressing peripheral blood (PB)-NK cells, laNK92 cells, and THP-1-CD16A monocyte-macrophages through flowcytometry and antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC) assays. Subsequently, laNK92 cells were selected as effector cells and genetically modified to express the nanoluciferase gene, enabling the monitoring of their viability in NK humanized NOG mice using quantitative bioluminescent imaging (qBLI). To evaluate the functionality of BiKE:E5C1 in vivo, we introduced firefly luciferase-expressing ovarian cancer cells via intraperitoneal injection into hIL-15 and hIL-2 NOG mice, creating a model of ovarian cancer metastasis. Once tumor establishment was confirmed, we treated the mice with laNK92 cells plus BiKE:E5C1 and the response to therapy was assessed using qBLI. Results: Our data demonstrate that BiKE:E5C1 activates not only laNK92 cells but also PB-NK cells and macrophages, significantly enhancing their anticancer activities. ADCC assay demonstrated that IgG Conclusions: Collectively, our in vivo findings underscore BiKE:E5C1's potential as an immune cell engager capable of activating immune cells for cancer cell elimination, thereby expanding the arsenal of available BiKEs for cancer immunotherapy. Competing Interests: Competing interests: AH and SK are inventors named on a patent (WO2023129819) that describes the BiKE technology. The intellectual property (IP) rights to the patented technology belong to Rutgers University. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) |
| Databáze: | MEDLINE |
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