Targeted chain-exchange-mediated reconstitution of a split type-I cytokine for conditional immunotherapy
ABSTRACTAntibody-cytokine fusions targeted against tumor-associated antigens (TAAs) are promising cancer immunotherapy agents, with many such molecules currently undergoing clinical trials. However, due to the limited number of tumor-specific targets, on-target off-tumor effects can lead to systemic...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2023-12-01
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| Series: | mAbs |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2023.2245111 |
| _version_ | 1797356305726308352 |
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| author | Vedran Vasic Can Buldun Manfred Ritz Steffen Dickopf Guy J. Georges Christian Spick Alessa Peuker Thomas Meier Klaus Mayer Ulrich Brinkmann |
| author_facet | Vedran Vasic Can Buldun Manfred Ritz Steffen Dickopf Guy J. Georges Christian Spick Alessa Peuker Thomas Meier Klaus Mayer Ulrich Brinkmann |
| author_sort | Vedran Vasic |
| collection | DOAJ |
| description | ABSTRACTAntibody-cytokine fusions targeted against tumor-associated antigens (TAAs) are promising cancer immunotherapy agents, with many such molecules currently undergoing clinical trials. However, due to the limited number of tumor-specific targets, on-target off-tumor effects can lead to systemic toxicity. Additionally, targeted cytokines can be scavenged by cytokine receptors on peripheral cells, decreasing tumor penetration. This study aims at overcoming these issues by engineering a platform for targeted conditionally active type I cytokines. Building on our previously reported PACE (Prodrug-Activating Chain Exchange) platform, we split the type I cytokine interleukin-4 (IL-4) to create two inactive IL-4 prodrugs, and fused these split IL-4 counterparts to the C-termini of antibody-like molecules that undergo proximity-induced chain exchange. In doing so, we developed IL-4 prodrugs that preferentially reconstitute into active IL-4 on target cells. We demonstrate that pre-assembled split IL-4 (without additional inactivation) retains activity and present two different strategies of splitting and inactivating IL-4. Using an IL-4 responsive cell-line, we show that IL-4 prodrugs are targeted to TAAs on target cells and regain activity upon chain exchange, primarily in a cis-activation setting. Furthermore, we demonstrate that split IL-4 complementation is also possible in a trans-activation setting, which opens up the possibility for activation of immune cells in the tumor vicinity. We demonstrate that targeted on-cell prodrug conversion is more efficient than nonspecific activation in-solution. Due to the structural similarity between IL-4 and other type I cytokines relevant in cancer immunotherapy such as IL-2, IL-15, and IL-21, cytokine-PACE may be expanded to develop a variety of targeted conditionally active cytokines for cancer immunotherapy. |
| first_indexed | 2024-03-08T14:24:42Z |
| format | Article |
| id | doaj.art-ee329adfb2144539ad1e235379420104 |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-03-08T14:24:42Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-ee329adfb2144539ad1e2353794201042024-01-13T11:27:51ZengTaylor & Francis GroupmAbs1942-08621942-08702023-12-0115110.1080/19420862.2023.2245111Targeted chain-exchange-mediated reconstitution of a split type-I cytokine for conditional immunotherapyVedran Vasic0Can Buldun1Manfred Ritz2Steffen Dickopf3Guy J. Georges4Christian Spick5Alessa Peuker6Thomas Meier7Klaus Mayer8Ulrich Brinkmann9Roche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyReagent Research and Design, Roche Diagnostics GmbH, Penzberg, GermanyReagent Research and Design, Roche Diagnostics GmbH, Penzberg, GermanyRoche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyRoche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich, Penzberg, GermanyABSTRACTAntibody-cytokine fusions targeted against tumor-associated antigens (TAAs) are promising cancer immunotherapy agents, with many such molecules currently undergoing clinical trials. However, due to the limited number of tumor-specific targets, on-target off-tumor effects can lead to systemic toxicity. Additionally, targeted cytokines can be scavenged by cytokine receptors on peripheral cells, decreasing tumor penetration. This study aims at overcoming these issues by engineering a platform for targeted conditionally active type I cytokines. Building on our previously reported PACE (Prodrug-Activating Chain Exchange) platform, we split the type I cytokine interleukin-4 (IL-4) to create two inactive IL-4 prodrugs, and fused these split IL-4 counterparts to the C-termini of antibody-like molecules that undergo proximity-induced chain exchange. In doing so, we developed IL-4 prodrugs that preferentially reconstitute into active IL-4 on target cells. We demonstrate that pre-assembled split IL-4 (without additional inactivation) retains activity and present two different strategies of splitting and inactivating IL-4. Using an IL-4 responsive cell-line, we show that IL-4 prodrugs are targeted to TAAs on target cells and regain activity upon chain exchange, primarily in a cis-activation setting. Furthermore, we demonstrate that split IL-4 complementation is also possible in a trans-activation setting, which opens up the possibility for activation of immune cells in the tumor vicinity. We demonstrate that targeted on-cell prodrug conversion is more efficient than nonspecific activation in-solution. Due to the structural similarity between IL-4 and other type I cytokines relevant in cancer immunotherapy such as IL-2, IL-15, and IL-21, cytokine-PACE may be expanded to develop a variety of targeted conditionally active cytokines for cancer immunotherapy.https://www.tandfonline.com/doi/10.1080/19420862.2023.2245111antibody engineeringantibody-cytokine fusionscancer immunotherapyconditional activation |
| spellingShingle | Vedran Vasic Can Buldun Manfred Ritz Steffen Dickopf Guy J. Georges Christian Spick Alessa Peuker Thomas Meier Klaus Mayer Ulrich Brinkmann Targeted chain-exchange-mediated reconstitution of a split type-I cytokine for conditional immunotherapy mAbs antibody engineering antibody-cytokine fusions cancer immunotherapy conditional activation |
| title | Targeted chain-exchange-mediated reconstitution of a split type-I cytokine for conditional immunotherapy |
| title_full | Targeted chain-exchange-mediated reconstitution of a split type-I cytokine for conditional immunotherapy |
| title_fullStr | Targeted chain-exchange-mediated reconstitution of a split type-I cytokine for conditional immunotherapy |
| title_full_unstemmed | Targeted chain-exchange-mediated reconstitution of a split type-I cytokine for conditional immunotherapy |
| title_short | Targeted chain-exchange-mediated reconstitution of a split type-I cytokine for conditional immunotherapy |
| title_sort | targeted chain exchange mediated reconstitution of a split type i cytokine for conditional immunotherapy |
| topic | antibody engineering antibody-cytokine fusions cancer immunotherapy conditional activation |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2023.2245111 |
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