Resiquimod (R-848) (Synonyms: Resiquimod, S 28463)

Resiquimod (R848) is an imidazoquinoline compound with potential antiviral activity. It is a low molecular weight synthetic molecule that has been evaluated in clinical studies for the treatment of infections caused by viruses such as herpes simplex virus and hepatitis C virus[1]. Resiquimod was found to reduce viral shedding and viral reoccurrence by activating various immune cells to produce an environment conductive for the T-helper 1 (Th1) immune responses[2-3]. Resiquimod is a selective ligand for Toll-like receptor (TLR) 7 in mouse and for TLR7 and TLR8 in human and has been shown to activate only TLR7 and TLR8[4].

Resiquimod(10 µg/ml; 6 or 12 h) induced the increase of high-affinity IgE receptor (FcεRI) expression in native mast cells [5].

Resiquimod 8(3 mg/kg;i.p ; three continuous days in a week for three weeks) exhibited a robust antitumoral effect. Resiquimod reduced tumor vasculature and induced tumor cell apoptosis. Resiquimod increased high mobility group Box 1 expression in tumor tissues and activated CD4+ T cells in the peripheral blood[6]. Resiquimod (10 g; i.p) induces anti-tumor responses and attenuates cachexia in murine models of pancreatic ductal adenocarcinoma (PDAC)[7]. The combination of Resiquimod (3 mg/kg were administered by retro-orbital injections (diluted in PBS, 100 µL per mouse) 1 day before, 1 day after, and 1 week after SBRT treatments (total of 3 times))and SBRT results in significant immune activation of the pancreatic tumor microenvironment (TME), including increased tumor antigen-specific CD8+ T cells, decreased regulatory T cells, and enhanced antigen-presenting cells maturation, as well as increased interferon gamma, granzyme B, and CCL5 along with decreased levels of interleukin 4 (IL-4), IL-6, and IL-10[8].

References:
[1]. Miller RL, Meng TC,et,al. The antiviral activity of Toll-like receptor 7 and 7/8 agonists. Drug News Perspect. 2008 Mar;21(2):69-87. doi: 10.1358/dnp.2008.21.2.1188193. PMID: 18389099.
[2]. Bernstein DI, Harrison CJ, ,et,al. Daily or weekly therapy with resiquimod (R-848) reduces genital recurrences in herpes simplex virus-infected guinea pigs during and after treatment. J Infect Dis. 2001 Mar 15;183(6):844-9. doi: 10.1086/319262. Epub 2001 Feb 13. PMID: 11237799.
[3]. Wu JJ, Huang DB,et,al. Resiquimod: a new immune response modifier with potential as a vaccine adjuvant for Th1 immune responses. Antiviral Res. 2004 Nov;64(2):79-83. doi: 10.1016/j.antiviral.2004.07.002. PMID: 15498602.
[4]. Heil F, Hemmi H,et,al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004 Mar 5;303(5663):1526-9. doi: 10.1126/science.1093620. Epub 2004 Feb 19. PMID: 14976262.
[5]. Agier J, Brzezińska-Błaszczyk E,et,al. The impact of TLR7 agonist R848 treatment on mast cell phenotype and activity. Cell Immunol. 2021 Jan;359:104241. doi: 10.1016/j.cellimm.2020.104241. Epub 2020 Oct 28. PMID: 33158544.
[6]. Yin T, He S,et,al.Toll-like receptor 7/8 agonist, R848, exhibits antitumoral effects in a breast cancer model. Mol Med Rep. 2015 Sep;12(3):3515-3520. doi: 10.3892/mmr.2015.3885. Epub 2015 Jun 3. PMID: 26043701.
[7]. Michaelis KA, Norgard MA,et,al. The TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer. Nat Commun. 2019 Oct 15;10(1):4682. doi: 10.1038/s41467-019-12657-w. Erratum in: Nat Commun. 2019 Nov 15;10(1):5257. PMID: 31615993; PMCID: PMC6794326.
[8]. Ye J, Mills BN,et,al. Toll-like receptor 7/8 agonist R848 alters the immune tumor microenvironment and enhances SBRT-induced antitumor efficacy in murine models of pancreatic cancer. J Immunother Cancer. 2022 Jul;10(7):e004784. doi: 10.1136/jitc-2022-004784. PMID: 35851308; PMCID: PMC9295644.