Imiquimod

Imiquimod (R837), an imidazoquinoline amine analog to guanosine, is an immune response modifier with potent antiviral and antitumor activities [1].

Imiquimod is approved for the topical treatment of genital warts, basal cell carcinoma, and bladder cancer. Imiquimod exerts its immune-modulating activity by inducing the production of pro-inflammatory cytokines, such as IFN-α and IL-12, leading to the activation of both innate and acquired immunity [2]. This activity of imiquimod is in part due to its capacity to bind to and stimulate Toll-like receptor (TLR) 7, suggesting a potential role of Imiquimod to act as an adjuvant [3, 4]. Preclinical studies in mice have shown the effectiveness of imiquimod in inducing immune responses to immunization using various vaccination strategies [5-7].

Imiquimod has been shown to increase both antibody and cell-mediated immune responsiveness induced by a DNA vaccine. In a genetically engineered mouse model, a DNA vaccine encoding HER2/neu adjuvanted with imiquimod was reported to significantly delay the development of spontaneous mammary tumors [6]. This antitumor effect was accompanied by a significant increase in Ag-specific antibody (Ab) production and cytotoxic T cell activity, as well as a switch from IgG1 to IgG2a Ab isotype, suggesting a Th1 polarization of the immune response.

TLR7 and TLR8

TLR7 and TLR8 are endosomal pattern recognition receptors that share structural homology [8]. Both receptors are activated by single-stranded RNA (ssRNA) molecules, however, they exhibit different ligand-binding specificities and cellular expression patterns suggesting that they have nonredundant specialized roles.

TLR7 is essentially expressed by plasmacytoid dendritic cells (pDCs) but is also found in B cells and other myeloid cells [2] while TLR8 is highly expressed by myeloid cells and is absent from pDCs and B cells [9].

The endosomal distribution of TLR7 and TLR8 allows them to scan for the presence of microbial RNA in the phagocytic cargo. Their activation leads to NF-κB-, AP1-, and interferon regulatory factor (IRF)-mediated production of type I interferons (IFN-α/β) and pro-inflammatory cytokines [9].

Structural analyses have revealed that both TLR7 and TLR8 possess two binding sites (designated as Site 1 and Site 2) which do not share the same specificities.

Site 1 is highly conserved between TLR7 and TLR8 and binds nucleosides (guanosine (G) for TLR7 and uridine (U) for TLR8) or base analogs. The ligand preference for TLR7 and TLR8 is thus explained by the presence of specific residues in Site 1. Site 1 occupancy allows receptor dimerization and signaling.

Site 2 is less conserved and binds ssRNA with U(U) and U(G) motifs, respectively [10, 11]. Of note, ssRNA-binding to Site 2 is not sufficient for the formation of a signaling-competent TLR dimer but it strongly enhances the binding affinity of Site 1 [3, 4]. Thus, TLR7 and TLR8 appear to sense distinct RNA-degradation products rather than full-length ssRNAs [11].

References:

1. Suader DN., 2000. Immunomodulatory and pharmacologic properties of Imiquimod. J Am Acad Dermatol 43: S6−S11.
2. Stanley MA., 2002. Imiquimod and the imidazoquinolines: mechanism of action and therapeutic potential. Clin Dermatol 27:571−577.
3. Hemmi H. et al. 2002. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol, 3(2):196-200.
4. Schon MP & Schon M., 2004. Immune modulation and apoptosis induction: two sides of the antitumoral activity of Imiquimod. Apoptosis 9: 291−298.
5. Thomsen LL et al., 2004. Imiquimod and resiquimod in a mouse model: adjuvants for DNA vaccination by particle mediated immunotherapeutic delivery. Vaccine 22: 1799−1809.
6. Smorlesi A. et al.,2005. Imiquimod and S-27609 as adjuvants of DNA vaccination in a transgenic murine model of HER2/neu-positive mammary carcinoma. Gene Ther. 12(17):1324-32.
7. Triozzi PL. et al., 2010. Regulation of the activity of an adeno-associated virus vector cancer vaccine administered with synthetic Toll-like receptor agonists. Vaccine. 28(50):7837-43.
8. Chuang T.H. & Ulevitch R.J., 2000. Cloning and characterization of a sub-family of human toll-like receptors: hTLR7, hTLR8, and hTLR9. Eur Cytokine Netw, 11:372-8.
9. Georg P. & Sander L.E., 2019. Innate sensors that regulate vaccine responses. Curr. Op. Immunol. 59:31.
10. Zhang Z. et al., 2018. Structural analyses of Toll-like receptor 7 reveal detailed RNA sequence specificity and recognition mechanism of agonistic ligands. Cell Rep. 25:3371.
11. Tanji H. et al., 2015. Toll-like receptor 8 senses degradation products of single-stranded RNA. Nat. Struct. Mol. Biol. 22:109.

Chemical structure of imiquimod

Chemical structure of CL075

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