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
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) o...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2024-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/3/e008295.full |
| _version_ | 1797221951784091648 |
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| author | Ge Yang Mohammad Massumi Shahryar Khoshtinat Nikkhoi Hajar Owji Mayara Grizotte-Lake Rick I Cohen Lazaro Gil Gonzalez Arash Hatefi |
| author_facet | Ge Yang Mohammad Massumi Shahryar Khoshtinat Nikkhoi Hajar Owji Mayara Grizotte-Lake Rick I Cohen Lazaro Gil Gonzalez Arash Hatefi |
| author_sort | Ge Yang |
| collection | DOAJ |
| description | 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 IgG1 Fc region had no impact on BiKE:E5C1’s anticancer activity. In vivo results reveal that both hIL-15 and hIL-2 NOG mouse models support the viability and proliferation of laNK92 cells. Furthermore, it was observed that BiKE:E5C1 activates laNK92 cells in mice, leading to eradication of cancer metastasis in both NK humanized hIL-15 and hIL-2 NOG mouse models.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. |
| first_indexed | 2024-04-24T13:13:36Z |
| format | Article |
| id | doaj.art-155b517c70c74416a35702828b6d5b6c |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-24T13:13:36Z |
| publishDate | 2024-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-155b517c70c74416a35702828b6d5b6c2024-04-05T01:35:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-03-0112310.1136/jitc-2023-008295Bispecific immune cell engager enhances the anticancer activity of CD16+ NK cells and macrophages in vitro, and eliminates cancer metastasis in NK humanized NOG miceGe Yang0Mohammad Massumi1Shahryar Khoshtinat Nikkhoi2Hajar Owji3Mayara Grizotte-Lake4Rick I Cohen5Lazaro Gil Gonzalez6Arash Hatefi7Rutgers, The State University of New Jersey, Piscataway, New Jersey, USARutgers, The State University of New Jersey, Piscataway, New Jersey, USARutgers, The State University of New Jersey, Piscataway, New Jersey, USARutgers, The State University of New Jersey, Piscataway, New Jersey, USATaconic Biosciences Inc, Germantown, New York, USARutgers, The State University of New Jersey, Piscataway, New Jersey, USASt Michael`s Hospital Keenan Research Centre for Biomedical Science, Toronto, Ontario, CanadaRutgers, The State University of New Jersey, Piscataway, New Jersey, USABackground 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 IgG1 Fc region had no impact on BiKE:E5C1’s anticancer activity. In vivo results reveal that both hIL-15 and hIL-2 NOG mouse models support the viability and proliferation of laNK92 cells. Furthermore, it was observed that BiKE:E5C1 activates laNK92 cells in mice, leading to eradication of cancer metastasis in both NK humanized hIL-15 and hIL-2 NOG mouse models.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.https://jitc.bmj.com/content/12/3/e008295.full |
| spellingShingle | Ge Yang Mohammad Massumi Shahryar Khoshtinat Nikkhoi Hajar Owji Mayara Grizotte-Lake Rick I Cohen Lazaro Gil Gonzalez Arash Hatefi 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 Journal for ImmunoTherapy of Cancer |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | https://jitc.bmj.com/content/12/3/e008295.full |
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