TL-532, a novel specific Toll-like receptor 3 agonist rationally designed for targeting cancers: discovery process and biological characterization
Authors:Sylvain Thierry1, Sarah Maadadi1, Aurore Berton1, Laura Dimier1, Clémence Perret1, Nelly Vey1, Saïd Ourfali2, Mathilde Saccas1, Solène Caron1, Mathilde Boucard-Jourdin1, Marc Colombel3, Bettina Werle1 and Marc Bonnin1
doi: 10.15698/mic2023.06.797
Volume 10, pp. 117 to 132, published 19/04/2023.
1 TOLLYS SAS, 60F avenue Rockefeller, Lyon, France; Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France.
2 Service d’Urologie et Chirurgie de la Transplantation, Hospices Civils de Lyon, Lyon, France. Université Claude Bernard Lyon 1; TOLLYS SAS, 60F avenue Rockefeller, Lyon, France; Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France.
3 Service d’Urologie et Chirurgie de la Transplantation, Hospices Civils de Lyon, Lyon, France; Univ Lyon, Université Claude Bernard Lyon 1.
Keywords:
Toll-like receptor 3, agonist, cancer therapy, apoptosis, inflammation.
Corresponding Author(s):
Conflict of interest statement:
ST, SM, AB, LD, CP, NV, SO, MS, SC, MBJ, BW, and MB are employees of TOLLYS SAS company (Lyon, France). A patent was filled in 2019 (Bonnin M. & Thierry S., WO2019/211492 A1, “TLR3 LIGANDS THAT ACTIVATE BOTH EPITHELIAL AND MYELOID CELLS”).
Please cite this article as:
Sylvain Thierry, Sarah Maadadi, Aurore Berton, Laura Dimier, Clémence Perret, Nelly Vey, Saïd Ourfali, Mathilde Saccas, Solène Caron, Mathilde Boucard-Jourdin, Marc Colombel, Bettina Werle and Marc Bonnin (2023). TL-532, a novel specific Toll-like receptor 3 agonist rationally designed for targeting cancers: discovery process and biological characterization. Microbial Cell 10(6): 117-132. doi: 10.15698/mic2023.06.797
© 2023 Thierry et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
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.