Tumor Regression upon Intratumoral and Subcutaneous Dosing of the STING Agonist ALG-031048 in Mouse Efficacy Models

• Published in: International journal of molecular sciences Vol. 24; no. 22; p. 16274
• Main Authors: Jekle, Andreas, Thatikonda, Santosh Kumar, Jaisinghani, Ruchika, Ren, Suping, Kinkade, April, Stevens, Sarah K, Stoycheva, Antitsa, Rajwanshi, Vivek K, Williams, Caroline, Deval, Jerome, Mukherjee, Sucheta, Zhang, Qingling, Chanda, Sushmita, Smith, David B, Blatt, Lawrence M, Symons, Julian A, Gonzalvez, Francois, Beigelman, Leonid
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.11.2023
• Subjects: Adenosine; Analysis; Animal experimentation; Antigens; Biological response modifiers; Cancer; Colon cancer; Cytokines; Dendritic cells; Ethylenediaminetetraacetic acid; immune checkpoint inhibitor; immuno-oncology; Interferon; Kinases; Ligands; STING agonist; syngeneic mouse model; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms242216274

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.