Tumor Regression upon Intratumoral and Subcutaneous Dosing of the STING Agonist ALG-031048 in Mouse Efficacy Models
Stimulator of interferon genes (STING) agonists have shown potent anti-tumor efficacy in various mouse tumor models and have the potential to overcome resistance to immune checkpoint inhibitors (ICI) by linking the innate and acquired immune systems. First-generation STING agonists are administered intratumorally; however, a systemic delivery route would greatly expand the clinical use of STING agonists. Biochemical and cell-based experiments, as well as syngeneic mouse efficacy models, were used to demonstrate the anti-tumoral activity of ALG-031048, a novel STING agonist. In vitro, ALG-031048 is highly stable in plasma and liver microsomes and is resistant to degradation via phosphodiesterases. The high stability in biological matrices translated to good cellular potency in a HEK 293 STING R232 reporter assay, efficient activation and maturation of primary human dendritic cells and monocytes, as well as long-lasting, antigen-specific anti-tumor activity in up to 90% of animals in the CT26 mouse colon carcinoma model. Significant reductions in tumor growth were observed in two syngeneic mouse tumor models following subcutaneous administration. Combinations of ALG-031048 and ICIs further enhanced the in vivo anti-tumor activity. This initial demonstration of anti-tumor activity after systemic administration of ALG-031048 warrants further investigation, while the combination of systemically administered ALG-031048 with ICIs offers an attractive approach to overcome key limitations of ICIs in the clinic.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
International journal of molecular sciences - 24(2023), 22 vom: 13. Nov. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jekle, Andreas [VerfasserIn] |
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| Links: |
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| Themen: |
Immune checkpoint inhibitor |
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| Anmerkungen: |
Date Completed 27.11.2023 Date Revised 27.11.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.3390/ijms242216274 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Jekle, Andreas |e verfasserin |4 aut | |
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| 520 | |a Stimulator of interferon genes (STING) agonists have shown potent anti-tumor efficacy in various mouse tumor models and have the potential to overcome resistance to immune checkpoint inhibitors (ICI) by linking the innate and acquired immune systems. First-generation STING agonists are administered intratumorally; however, a systemic delivery route would greatly expand the clinical use of STING agonists. Biochemical and cell-based experiments, as well as syngeneic mouse efficacy models, were used to demonstrate the anti-tumoral activity of ALG-031048, a novel STING agonist. In vitro, ALG-031048 is highly stable in plasma and liver microsomes and is resistant to degradation via phosphodiesterases. The high stability in biological matrices translated to good cellular potency in a HEK 293 STING R232 reporter assay, efficient activation and maturation of primary human dendritic cells and monocytes, as well as long-lasting, antigen-specific anti-tumor activity in up to 90% of animals in the CT26 mouse colon carcinoma model. Significant reductions in tumor growth were observed in two syngeneic mouse tumor models following subcutaneous administration. Combinations of ALG-031048 and ICIs further enhanced the in vivo anti-tumor activity. This initial demonstration of anti-tumor activity after systemic administration of ALG-031048 warrants further investigation, while the combination of systemically administered ALG-031048 with ICIs offers an attractive approach to overcome key limitations of ICIs in the clinic | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a immune checkpoint inhibitor | |
| 650 | 4 | |a immuno-oncology | |
| 650 | 4 | |a syngeneic mouse model | |
| 700 | 1 | |a Thatikonda, Santosh Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Jaisinghani, Ruchika |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Suping |e verfasserin |4 aut | |
| 700 | 1 | |a Kinkade, April |e verfasserin |4 aut | |
| 700 | 1 | |a Stevens, Sarah K |e verfasserin |4 aut | |
| 700 | 1 | |a Stoycheva, Antitsa |e verfasserin |4 aut | |
| 700 | 1 | |a Rajwanshi, Vivek K |e verfasserin |4 aut | |
| 700 | 1 | |a Williams, Caroline |e verfasserin |4 aut | |
| 700 | 1 | |a Deval, Jerome |e verfasserin |4 aut | |
| 700 | 1 | |a Mukherjee, Sucheta |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Qingling |e verfasserin |4 aut | |
| 700 | 1 | |a Chanda, Sushmita |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, David B |e verfasserin |4 aut | |
| 700 | 1 | |a Blatt, Lawrence M |e verfasserin |4 aut | |
| 700 | 1 | |a Symons, Julian A |e verfasserin |4 aut | |
| 700 | 1 | |a Gonzalvez, Francois |e verfasserin |4 aut | |
| 700 | 1 | |a Beigelman, Leonid |e verfasserin |4 aut | |
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