Review Article Imiquimod applied topically: a novel immune response modifier and new class of drug

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Abstract

Imiquimod (S-26308, R-837) (1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4 amine), an immune response modifier, demonstrates potent antiviral and antitumor activity in animal models (see structure in Fig. 1

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Fig. 1. R 837, Imiquimod.

). The drug exhibits no direct antiviral or antiproliferative activity when tested in a number of cell culture systems. Imiquimods activity was discovered while screening for anti-herpes virus activity. One of the first analogs in the series, S-25059 was tested in the early 1980s and due to slight toxicity, caused slightly reduced herpes cytopathology in Vero cell cultures. Follow-up testing in herpes infected guinea pigs showed complete protection toward lesion development. Activity of these drugs results primarily from interferon alpha (IFN-α) induction and other cytokine induction. At least part of the cytokine induction is mediated through NF-κB activation. These cytokines stimulate several other aspects of the innate immune response. In addition, imiquimod stimulates acquired immunity, in particular the cellular arm which is important for control of viral infections and various tumors. This effect is mediated by drug induced IFN-α and Interleukin-12 (IL-12) and IFN-γ induced by these cytokines. Imiquimod is expected to be effective where exogenous IFN-α has shown utility and where enhancement of cell-mediated immunity is needed. The following is a brief review of the preclinical pharmacology of imiquimod and the clinical results of genital wart trials. The mechanism of action of topically applied imiquimod will likely lead to benefits in several other chronic virus infections and tumors of the skin. Two other reviews on imiquimod that focus mainly on the clinical results have been published (Beutner and Geisse, 1997; Slade et al., 1998).

Section snippets

Effects on innate immunity

When incubated with mouse spleen cells in vitro, imiquimod at 0.2 μg/ml induces the synthesis and release of IFN, IL-6, tumor necrosis factor-α (TNF-α) and probably other cytokines (Reiter et al., 1994). Imiquimod also causes non-specific B-cell proliferation which may be mediated directly by the drug and not through cytokine induction (Tomai et al., 1994).

The mouse macrophage cell line, RAW 264.7, produces TNF in response to 3 μg/ml of imiquimod. Saturable specific binding of closely related

Effects on acquired immunity

Although imiquimod does not stimulate T cells to divide or directly induce T cell cytokines such as IL-2, IL-4 or IL-5, imiquimod is capable of indirectly stimulating production of the T helper type 1 (Th1) cytokine, IFN-γ, in mouse splenic and bone marrow cultures as well as human PBMC cultures. Production of IFN-γ in response to imiquimod is inhibited by antibodies to IL-12 and IFN-α, demonstrating the importance of these monocyte/macrophage cytokines (Tomai et al., 1998). The mechanism of

Clinical mechanism of action study

The data generated in animal models suggest that imiquimods antiviral and antitumor effects are largely mediated through the induction of cytokines that drive the innate and cell-mediated immune response. A study was carried out in humans to further explore the drugs mechanism of action (Tyring et al., 1998). The objective of this study was to evaluate the mechanism of action of imiquimod 5% cream when applied topically to genital warts in human patients by: (1) investigating local and systemic

Summary of clinical efficacy trials

Imiquimod cream was applied topically and tested for efficacy in patients with external genital and/or perianal warts (condylomata acuminata). Genital warts, the most common viral sexually transmitted disease, was chosen as the first clinical target because injectable IFN-α had demonstrated some benefit and the current therapies do not meet the patients or physicians needs. Patient dissatisfaction with current therapeutic options is significant due to pain, tissue destruction, high recurrence

Oral delivery

Some clinical testing of imiquimod was also carried out by the oral route. A single dose study in normal volunteers indicated that measurable serum IFN levels were obtained in four of six subjects after 200 mg and in six of six subjects after 300 mg. Peak levels of IFN were seen at 12 h after dosing and levels returned to baseline by 24 h. Activity of 2,5-AS was elevated for 96 h after the 300 mg dose and this activity correlated with antiviral activity in the subject PBMCs. The drug was well

New class of drug

The preclinical and mechanism of action study in patients indicate that topically applied imiquimod results in the induction of several cytokines at the treatment site. Cytokines such as IFN and others inhibit virus production and inhibit tumor cell growth. The drug also enhances aspects of the cell mediated immune (CMI) response and may result in long term protection from the initial virus or tumor. Application of the drug to warts by wart patients, in the privacy of their own home produced a

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