A novel strategy to generate immunocytokines with activity-on-demand using small molecule inhibitors
Abstract Cytokine-based therapeutics have been shown to mediate objective responses in certain tumor entities but suffer from insufficient selectivity, causing limiting toxicity which prevents dose escalation to therapeutically active regimens. The antibody-based delivery of cytokines significantly...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2024-03-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s44321-024-00034-0 |
| _version_ | 1797199250399952896 |
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| author | Giulia Rotta Ettore Gilardoni Domenico Ravazza Jacqueline Mock Frauke Seehusen Abdullah Elsayed Emanuele Puca Roberto De Luca Christian Pellegrino Thomas Look Tobias Weiss Markus G Manz Cornelia Halin Dario Neri Sheila Dakhel Plaza |
| author_facet | Giulia Rotta Ettore Gilardoni Domenico Ravazza Jacqueline Mock Frauke Seehusen Abdullah Elsayed Emanuele Puca Roberto De Luca Christian Pellegrino Thomas Look Tobias Weiss Markus G Manz Cornelia Halin Dario Neri Sheila Dakhel Plaza |
| author_sort | Giulia Rotta |
| collection | DOAJ |
| description | Abstract Cytokine-based therapeutics have been shown to mediate objective responses in certain tumor entities but suffer from insufficient selectivity, causing limiting toxicity which prevents dose escalation to therapeutically active regimens. The antibody-based delivery of cytokines significantly increases the therapeutic index of the corresponding payload but still suffers from side effects associated with peak concentrations of the product in blood upon intravenous administration. Here we devise a general strategy (named “Intra-Cork”) to mask systemic cytokine activity without impacting anti-cancer efficacy. Our technology features the use of antibody-cytokine fusions, capable of selective localization at the neoplastic site, in combination with pathway-selective inhibitors of the cytokine signaling, which rapidly clear from the body. This strategy, exemplified with a tumor-targeted IL12 in combination with a JAK2 inhibitor, allowed to abrogate cytokine-driven toxicity without affecting therapeutic activity in a preclinical model of cancer. This approach is readily applicable in clinical practice. |
| first_indexed | 2024-04-24T07:12:46Z |
| format | Article |
| id | doaj.art-3f9295ee87c944c5ae3975d61e53a157 |
| institution | Directory Open Access Journal |
| issn | 1757-4684 |
| language | English |
| last_indexed | 2024-04-24T07:12:46Z |
| publishDate | 2024-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-3f9295ee87c944c5ae3975d61e53a1572024-04-21T11:26:48ZengSpringer NatureEMBO Molecular Medicine1757-46842024-03-0116490492610.1038/s44321-024-00034-0A novel strategy to generate immunocytokines with activity-on-demand using small molecule inhibitorsGiulia Rotta0Ettore Gilardoni1Domenico Ravazza2Jacqueline Mock3Frauke Seehusen4Abdullah Elsayed5Emanuele Puca6Roberto De Luca7Christian Pellegrino8Thomas Look9Tobias Weiss10Markus G Manz11Cornelia Halin12Dario Neri13Sheila Dakhel Plaza14Philochem AGPhilochem AGPhilochem AGPhilochem AGLaboratory for Animal Model Pathology (LAMP), Institute of Veterinary Pathology, University of ZurichPhilochem AGPhilochem AGPhilochem AGDepartment of Medical Oncology and Hematology, University Hospital Zurich and University of ZurichDepartment of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of ZurichDepartment of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of ZurichDepartment of Medical Oncology and Hematology, University Hospital Zurich and University of ZurichInstitute of Pharmaceutical Sciences, ETH ZurichPhilochem AGPhilochem AGAbstract Cytokine-based therapeutics have been shown to mediate objective responses in certain tumor entities but suffer from insufficient selectivity, causing limiting toxicity which prevents dose escalation to therapeutically active regimens. The antibody-based delivery of cytokines significantly increases the therapeutic index of the corresponding payload but still suffers from side effects associated with peak concentrations of the product in blood upon intravenous administration. Here we devise a general strategy (named “Intra-Cork”) to mask systemic cytokine activity without impacting anti-cancer efficacy. Our technology features the use of antibody-cytokine fusions, capable of selective localization at the neoplastic site, in combination with pathway-selective inhibitors of the cytokine signaling, which rapidly clear from the body. This strategy, exemplified with a tumor-targeted IL12 in combination with a JAK2 inhibitor, allowed to abrogate cytokine-driven toxicity without affecting therapeutic activity in a preclinical model of cancer. This approach is readily applicable in clinical practice.https://doi.org/10.1038/s44321-024-00034-0Cancer ImmunotherapyTumor TargetingAntibody-Cytokine FusionsTolerabilitySmall Molecule Inhibitors |
| spellingShingle | Giulia Rotta Ettore Gilardoni Domenico Ravazza Jacqueline Mock Frauke Seehusen Abdullah Elsayed Emanuele Puca Roberto De Luca Christian Pellegrino Thomas Look Tobias Weiss Markus G Manz Cornelia Halin Dario Neri Sheila Dakhel Plaza A novel strategy to generate immunocytokines with activity-on-demand using small molecule inhibitors EMBO Molecular Medicine Cancer Immunotherapy Tumor Targeting Antibody-Cytokine Fusions Tolerability Small Molecule Inhibitors |
| title | A novel strategy to generate immunocytokines with activity-on-demand using small molecule inhibitors |
| title_full | A novel strategy to generate immunocytokines with activity-on-demand using small molecule inhibitors |
| title_fullStr | A novel strategy to generate immunocytokines with activity-on-demand using small molecule inhibitors |
| title_full_unstemmed | A novel strategy to generate immunocytokines with activity-on-demand using small molecule inhibitors |
| title_short | A novel strategy to generate immunocytokines with activity-on-demand using small molecule inhibitors |
| title_sort | novel strategy to generate immunocytokines with activity on demand using small molecule inhibitors |
| topic | Cancer Immunotherapy Tumor Targeting Antibody-Cytokine Fusions Tolerability Small Molecule Inhibitors |
| url | https://doi.org/10.1038/s44321-024-00034-0 |
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