Tumor Regression upon Intratumoral and Subcutaneous Dosing of the STING Agonist ALG-031048 in Mouse Efficacy Models
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Published:2023-11-13
Issue:22
Volume:24
Page:16274
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Jekle Andreas1ORCID, Thatikonda Santosh Kumar1, Jaisinghani Ruchika1, Ren Suping1, Kinkade April1, Stevens Sarah K.1, Stoycheva Antitsa1, Rajwanshi Vivek K.1, Williams Caroline1, Deval Jerome1, Mukherjee Sucheta1, Zhang Qingling1, Chanda Sushmita1, Smith David B.1, Blatt Lawrence M.1, Symons Julian A.1, Gonzalvez Francois2ORCID, Beigelman Leonid1
Affiliation:
1. Aligos Therapeutics, Inc., South San Francisco, CA 94080, USA 2. Aligos Belgium BV, 3001 Leuven, Belgium
Abstract
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.
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference29 articles.
1. STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors;Deng;Immunity,2014 2. STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors;Woo;Immunity,2014 3. STING-dependent cytosolic DNA sensing pathways;Barber;Trends Immunol.,2014 4. Role of the cGAS–STING pathway in cancer development and oncotherapeutic approaches;Khoo;Embo Rep.,2018 5. Amouzegar, A., Chelvanambi, M., Filderman, J.N., Storkus, W.J., and Luke, J.J. (2021). STING Agonists as Cancer Therapeutics. Cancers, 13.
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