Engineered IL-18 variants with half-life extension and improved stability for cancer immunotherapy
Background The pro-inflammatory cytokine, interleukin-18 (IL-18), plays an instrumental role in bolstering anti-tumor immunity. However, the therapeutic application of IL-18 has been limited due to its susceptibility to neutralization by IL-18 binding protein (IL-18BP), short in vivo half-life, and...
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BMJ Publishing Group
2025-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/7/e011789.full |
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| author | Yue Zhao Yan Qu Marina Moskalenko Dawei Sun Travis W Bainbridge Matthieu Masureel Lifen Wang Robert Herrera Maciej T Paluch Kazi Tasneem Harpinder Saini Manal Sadek Mandy Kwong Yoon Min Kim Jay M Bhatt Christine Tam Pamela Pui Fung Chan Ayse Meric Ovacik Jonathan T Sockolosky Nathaniel R West Beyza Bulutoglu |
| author_facet | Yue Zhao Yan Qu Marina Moskalenko Dawei Sun Travis W Bainbridge Matthieu Masureel Lifen Wang Robert Herrera Maciej T Paluch Kazi Tasneem Harpinder Saini Manal Sadek Mandy Kwong Yoon Min Kim Jay M Bhatt Christine Tam Pamela Pui Fung Chan Ayse Meric Ovacik Jonathan T Sockolosky Nathaniel R West Beyza Bulutoglu |
| author_sort | Yue Zhao |
| collection | DOAJ |
| description | Background The pro-inflammatory cytokine, interleukin-18 (IL-18), plays an instrumental role in bolstering anti-tumor immunity. However, the therapeutic application of IL-18 has been limited due to its susceptibility to neutralization by IL-18 binding protein (IL-18BP), short in vivo half-life, and unfavorable physicochemical properties.Methods In order to overcome the poor drug-like properties of IL-18, we installed an artificial disulfide bond, removed the native, unpaired cysteines, and fused the stabilized cytokine to an IgG Fc domain. The stability, potency, pharmacokinetic and pharmacodynamic properties as well as efficacy of disulfide-stabilized IL-18 Fc-fusion (dsIL-18-Fc) were assessed via in vitro and in vivo studies.Results The stability and mammalian host cell production yields of dsIL-18-Fc were improved, compared to the wild-type (WT) cytokine, while maintaining its biological potency and interactions with IL-18 receptor α (IL-18Rα) and IL-18BP. Recombinant fusion of the cytokine to an IgG Fc domain provided extended half-life. Notably, despite maintaining sensitivity to IL-18BP, dsIL-18-Fc was effective at activating both T and natural killer (NK) cells, and elicited a strong anti-tumor response, either as a single agent, or in conjunction with anti-programmed cell death-ligand 1 (anti-PD-L1) therapy.Conclusions We engineered IL-18 for reinforced stability, extended half-life, and improved manufacturability. The therapeutic benefit of dsIL-18-Fc, coupled with a more favorable manufacturability profile and enhanced drug-like properties, underscores the potential utility of this engineered cytokine in cancer immunotherapy. |
| format | Article |
| id | doaj-art-0eaa0c2f92024555b88b4cb2a4bbaaaa |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-0eaa0c2f92024555b88b4cb2a4bbaaaa2025-08-20T03:27:48ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-07-0113710.1136/jitc-2025-011789Engineered IL-18 variants with half-life extension and improved stability for cancer immunotherapyYue Zhao0Yan Qu1Marina Moskalenko2Dawei Sun3Travis W Bainbridge4Matthieu Masureel5Lifen Wang6Robert Herrera7Maciej T Paluch8Kazi Tasneem9Harpinder Saini10Manal Sadek11Mandy Kwong12Yoon Min Kim13Jay M Bhatt14Christine Tam15Pamela Pui Fung Chan16Ayse Meric Ovacik17Jonathan T Sockolosky18Nathaniel R West19Beyza Bulutoglu204 Biochemical and Cellular Pharmacology, Genentech Inc, South San Francisco, California, USA3 Translational Oncology, Genentech Inc, South San Francisco, California, USA3 Translational Oncology, Genentech Inc, South San Francisco, California, USA1 Protein Sciences, Genentech Inc, South San Francisco, California, USA1 Protein Sciences, Genentech Inc, South San Francisco, California, USA1 Protein Sciences, Genentech Inc, South San Francisco, California, USA2 Discovery Oncology, Genentech Inc, South San Francisco, California, USA4 Biochemical and Cellular Pharmacology, Genentech Inc, South San Francisco, California, USA1 Protein Sciences, Genentech Inc, South San Francisco, California, USA5 Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc, South San Francisco, California, USA4 Biochemical and Cellular Pharmacology, Genentech Inc, South San Francisco, California, USA4 Biochemical and Cellular Pharmacology, Genentech Inc, South San Francisco, California, USA4 Biochemical and Cellular Pharmacology, Genentech Inc, South San Francisco, California, USA1 Protein Sciences, Genentech Inc, South San Francisco, California, USA1 Protein Sciences, Genentech Inc, South San Francisco, California, USA1 Protein Sciences, Genentech Inc, South San Francisco, California, USA4 Biochemical and Cellular Pharmacology, Genentech Inc, South San Francisco, California, USA5 Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc, South San Francisco, California, USA6 Antibody Engineering, Genentech Inc, South San Francisco, California, USA2 Discovery Oncology, Genentech Inc, South San Francisco, California, USA1 Protein Sciences, Genentech Inc, South San Francisco, California, USABackground The pro-inflammatory cytokine, interleukin-18 (IL-18), plays an instrumental role in bolstering anti-tumor immunity. However, the therapeutic application of IL-18 has been limited due to its susceptibility to neutralization by IL-18 binding protein (IL-18BP), short in vivo half-life, and unfavorable physicochemical properties.Methods In order to overcome the poor drug-like properties of IL-18, we installed an artificial disulfide bond, removed the native, unpaired cysteines, and fused the stabilized cytokine to an IgG Fc domain. The stability, potency, pharmacokinetic and pharmacodynamic properties as well as efficacy of disulfide-stabilized IL-18 Fc-fusion (dsIL-18-Fc) were assessed via in vitro and in vivo studies.Results The stability and mammalian host cell production yields of dsIL-18-Fc were improved, compared to the wild-type (WT) cytokine, while maintaining its biological potency and interactions with IL-18 receptor α (IL-18Rα) and IL-18BP. Recombinant fusion of the cytokine to an IgG Fc domain provided extended half-life. Notably, despite maintaining sensitivity to IL-18BP, dsIL-18-Fc was effective at activating both T and natural killer (NK) cells, and elicited a strong anti-tumor response, either as a single agent, or in conjunction with anti-programmed cell death-ligand 1 (anti-PD-L1) therapy.Conclusions We engineered IL-18 for reinforced stability, extended half-life, and improved manufacturability. The therapeutic benefit of dsIL-18-Fc, coupled with a more favorable manufacturability profile and enhanced drug-like properties, underscores the potential utility of this engineered cytokine in cancer immunotherapy.https://jitc.bmj.com/content/13/7/e011789.full |
| spellingShingle | Yue Zhao Yan Qu Marina Moskalenko Dawei Sun Travis W Bainbridge Matthieu Masureel Lifen Wang Robert Herrera Maciej T Paluch Kazi Tasneem Harpinder Saini Manal Sadek Mandy Kwong Yoon Min Kim Jay M Bhatt Christine Tam Pamela Pui Fung Chan Ayse Meric Ovacik Jonathan T Sockolosky Nathaniel R West Beyza Bulutoglu Engineered IL-18 variants with half-life extension and improved stability for cancer immunotherapy Journal for ImmunoTherapy of Cancer |
| title | Engineered IL-18 variants with half-life extension and improved stability for cancer immunotherapy |
| title_full | Engineered IL-18 variants with half-life extension and improved stability for cancer immunotherapy |
| title_fullStr | Engineered IL-18 variants with half-life extension and improved stability for cancer immunotherapy |
| title_full_unstemmed | Engineered IL-18 variants with half-life extension and improved stability for cancer immunotherapy |
| title_short | Engineered IL-18 variants with half-life extension and improved stability for cancer immunotherapy |
| title_sort | engineered il 18 variants with half life extension and improved stability for cancer immunotherapy |
| url | https://jitc.bmj.com/content/13/7/e011789.full |
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