Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapy
Novel engineered IL-2 agonists strive to increase the therapeutic window of aldesleukin (human IL-2) by increasing selectivity toward effector over regulatory T cells and reducing dose-limiting toxicities. Here we describe ANV419, an IL-2/anti-IL2 antibody fusion protein designed for selective IL-2...
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2381891 |
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| author | Patrizia Murer Barbara Brannetti Jean-Michel Rondeau Laetitia Petersen Nicole Egli Simone Popp Catherine Regnier Kirsten Richter Andreas Katopodis Christoph Huber |
| author_facet | Patrizia Murer Barbara Brannetti Jean-Michel Rondeau Laetitia Petersen Nicole Egli Simone Popp Catherine Regnier Kirsten Richter Andreas Katopodis Christoph Huber |
| author_sort | Patrizia Murer |
| collection | DOAJ |
| description | Novel engineered IL-2 agonists strive to increase the therapeutic window of aldesleukin (human IL-2) by increasing selectivity toward effector over regulatory T cells and reducing dose-limiting toxicities. Here we describe ANV419, an IL-2/anti-IL2 antibody fusion protein designed for selective IL-2 receptor βγ (IL-2 Rβγ) activation by sterically hindering IL-2 from binding to IL-2 Rα. The fusion protein has an IL-2 connected to the light chain complementarity-determining region (CDR) domain of a humanized antibody that binds to IL-2 at the same epitope as IL-2 Rα. Optimization of the selectivity and pharmacological properties led to the selection of ANV419. ANV419 preferentially expands CD8+ T cells and natural killer (NK) cells over Tregs and can be safely administered at doses that elicit strong pharmacodynamic effects and efficacy in mouse tumor models. Its anti-tumor efficacy was enhanced when combined with programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors. ANV419 also enhances the NK cell killing capacity and increases tumor growth inhibition when used alongside trastuzumab in a Her-2+ xenograft mouse model. In cynomolgus monkeys, the estimated half-life of ANV419 is 24 h, and doses that induced sustained expansion of effector cells were well tolerated without the severe toxicities typically observed with high-dose IL-2. These data support the clinical development of ANV419 in solid tumors and hematological malignancies as monotherapy and in combination with checkpoint inhibitors or agents that induce antibody-dependent cellular cytotoxicity. ANV419 is currently in Phase 1/2 clinical development and may provide cancer patients with a wider therapeutic window than aldesleukin. |
| format | Article |
| id | doaj-art-c58320a3176c45a68cbb1b5dbf7c8122 |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-c58320a3176c45a68cbb1b5dbf7c81222025-01-31T04:19:37ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2381891Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapyPatrizia Murer0Barbara Brannetti1Jean-Michel Rondeau2Laetitia Petersen3Nicole Egli4Simone Popp5Catherine Regnier6Kirsten Richter7Andreas Katopodis8Christoph Huber9Anaveon AG, Basel, SwitzerlandNovartis Institutes for BioMedical Research, Cambridge, MA, USANovartis Institutes for Biomedical Research, Basel, SwitzerlandAnaveon AG, Basel, SwitzerlandAnaveon AG, Basel, SwitzerlandNovartis Institutes for Biomedical Research, Basel, SwitzerlandNovartis Institutes for Biomedical Research, Basel, SwitzerlandAnaveon AG, Basel, SwitzerlandAnaveon AG, Basel, SwitzerlandAnaveon AG, Basel, SwitzerlandNovel engineered IL-2 agonists strive to increase the therapeutic window of aldesleukin (human IL-2) by increasing selectivity toward effector over regulatory T cells and reducing dose-limiting toxicities. Here we describe ANV419, an IL-2/anti-IL2 antibody fusion protein designed for selective IL-2 receptor βγ (IL-2 Rβγ) activation by sterically hindering IL-2 from binding to IL-2 Rα. The fusion protein has an IL-2 connected to the light chain complementarity-determining region (CDR) domain of a humanized antibody that binds to IL-2 at the same epitope as IL-2 Rα. Optimization of the selectivity and pharmacological properties led to the selection of ANV419. ANV419 preferentially expands CD8+ T cells and natural killer (NK) cells over Tregs and can be safely administered at doses that elicit strong pharmacodynamic effects and efficacy in mouse tumor models. Its anti-tumor efficacy was enhanced when combined with programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors. ANV419 also enhances the NK cell killing capacity and increases tumor growth inhibition when used alongside trastuzumab in a Her-2+ xenograft mouse model. In cynomolgus monkeys, the estimated half-life of ANV419 is 24 h, and doses that induced sustained expansion of effector cells were well tolerated without the severe toxicities typically observed with high-dose IL-2. These data support the clinical development of ANV419 in solid tumors and hematological malignancies as monotherapy and in combination with checkpoint inhibitors or agents that induce antibody-dependent cellular cytotoxicity. ANV419 is currently in Phase 1/2 clinical development and may provide cancer patients with a wider therapeutic window than aldesleukin.https://www.tandfonline.com/doi/10.1080/19420862.2024.2381891ANV419cancer immunotherapyeffector T cellsIL-2Rβγ agonistimmunocytokineimmunotherapy |
| spellingShingle | Patrizia Murer Barbara Brannetti Jean-Michel Rondeau Laetitia Petersen Nicole Egli Simone Popp Catherine Regnier Kirsten Richter Andreas Katopodis Christoph Huber Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapy mAbs ANV419 cancer immunotherapy effector T cells IL-2Rβγ agonist immunocytokine immunotherapy |
| title | Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapy |
| title_full | Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapy |
| title_fullStr | Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapy |
| title_full_unstemmed | Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapy |
| title_short | Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapy |
| title_sort | discovery and development of anv419 an il 2 anti il 2 antibody fusion protein with potent cd8 t and natural killer cell stimulating capacity for cancer immunotherapy |
| topic | ANV419 cancer immunotherapy effector T cells IL-2Rβγ agonist immunocytokine immunotherapy |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2381891 |
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