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TL-532, a novel specific Toll-like receptor 3 agonist rationally designed for targeting cancers: discovery process
Sylvain Thierry1, Sarah Maadadi1, Aurore Berton1
1TOLLYS SAS, 60F avenue Rockefeller, Lyon, France; Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France.
Abstract:
Toll-like receptor 3 (TLR3) is an innate immune receptor that recognizes double-stranded RNA (dsRNA) and induces inflammation in immune and normal cells to initiate anti-microbial responses. TLR3 acts also as a death receptor only in cancer cells but not in their normal counterparts, making it an attractive target for cancer therapies. To date, all of the TLR3-activating dsRNAs used at preclinical or clinical stages have major drawbacks such as structural heterogeneity, toxicity, and lack of specificity and/or efficacy. We conducted the discovery process of a new family of TLR3 agonists that are chemically manufactured on solid-phase support and perfectly defined in terms of sequence and size. A stepwise discovery process was performed leading to the identification of TL-532, a 70 base pair dsRNA that is potent without transfection reagent and is highly specific for TLR3 without activating other innate nucleic sensors such as RIG-I/MDA5, TLR7, TLR8, and TLR9. TL-532 induces inflammation in murine RAW264.7 myeloid macrophages, in human NCI-H292 lung cancer cells, and it promotes immunogenic apoptosis in tumor cells in vitro and ex vivo without toxicity towards normal primary cells. In conclusion, we identified a novel TLR3 agonist called TL-532 that has promising anticancer properties.
Insights
Researchers discovered TL-532, a novel double-stranded RNA (dsRNA) that activates Toll-like receptor 3 (TLR3). This potent TLR3 agonist shows promise as a targeted cancer therapy by inducing tumor cell death without harming normal cells.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Toll-like receptor 3 (TLR3) recognizes double-stranded RNA (dsRNA), initiating antimicrobial responses.
- TLR3 functions as a death receptor specifically in cancer cells, presenting a therapeutic target.
- Existing dsRNA TLR3 agonists have limitations including heterogeneity, toxicity, and lack of specificity.
Purpose of the Study:
- To discover and characterize a novel, chemically defined dsRNA TLR3 agonist.
- To evaluate the specificity, potency, and therapeutic potential of the identified agonist in cancer models.
Main Methods:
- Solid-phase synthesis of chemically defined dsRNAs.
- Stepwise discovery process to identify potent and specific TLR3 agonists.
- In vitro and ex vivo assays using cancer cell lines and primary cells to assess TLR3 activation, inflammation, and apoptosis.
Main Results:
- Identification of TL-532, a 70 base pair dsRNA, as a potent TLR3 agonist.
- TL-532 demonstrated high specificity for TLR3, without activating other innate nucleic acid sensors.
- TL-532 induced inflammation and immunogenic apoptosis in cancer cells without toxicity to normal cells.
Conclusions:
- TL-532 is a novel, chemically defined dsRNA that potently and specifically activates TLR3.
- TL-532 exhibits promising anticancer properties, including induction of immunogenic apoptosis in tumor cells.
- This new TLR3 agonist represents a potential therapeutic agent for cancer treatment.
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