Review
Post Screen
Current and future drugs targeting one class of innate immunity receptors: the Toll-like receptors

https://doi.org/10.1016/j.drudis.2006.11.007Get rights and content

Innate immunity receptors are germline-encoded receptors that can sense molecular signatures of pathogens and cancer cells. Recent advances in immunology demonstrate the key role of these receptors in inflammation and initiation of subsequent immune responses, including adaptive immunity. Pharmaceutical interest in this field has grown with the retrospective demonstration that some marketed drugs targeting cancer or infectious diseases act via those receptors. In this review, I present an update on the scientific rationale for targeting one class of innate immunity receptor, the Toll-like receptors, and an update on the development status of corresponding drug candidates in infectious diseases, cancer, allergy and vaccines.

Introduction

The mammalian immune system protects against invading pathogens and cancer cells and can be divided into two major components: the innate immune response and the adaptive immune response. The former is composed of several types of cells, including dendritic cells (DCs), macrophages and monocytes, polynuclear cells (e.g. neutrophils and mast cells), natural killer (NK) cells, γδ T cells and natural killer T cells (NKT cells). The innate immune system detects large classes of pathogens or abnormal cells through a limited number of germline-encoded receptors such as Toll-like receptors (TLRs), and serves as a first line of defense against infectious agents, preventing rapidly dividing pathogens from overwhelming the infected organism.

The adaptive immune response is the basis of immunological memory, used by vaccines. It is mediated through T cells and B cells bearing clonal receptors (i.e. T-cell receptors and antibodies) generated randomly through somatic recombination. The T and B cells that express receptors with high affinity and specificity for molecular structures of pathogens or abnormal cells undergo clonal expansion, exert their effector function and are conserved as memory cells.

Interest in innate immunity cells and receptors has recently increased because their central role in triggering inflammatory signals that are necessary for a subsequent immune response cascade was demonstrated, and because it was found recently that innate immunity signals serve as gatekeepers for mounting an efficient adaptive immune response. Thus, coordinated actions of innate and adaptive immune cells will eventually lead to the complete removal of the pathogen and to the generation of memory, which will guarantee a more rapid and accurate response in case of re-infection (Table 1; Figure 1).

The structures recognized by innate immunity cells are a limited array of conserved molecules that represent the molecular signature of pathogens and transformed cells. These structures, usually called pathogen-associated molecular patterns (PAMPs), are highly conserved (e.g. bacterial cell wall components) and are often essential for pathogen survival.

Innate immunity receptors, referred to as pattern recognition receptors (PRRs), are a class of proteins capable of recognizing PAMPs. The recently discovered TLRs represent the best-characterized class of PRR. Ten different TLRs have been identified, each of them recognizing one, or several, PAMP. Signaling through PRRs is transmitted through evolutionary conserved inflammation pathways, for example via nuclear factor-κB (NF-κB) and activation of interferon regulatory factor (IRF), explaining the central role of PRRs in triggering inflammation processes that further enhance activation of innate immune effectors, and are necessary for the development of potent adaptive responses.

Genetic PRR defects lead to increased risks for different types of infections and cancer [1]. Agonists of PRRs are, therefore, attractive targets to stimulate both arms of the immune response in infectious diseases and cancer indications; conversely, antagonists can be important in controlling some chronic inflammation processes. The natural PRR ligands, or PAMPs, are often the basis for first generation agonist molecules that can be developed for proof-of-concept experiments in preclinical models or in early clinical trials. This strategy has been applied to several TLRs, and a few other innate immunity receptors such as receptors of γδ T cells 2, 3 and NK cells 4, 5. Because drugs targeting TLRs are much more advanced in clinical development, this review will focus on this family of receptors, describe the current understanding of TLR function and the scientific rationale for developing TLR agonists, as well as the current status of drugs that target these receptors in vaccines, infectious disease, allergy and cancer.

Section snippets

Toll-like receptors: key receptors for inflammatory processes

Only six years have passed since the discovery of the first TLR 6, 7, 8, and rarely has a research field exploded so rapidly. All the TLRs (i.e. ten human TLRs) have now been cloned, a lot of their ligands discovered and the main signaling pathways identified – following homology searches in the human genome, the list seems to be closed. Many excellent in-depth reviews have been published describing the natural ligands and molecular pathways of signal transduction 9, 10, 11 and they are briefly

Clinical trials involving Toll-like receptor agonists

The rationale for using TLR agonists that trigger inflammation will result in the production of cytokines, activation of innate immunity effector cells and, eventually, the adaptive immune response against cancer cells or infectious agents that could lead to long-term protection. Depending on the type of inflammatory signals they induce, different agonists targeting different receptors have been developed as vaccine adjuvants, anti-infectious agents, anticancer agents and in anti-allergy

Future challenges in the use of Toll-like receptor agonists

Although the clinical results mentioned here are encouraging in several indications, questions remain to be answered so that a clear rationale about how to use TLR agonists can be formed.

First, although most molecules in development are agonists, several preclinical data show the involvement of innate immunity receptors, such as TLR9 [42] and NKG2D [43], in some chronic inflammatory diseases [10]. Indeed, some self molecular structures are very similar or identical to TLR ligands and, if

Concluding remarks

From their mechanism of action, innate immunity receptor agonists have an obvious potential interest as vaccine-adjuvant or anti-infectious agents. TLR agonists have already demonstrated their value in these indications as vaccine adjuvants (e.g. MPL – a vaccine adjuvant for HBV) and stand-alone therapies (e.g. imiquimod – a cream for the treatment of genital warts). Encouraging results in early-phase clinical trials in HBV and HCV show that TLR agonists could be important in other therapeutic

Acknowledgements

I thank Y. Morel, C. Paturel and L. Voellmy for helpful discussions and critical reading of the article.

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