New Advances and Potential Therapies for the Treatment of Asthma

Biodrugs 2004; 18 (4): 211-223NOVEL THERAPEUTIC STRATEGIES 1173-8804/04/0004-0211/$31.00/0

© 2004 Adis Data Information BV. All rights reserved.

New Advances and Potential Therapies for theTreatment of AsthmaMaria G. Belvisi, David J. Hele and Mark A. Birrell

Respiratory Pharmacology Group, Cardiothoracic Surgery, National Heart & Lung Institute, Faculty of Medicine, ImperialCollege, London, UK

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2111. Therapeutic Approaches Targeting Specific Components or Steps in the Allergic Response in Asthma . . . . . . . . . . . . . . . . . . . . . . . 212

1.1 T Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2121.1.1 Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2121.1.2 Antigen Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2131.1.3 T-Cell Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2141.1.4 T-Cell Phenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2141.1.5 T-Cell Chemotaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

1.2 Eosinophils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2151.3 Mast Cells/Basophils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216

1.3.1 IgE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2161.3.2 Histamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2171.3.3 Leukotrienes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2181.3.4 Tryptase/Chymase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

1.4 Other Mediators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2181.4.1 Adenosine Receptor Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2181.4.2 Prostanoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2181.4.3 TNFα . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

2. General Anti-Inflammatory Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2192.1 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2192.2 Phosphodiesterase 4 Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2192.3 p38 Mitogen-Activated Protein Kinase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2192.4 Peroxisome Proliferator-Activated Receptor Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2202.5 Lipoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

Asthma is a disease of the airways with an underlying inflammatory component. The prevalence andAbstracthealthcare burden of asthma is still rising and is predicted to continue to rise in the current century. Inhaledβ2-adrenoceptor agonists and corticosteroids form the basis of the treatments available to alleviate the symptomsof asthma. There is a need for novel, safe treatments to tackle the underlying inflammation that characterizesasthma pathology. Furthermore, there is a requirement for new treatments to be developed as oral therapy inorder to alleviate patient compliance issues, especially in children. A multitude of new approaches and newtargets are being investigated, which may provide opportunities for novel therapeutic interventions in thisdebilitating disease. For simplicity, these approaches can be divided into two categories. The first comprisestherapies directed against specific components or steps seen in allergic asthma. By ‘components’ we mean thekey inflammatory cells (T cells [in particular Th2], B cells, eosinophils, mast cells, basophils and antigenpresenting cells [APC]) and mediators (immunoglobulin E [IgE], cytokines, histamines, leukotrienes and

212 Belvisi et al.

prostanoids) believed to be involved in the chronic inflammation seen in asthma. By ‘steps’ we mean the allergicresponse, such as antigen processing and presentation, Th2-cell activation, B-cell isotype switching, mast cellinvolvement and airway remodeling. The other category of novel approaches to disease modification in asthmaencompasses general anti-inflammatory therapies including phosphodiesterase 4 (PDE4) inhibitors, p38mitogen-activated protein kinase (MAPK) inhibitors, peroxisome proliferator-activated receptor-γ (PPARγ)agonists, and lipoxins.

Inhaled β2-adrenoceptor agonists and corticosteroids form the The recognition of asthma as an inflammatory disorder hasshifted the focus of treatment from bronchodilator therapy tobasis of the treatments available to alleviate the symptoms ofanti-inflammatory drugs.[4] The aim of new therapies to treat theasthma. However, although in most cases effective treatments aredisease should therefore be directed at inhibiting airway inflam-available to control this disease, many patients are reluctant to usemation and modifying the progression of the disease, an approachinhaled corticosteroids because of the risk of adverse effects.that may improve the long-term morbidity associated with asthma.Therefore, despite their use, the prevalence and burden of asthmaAn excellent review by Holtzman (2003)[5] has recently beenis still increasing[1] and in industrialized countries asthma accountspublished that describes the recent drug discovery efforts beingfor 1% of all healthcare costs.[2] In the last 10 years, a largeadopted for the development of new asthma therapeutics.proportion of effort from within the pharmaceutical industry has

focused on optimizing existing therapies by improving the thera-1. Therapeutic Approaches Targeting Specificpeutic ratio and extending the duration of action of inhaled cortico-Components or Steps in the Allergic Responsesteroids to achieve once-a-day asthma control. New β2-adre-in Asthmanoceptor agonists have also been developed with a longer duration

of action. Taking this philosophy further and incorporating a newstrategy for improving patient compliance has led to the develop- 1.1 T Cellsment of therapies combining corticosteroids with long acting

There is considerable evidence to support a critical role for Tβ2-adrenoceptor agonist bronchodilators. However, there are somecells (particularly the involvement of T helper type 2 [Th2] cells)asthmatic patients at the more severe end of the scale that do notin asthma. Interestingly, there appears to be immune deviationderive enough benefit from the drugs currently in clinical use.from Th1 to Th2 cells in this disease, which may be caused by theThus, there is a need for more effective therapies to treat thisinability to inhibit the normal rise in the number of Th2 cellsdisease. To this end, research into the inflammatory mechanismsrelative to Th1 seen at birth. One theory (the ‘hygiene hypothesis’)that underlie asthma pathology is ongoing, in the hope of provid-suggests that this may be caused by the absence of bacterialing novel and more effective treatments for these diseases.[1]

infections and endotoxins which would normally stimulate the Th1Asthma is defined as a chronic inflammatory disorder of the

response.[6] Activated Th2 cells are believed to be directly orairways, and inflammation is believed to be the underlying cause

indirectly involved in most of the aspects of the inflammatoryof the symptoms of asthma: wheezing, breathlessness, chest tight-

response seen in asthma. For this reason, a great deal of research isness, and cough. Often these acute episodes may be triggered by a

focused on impacting on Th2 cell phenotype and function.specific allergen, exercise, stress, cold air, or upper respiratory

1.1.1 Immunotherapytract infections. These symptoms are associated with airflow limi-tation that is partly reversible, and with airway hyperreactivity to The aim of immunotherapy is to dampen the immune responsevarious stimuli that is thought to be as a result of the chronic to allergens and desensitize the asthmatic patient.[7] This has beeninflammatory process.[3] The inflammatory lesion seen in the achieved in the treatment of allergy (e.g. hay fever) by the subcuta-asthmatic airway is characterized by an infiltration of T cells, neous injection of small amounts of purified allergen[8] but haseosinophils, mast cells, macrophages and, in severe asthma or been less successful for the treatment of asthma. The obviousduring exacerbations, neutrophils. In addition to the influx of advantage of this sort of approach over the traditional smallinflammatory cells, changes in resident cells are also apparent in molecule anti-asthma drug is that specific allergen immunotherapythe asthmatic airway, and these phenomena contribute to the may suppress symptoms for several years after treatment is dis-airway remodeling seen in this disease (e.g. increase in the thick- continued. However, there are certain limitations to this form ofness of the airway smooth muscle layer, increase in goblet cell therapy, including the following: (i) the tolerance to one particularnumbers in the airway epithelium). allergen may not extend to other allergens; (ii) this approach

© 2004 Adis Data Information BV. All rights reserved. Biodrugs 2004; 18 (4)

Novel Therapies for Asthma 213

IL-5, IL-4, IL-13

Th2 cell

Therapeutic interventions

TCR

MHC II

CD28

B7 family

Cytokine modulators

Specific allergen immunotherapy,e.g. peptide sequences of Fel d 1

Inhibition of antigen presentation,e.g. cathespin S and F inhibitors

Inhibition of co-stimulation, e.g. ICOS, CD80/CD86 inhibitors,CTLA4-Ig

Inhibition of Th2 cell phenotype,e.g. IFNγ, IL-12, IL-18,CpG DNA immunotherapy,Mycobacterium vaccae,Notch ligands, CrTH2 receptor antagonist

Antigen presenting cell (e.g. dendritic cell)

Fig. 1. Different strategies can be employed to inhibit antigen presentation and T-cell activation including: (i) allergen immunotherapy; (ii) inhibition ofantigen presentation; (iii) inhibition of costimulatory pathways; (iv) inhibition of T helper 2 (Th2) cell phenotype; and (v) blockade of specific Th2 cytokines.All interventions are shown in boxes. ICOS = inducible costimulator; IFN = interferon; IL = interleukin; MHC II = major histocompatibility complex class II;TCR = T-cell receptor.

would not be possible in nonatopic (intrinsic) and occupational on cell surfaces for recognition by CD4(+) T cells. Proteolysis isasthma even though Th2 cells are believed to be involved; and required in this process both for degradation of the invariant chain(iii) the potential exists for adverse effects and in particular ana- protein (Ii) [CD74] to a ~3-kD peptide termed CLIP (class II–as-phylaxis, however, the use of purified extracts and hypoallergenic sociated invariant chain peptide) from class II-CD74 complexes toisoforms of these allergens has reduced the risk of anaphylactic allow subsequent binding of peptides, and for generation of theshock. In fact, many allergens are available as recombinant DNA- antigenic peptides. Enzymes such as aspartate proteases (e.g.derived peptides and can be presented directly to T cells, causing cathepsin D) and cysteine proteases (e.g. cathepsins B, S and L)an alteration in the T-cell response.[9] One recent improvement to are thought to be involved in this process. The cysteine en-this approach has been the use of peptide sequences corresponding doprotease, cathepsin S, mediates CD74 degradation in human andto T-cell epitopes of the allergen. These short, synthetic, allergen- mouse antigen-presenting cells and therefore it has been suggestedderived peptides induce T-cell anergy/tolerance, but because of that selective inhibition of cathepsin S may have an importanttheir length are unable to cross-link IgE, making them safer to therapeutic target in modulating class II-restricted immuneadminister as they are not able to cause anaphylaxis. Using pep- processes such as asthma. Indeed, in a murine model of allergictides from the sequence of the cat allergen, Fel d 1, investigators inflammation, a selective cathepsin S inhibitor has been shown tohave demonstrated the ability to induce transient T-cell activation, block increases in IgE titers and eosinophil infiltration into theresulting in isolated late asthmatic reactions, which are followed lungs.[12] There are currently efforts underway by several biotech-by prolonged periods of allergen-specific hyporesponsiveness, nology companies to develop small molecule inhibitors of theboth to peptide re-challenge and to cutaneous challenge with cathepsin family (and in particular, cathepsin S) for the treatmentwhole allergen. Thus, peptide therapy may prove safe and effica- of a wide range of inflammatory and autoimmune disorders, but ascious in the treatment of allergic diseases[10,11] (see figure 1). yet no clinical data exist.

Recent experiments show that cathepsin F, in a subset of APCs,1.1.2 Antigen Processing can also efficiently degrade CD74. Therefore, it would seem thatCD4+ T helper cells can only recognize, and hence be activated, different APCs can use distinct proteases to mediate MHC class II

by exogenous antigens that are presented by major histocompa- maturation and peptide loading, suggesting that other cathepsinstibility complex (MHC) class II molecules on antigen presenting may also be attractive targets for small molecule intervention forcells (APCs). MHC class II molecules display antigenic peptides the treatment of asthma[13] (see figure 1).


214 Belvisi et al.

1.1.3 T-Cell Activation might actually exacerbate, lung inflammatory responses to inhaledActivation of naive T cells occurs through the delivery of two antigen.

signals. The first signal is triggered by the cognate interaction Another approach to suppress Th2 responses by stimulation ofbetween the CD4+ T-cell receptor and the APC-bound antigen to

Th1 responses is the use of CpG oligodeoxynucleotides (ODN).the MHC-II; the second occurs via co-stimulatory molecule inter-

These are synthetic oligodeoxynucleotides with immunostimu-actions, such as CD28 interacting with B7 molecules (CD80)/

latory sequences which, when used either alone or in combination(CD86). Without this co-stimulation, not only does the T cell not

with allergen, suppress Th2 responses. Strong immunostimulatorybecome activated but it can adopt a non-responsive state whereby

events are often driven by sequences containing unmethylatedeven with further correct stimulation present the T cell does not

CpG motifs that are more evident in microbial rather than verte-become activated. However, CD80/86-mediated co-stimulatory

brate DNA and so can be recognized by the innate immune system.pathways may be redundant and it may be necessary to block more

These motifs are thought to promote a switch from the usual Th2than one co-stimulatory molecule to achieve therapeutic efficacy.phenotype to Th1 responses through a signaling pathway involvingIt is for this reason that attention has recently focused on other co-Toll-like receptor 9.[21,22] In a recent study, CpG DNA-basedstimulatory pathways including inducible costimulator (ICOS)/immunotherapy inhibited acute and chronic markers of inflamma-B7-related protein (RP)-1 and PD-1/B7H-1.[14] The ICOS/tion and enhanced the release of IL-10 in an allergic mouseB7-RP-1 interaction has been characterized primarily as a co-model,[23] suggesting the involvement of Treg cells. In fact, it isstimulatory pathway that orchestrates events downstream of T-cellbelieved that the effects seen with CpG DNA treatment are notactivation, and ICOS has been singled out by its association withsolely due to promoting a Th1 response but also due to increasingTh2 effector activity. In fact, inhibition of ICOS during allergenthe number of Treg cells. The ability to increase Treg cells haschallenge has been shown to attenuate eosinophil accumulation inreceived a great deal of interest recently not only for the treatmentthe airway, IgE production, and cytokine release in theof asthma but also for autoimmune diseases. Clinical studies havebronchoalveolar lavage (BAL) fluid in models of antigen-inducednot been reported but clinical trials utilizing CpG ODNs areallergic airway inflammation.[15,16]

ongoing.[24] However, there are several phase I and phase II trialsAnother approach along the same theme has been to explore theunderway in a number of different therapeutic areas, includingeffects of CTLA4, which is a molecule expressed on activated Tasthma, and early indications are that CpG ODNs are well tolerat-cells and appears to act as an endogenous inhibitor of T-celled.[25] Recently work has been published suggesting stimulation ofactivation. Interestingly, a soluble fusion protein constructthe Notch pathway or exposure to heat-killed mycobacterium(CTLA4-Ig) is effective at blocking airway hyperreactivity, eosi-vaccae may also be a way of increasing Treg cells[26,27] and therebynophilia and IgE levels in a murine model of allergic asthma[17,18]

suppressing the Th2 phenotype.(see figure 1).

An alternative strategy to suppress the Th2 phenotype seen in1.1.4 T-Cell Phenotypethe asthmatic airway is to reduce the amount of key cytokinesDuring an immune response, naive CD4+ T helper cells canreleased by these cells (eg. IL-4, IL-5, IL-13) or to inhibit thedifferentiate into three main types, Th1, Th2 and Treg. There arepathway stimulated by these cytokines. IL-4 and IL-13 have beenmany factors that contribute to the decision as to which sub-type oflinked with not only Th2 phenotype switching but also many otherT helper cell is produced, including the dose of antigen, thefacets of the disease process including B-cell isotype switching,strength of T-cell receptor ligation, and the tissue the antigen isairway eosinophilia, airway hyperreactivity and airway remodel-exposed to, but the most important factor is reported to be theing. Beneficial effects were achieved in asthmatics using an in-cytokine profile present. For example, interleukin (IL)-12 andhaled soluble IL-4 receptor, altrakincept, an agent that sequestersinterferon (IFN)γ promote differentiation into Th1 cells, whereasIL-4 without mediating cellular activation.[28] IL-4 shares manyIL-4 promotes differentiation into Th2 cells. Additional mecha-biological functions with IL-13 as the IL-4 receptor α chain formsnisms that favor a Th1 cell phenotype include the expression ofan important component of both the IL-4 and IL-13 receptors.IL-12β2 receptor and production of IL-12 and IL-18 versus IL-10.Another study showed that a murine IL-4 receptor antagonist thatAlso, the cytokine profile that each T cell sub-type releases caninhibits IL-4 and IL-13-induced responses also inhibited antigen-inhibit the other, i.e. IFNγ tends to inhibit Th2 cell production andinduced airway eosinophilia and airway hyperreactivity in a mu-IL-4 inhibits Th1 cell production. In patients with asthma, not onlyrine model of asthma.[29] However, other groups have shown thatdid the administration of IFNγ not impact on symptoms, but it alsobecause IL-13 shares many of the biological functions of IL-4 andresulted in increased numbers of lymphocytes in the airways.[19,20]

is independently involved in other disease manifestations, thisThus, Th1 effector T cells do not appear to be able to prevent, and



cytokine, rather than IL-4, should be targeted for disease modifica- ing clinical trials for asthma although results have not yet beention.[30] reported. The hunt is also on for small molecule antagonists of

other chemokine receptors. As a cautionary note, because of theAnother way of impacting on IL-4 and IL-13 triggered eventsredundancy seen with chemokines and chemokine receptors, it iswould be to inhibit the IL-4/IL-13 receptor signaling pathway.yet to be determined whether the actions of specific antagonistsRecent research has involved exploring the possibility of targetingwill be enough to impact on the inflammation or disease state seenthe transcription factors activated by IL-4/IL-13, such as signalin patients with asthma.transducer and activator of transcription 6 (STAT6), GATA-bind-

ing protein 3 (GATA3) and friend of GATA1 (FOG1). In a murinemodel of allergic inflammation, Tomkinson et al. (2002)[31] have 1.2 Eosinophilsshown that the development of airway hyperreactivity was depen-dent on STAT6 (figure 1). Eosinophilic inflammation is a characteristic of the airway

inflammation seen in asthma and is believed to play a possible role1.1.5 T-Cell Chemotaxis in the disease pathogenesis.[41] A great deal of research has beenThe trafficking of Th2 cells to the lung and to and from the geared to inhibit eosinophil recruitment into the airways. The

lymph nodes are thought to be a key early step in the pathogenesis research includes impacting on cells believed to be involved inof asthma.[32] Th2 cells have been shown to preferentially express eosinophil recruitment such as Th2 cells (outlined above) and mastthe chemokine receptors CCR3, CCR4, CCR8, CXCR4 and the cells (outlined below). Other strategies have involved the use ofprostaglandin D2 receptor CRTH2, while Th1 cells preferentially general anti-inflammatory therapies, which will be discussed later.express CCR5, CXCR3, CXCR6 and CX3CR1.[33] It has been More direct approaches for reducing eosinophilic recruitment intosuggested that inhibiting the expression of the relevant the airway have involved impacting on the cytokines implicated inchemokines or blockade of the chemokine receptor may represent eosinophil differentiation and chemotaxis, such as IL-5. A human-attractive targets for asthma therapy. One example of the effective- ized antibody against IL-5, mepolizumab, has been developed andness of blocking the expression of chemokines comes from work tested in the clinic. Interestingly, it markedly reduced circulatingreported by Mathew et al.[34] in which they showed, in a murine and sputum eosinophils in patients with asthma but was withoutallergen model, that STAT6 controls chemokine production and effect on early and late responses to allergen challenge, and did notTh2 cell trafficking in allergic pulmonary inflammation. reduce airway reactivity to methacholine challenge.[42] A study to

determine the effect of mepolizumab on airway tissue eosinophilsTargeting a specific chemokine is problematic because of thehas shown that it reduces but does not deplete eosinophils from theamount of redundancy in the ligand/receptor interactions. CCR3airway or bone marrow, suggesting that the role of the eosinophilreceptors can be activated by a number of chemokines includingin asthma is at present unclear.[43] A preliminary study with aeotaxin, CCL5 and monocyte chemotactic protein 4 (MCP-4,different humanized antibody against IL-5, reslizumab, has report-CCL13); these chemokines in turn can activate other chemokineed similar results.[44] A recent safety study by the same groupreceptors. Because of this, many pharmaceutical companies haveshowed that the antibody was without adverse effects and that itattempted to find chemokine receptor antagonists rather thandemonstrated an improvement in baseline forced expiratory vol-target specific chemokines. Specific chemokine receptor antago-ume in 1 second (FEV1) in patients with severe persistent asth-nists would inhibit the actions of a number of chemokines on thatma.[45] Further, more powerful clinical studies are needed to con-receptor. An additional advantage with receptor blockade is thefirm this observation.inhibition of chemotaxis of other inflammatory cells. For example,

CCR3 receptors, as well as being present on Th2 cells, are also It would seem from the information available that inhibitingpresent on eosinophils and mast cells, both of which are thought to IL-5 alone is not sufficient to deplete lung tissue eosinophils. Evenbe involved in the inflammation seen in asthma. Many pharmaceu- in animal models of asthma there was residual eosinophilia in thetical companies have small-molecule CCR3 receptor antagonists airways after anti-IL-5 therapy.[46] It has been suggested thatin development including SB297006, SB238437,[35] and combination therapy of anti-IL-5 (to block bone marrow matura-UCB35625,[36] and others that are in the pipeline from Bristol tion of eosinophils) and a CCR3 receptor antagonist (to blockMyers Squibb,[37] Abbott[38] Novartis, Roche, Merck, Banyu and eosinophil lung tissue accumulation) may lead to a more promis-AstraZeneca.[39] Studies described recently in both rodents and ing therapy in the clinic than the use of an anti-IL-5 therapyprimates using two different CCR3 antagonists, RO1164875 and alone.[47] Another possibility is that the apparent lack of efficacyRO3202947, showed reductions in eosinophil influx and airway seen in some of these studies may be due to redundancy, in that thehyper-responsiveness.[40] Some of these compounds are undergo- role of IL-5 could be performed by granulocyte-macrophage colo-


216 Belvisi et al.

Th2 cell

B cellMast cell Eosinophil

IgE Mediator releaseMajor basic protein

IL-4,5,13IL-4,5,13

IL-4 IL-5

Asthma phenotype

Anti-IL-4, 13, 5

Anti-IgE

Mast cell inhibitors,e.g. anti-histamines,LT receptor antagonists,tryptase/chymase inhibitors,PAR-2 antagonist

Mediator release,e.g. histamine, lipidscytokines

Eosinophilchemotaxis inhibitors,e.g. CCR3antagonist

Adhesion inhibitors,e.g.VLA4 inhibitor

Fig. 2. Inhibition of specific inflammatory processes and in particular eosinophil, mast cell and B-cell functions. Several therapeutic strategies may bepossible to inhibit eosinophil chemotaxis and function (e.g. blockade of adhesion molecules and chemokine receptors). IgE, from B cells, can be blockedusing an IgE monoclonal antibody and mast cell mediators inhibited by selective blockers (e.g. antihistamines, leukotriene [LT] receptor antagonists,tryptase/chymase inhibitors, protease-activated receptor-2 [PAR-2] receptor antagonists). Cytokines (IL-4, 5, 13), from Th2 cells, can be blocked bymonoclonal antibodies or soluble receptors. All interventions are shown in boxes. CCR3 = chemokine, cc motif, receptor 3; IL = interleukin; Th2 = T helper2; VLA4 = very late antigen-4.

ny stimulating factor (GM-CSF) or IL-3 after IL-5 has been 1.3 Mast Cells/Basophils

eliminated. Therefore, an approach that may have more impactMast cells and basophils have been reported to be present inwould be to interfere with the common pathway that these

BAL fluid and bronchial biopsies from asthmatic lungs, and,cytokines signal through. A monoclonal antibody (BION-1) di-although not necessarily increased in number, they are in a height-rected against the common βc (signaling) subunit of the cytokineened activity state.[54,55] These cells are linked to the allergicreceptor has been developed which allows the simultaneous inhi-response, in that allergen can trigger degranulation by cross-bition of all three cytokines.[48] Ramshaw et al.[49] have solved thelinking specific IgE bound to the FcεRI receptor on cells.structure of BION-1 bound to the βc subunit and revealed an areaMediators released upon degranulation have been implicated inwhich should prove an attractive target for the rational design ofthe early and late response in atopic asthma (eg. histamine, leuko-small-molecule inhibitors of βc function.trienes, tryptase, chymase) [see figure 2].

Another area of interest for inhibiting airway eosinophilia isinhibition of very late antigen-4 (VLA-4). VLA-4 is a heter- 1.3.1 IgEodimeric cell surface molecule found on mononuclear cells and its Several therapies have been proposed to reduce the amount ornatural ligand is vascular cell adhesion molecule (VCAM-1). The effect of IgE, thereby reducing the degranulation of mast cell andVLA-4 receptor is believed to be responsible for mononuclear cell basophils. Some of these involve inhibiting the B-cell isotypetrafficking and anti-VLA-4 and VLA-4 antagonists have been switching, proliferation and activation by either impacting on IL-4shown to impact on animal models of asthma.[50-52] Initial commu- (and IL-13) whether it be directly or by interrupting downstreamnications, however, have indicated little efficacy of anti-VLA-4 signaling (discussed above). Similarly, interruption of FcεRI sig-mAb in asthma despite success in other inflammatory condi- naling by blocking its interaction with ligand or downstreamtions.[53] It has been suggested that if this agent was retested in a signaling molecules such as spleen tyrosine kinase (SYK) are alsopatient population that was purely atopic, and the delivery was strategies under investigation. However, the therapy that has re-improved, this type of therapy may still show beneficial effects ceived most interest recently is the one designed to deplete IgE.(see figure 2). Depleting IgE in animal models by the use of an anti-IgE mAb has



been shown to reduce eosinophilic inflammation.[56] Phase III cyclase and activation leads to increasing levels of cAMP. Instudies have been conducted with the recombinant human anti- contrast, the HR3 receptor is negatively coupled to adenylylIgE, omalizumab, resulting in a reduction in early and late phase cyclase, and signaling involves G(i/o), leading to inhibition ofresponses and reduced eosinophil counts in sputum, and the treat- cAMP. HR3 receptors have been found as pre-junctional receptorsment has been shown to be safe and well tolerated.[57,58] A reduc- both in the peripheral and central nervous system. HR4 receptorstion in inhaled corticosteroid requirement has also been demon- are coupled to G(i/o), inhibiting forskolin-induced cAMP forma-strated in patients receiving omalizumab.[59] The importance of tion (similar to the HR3). HR4 receptors demonstrate high levelsomalizumab as an add-on therapy when treating patients with of expression on neutrophils, eosinophils and T cells.severe asthma has been demonstrated in three large placebo con-

Recent data suggests that histamine affects the maturation oftrolled trials. Omalizumab treatment halved the rate of significant

the immune cells and alters their activation, polarization, chemo-asthma exacerbations, reduced the number of re-hospitalizations,

taxis and effector functions. Histamine also regulates antigen-improved quality of life and asthma symptom scores, and im-

specific T cells. Furthermore, it has been suggested that differen-proved baseline peak expiratory flow rate.[60-62] The greatest bene-tial patterns of expression on Th1 and Th2 cells determine T-cellfit with this treatment was seen in patients with the most severeresponses following histamine stimulation. Th1 cells expressasthma. These results suggest that specific inhibition of IgE maypredominantly, but not exclusively, the HR1 receptor, whereasprovide an important novel therapeutic option for the treatment ofTh2 cells express increased levels of the HR2 receptor.[70] It hassevere asthma.been suggested that histamine enhances Th1 type responsesthrough the activation of the HR1 receptor, whereas both Th1 and

1.3.2 HistamineTh2 type responses are negatively regulated by activation of the

Histamine was one of the first mediators implicated in the HR2 receptor. In fact, in mice the deletion of the HR1 receptorpathophysiology of asthma. Histamine binds and activates four results in a dominant Th2 type phenotype with the secretion ofdifferent G protein coupled receptors (HR1–4). Elevated levels of IL-4 and IL-13, whereas deletion of the HR2 receptor results inhistamine have been measured in BAL fluid from asthmatic pa- upregulation of Th1 and Th2 responses.tients compared with non-asthmatic individuals.[63] Histamine is

Interestingly, the effect of histamine on eosinophil migrationreleased from mast cells and basophils and can cause bronchocon-

depends on dose. High doses of histamine inhibit chemotaxis viastriction,[64] plasma extravasation,[65] mucus secretion,[66] induceactivation of HR2 and low doses enhance eosinophil chemotaxisairway smooth muscle proliferation[67] and augment cholinergicthrough activation of the HR1. A role for the HR4 receptor inbronchoconstriction[68] through its actions on HR1 receptors. Ineosinophil chemotaxis has also been suggested. A similar profile isisolated airway smooth muscle preparations from asthmatic pa-observed on dendritic cells with HR2 acting as a suppressivetients and non-asthmatic individuals, it has been shown that themolecule for antigen presenting capacity, while HR1 and HR3 actcontraction responses to histamine are the same, which suggestsas positive stimulators. In immature dendritic cells, histaminethat airway hyper-responsiveness to histamine in the asthmaticinduces intracellular Ca++ flux, actin polymerization, and chemo-lung is not due to alteration in HR1 receptors in the airways.[69]

taxis as a result of stimulation of the HR1 and HR3 receptorOther histamine receptors, HR2 and HR3, have also been identi-subtypes. Mature dendritic cells lose these responses and hista-fied in human airways. Although their relevance in asthmaticmine, via the HR2 receptor, dose-dependently enhances intracellu-airway inflammation is not known, activation of HR2 on airwaylar cAMP levels and stimulates IL-10 secretion, while inhibitingepithelial cells can cause release of prostaglandin E2 (PGE2),the production of IL-12.[70] Therefore, it would appear that onwhich despite being a tussive agent, is thought to have beneficialbalance HR1 receptors are involved in activating immune cellsbronchodilatory activity in the airways.[64]

whereas HR2 receptors are involved in suppressing inflammatoryThe G-protein G(q/11)-coupled HR1 receptor is responsible for

responses.many of the symptoms observed in allergic diseases. Activation of

Thus far antihistamine therapy has been shown to provide onlyG(q/11) stimulates inositol phosphate signaling pathways result-limited clinical benefit for patients with asthma.[71] However,ing in formation of inositol -1,4,5-triphosphate and diacylglycerolrecently there have been suggestions[72] that there may be a role forand a consequent increase in intracellular calcium concentrations.second-generation antihistamines in treating asthma, with patientIn addition, HR1 has been shown to activate phospholipase D, A2

selection as well as dosing regimens being important therapeuticand NF-kβ, however the functional consequences of this are notknown. The HR2 receptor is positively coupled to adenylyl considerations.


218 Belvisi et al.

1.3.3 Leukotrienes flux when compared with wild type mice.[85] Airway hyperreactiv-Cysteinyl leukotrienes are important pro-inflammatory ity was similarly affected. APC-366 has been tested in a short-term

mediators in the pathogenesis of asthma. They are formed when study in patients with atopic asthma, where it reduced the latearachidonic acid is metabolized via 5-lipoxygenase to give rise to asthmatic response and the fall in FEV1 caused by antigen chal-leukotrienes C4, D4 and E4. The only development of a novel drug lenge.[86] An inhibitor at the PAR2 receptor may also be worthy ofclass for the treatment of asthma in recent years has been the investigation.introduction of cysteinyl leukotriene antagonists such as

1.4 Other Mediatorsmontelukast, zafirlukast, and pranlukast, and the 5-lipoxygenaseinhibitor, zileuton.[73] The cysteinyl leukotrienes are potent

1.4.1 Adenosine Receptor Ligandsbronchoconstricting agents that have been shown to play a role inAdenosine has long been implicated in the pathophysiology ofboth the increase in airway hyperreactivity seen in asthma and in

asthma and there is much evidence in the literature to support thisairway remodeling. Recent evidence from a murine model ofconcept.[87-90] A recent review highlights the A1, A2A and A2Basthma has shown that a leukotriene receptor antagonist can inhib-receptor-selective molecules currently in development.[91]it the remodeling process, including eosinophil trafficking andEPI-2010, an antisense oligonucleotide that targets the human A1degranulation, cytokine release, mucus gland hyperplasia andreceptor,[92] entered phase II clinical trials in 2001 as an inhaledhypersecretion, smooth muscle cell hyperplasia, collagen deposi-formulation for asthma, but development has since been discontin-tion, and lung fibrosis.[74] A review of the benefits achieved byued. Activation of the A2A receptor is known to suppress inflam-using anti-leukotrienes as an add-on therapy to inhaled corticoste-mation and is therefore another potential target. To this end, aroids showed a modest improvement in asthma control but did notselective A2A receptor agonist, CGS-21680, was developed thatallow a lowering of the steroid dose.[75] Another review proposesshowed anti-inflammatory activity similar to that of the steroidthat these compounds provide an effective anti-inflammatorybudesonide in an animal model of allergic asthma.[93] This com-treatment for asthma.[76] While there is evidence that the leuko-pound did not advance to the clinic. GW-328267, an inhaled A2Atriene antagonists are effective anti-asthma agents in young peo-receptor agonist, is in phase I clinical development for asthma andple, there are suggestions that they are less effective in those agedCOPD.[94] There is evidence to support the involvement of the A2Bover 50 years,[77] that the long acting β-agonists are more effec-receptor in mast cell activation, and selective antagonists for thistive,[78] and that some patients respond better than others.[9] Therereceptor could be beneficial in asthma.[90] There are no selectiveis evidence to suggest that leukotriene antagonists may provideA3 receptor antagonists in clinical development, although there iseffective therapy for aspirin-sensitive asthma and exercise-in-a report in the literature suggesting that adenosine acting at the A3duced asthma.[79] This suggests that it may be possible to predictreceptor may contribute to the anti-inflammatory activity of theo-which patients will respond well to these drugs, and thereforephylline in vivo.[95] It has also been suggested that both agonistscareful patient selection in the future may reveal the benefits ofand antagonists at the A3 receptor may have potential in thethese compounds.treatment of asthma, as adenosine exhibits both pro- and anti-

1.3.4 Tryptase/Chymaseinflammatory actions via this receptor.[96]

The degranulation of mast cells is an important event in allergic1.4.2 Prostanoidsasthma, and results in the release of many different mediators such

as histamine and the serine protease, tryptase. Tryptase is thought Prostanoids consist of several groups of lipid mediators, pros-to play a role in airway remodeling, increased mucus secretion,[80] taglandins, prostacyclin, and thromboxanes, which are generatedand fibroblast proliferation via protease-activated receptor-2 from arachidonic acid, mainly through the cyclo-oxygenase path-(PAR2)[81] in asthma. Tryptase inhibitors including APC-366,[82] way. One of the prostaglandins produced, PGE2, is thought to haveAMG-126737[83] and MOL-6131[84] have been developed and beneficial effects in the airways. It has been shown, at low concen-tested in animal models and the results from these studies support trations, to relax human airway smooth muscle in vitro[97] andthe notion that selective inhibition of tryptase is a reasonable exhibit bronchodilation in vivo in healthy subjects, but may inducetherapeutic target for asthma. Further recent evidence has demon- airway constriction in asthmatic patients through activation ofstrated a role for PAR2 in the development of allergic inflamma- reflex cholinergic bronchoconstriction.[98] PGE2 also inhibits thetion in the airway. Wild type mice and mice lacking or overexpres- proliferation of airway smooth muscle[99] and the release ofsing PAR2 were subjected to antigen challenge; those lacking mediators from mast cells, monocytes, neutrophils and eosino-PAR2 showed a greatly reduced eosinophil influx into the airways phils. Inhalation of PGE2 has been suggested to reduce early andwhile those over expressing PAR2 showed greatly enhanced in- late responses to allergen challenge.[100] However, PGE2 also



exhibits tussive effects.[101] Other prostanoids such as PGD2, portions of these inhaled glucocorticoids reaching the systemicPGF2α, the isoprostane 8-epi-PGF2α, and thromboxanes have circulation. These adverse effects have led to the search not onlybeen shown to constrict human airways in vitro.[102,103] In the for novel anti-inflammatory approaches but also for improvedclinic, non-selective prostanoid receptor antagonists and corticosteroids.[112] Several new corticosteroids are in develop-thromboxane synthase inhibitors have not shown any beneficial ment, including mometasone furoate,[113,114] and some of these areeffects in patients with asthma. The anti-inflammatory actions of predicted to have a reduced adverse-effect profile, including thePGE2 have led to the suggestion that prostanoid receptor agonists soft steroid loteprednol etabonate,[115] and ciclesonide.[116,117] Re-may be useful for the treatment of airway inflammatory diseases. cent studies with ciclesonide have demonstrated both efficacy inIn particular, the focus has been on the development of agonists at the treatment of asthma[118,119] and an improved adverse-effectthe prostaglandin E receptor 2 (EP2), as this receptor is positively profile.[120,121]

coupled to adenylyl cyclase. The provision of longer acting β-agonists such as formoteroland salmeterol has also been a goal for the pharmaceutical indus-

1.4.3 TNFαtry, as have combinations of steroids and β-agonists such as

TNFα is also implicated in the inflammatory response in asth-fluticasone with salmeterol, or budesonide with formoterol. This

ma, and has already proved to be an attractive target with theapproach may confer advantages in both treatment and compli-

development of etanercept, a soluble TNF receptor hybrid mole-ance.

cule, and infliximab, an antibody against TNFα.[104] Adalimumabis a humanized monoclonal antibody against TNFα that was

2.2 Phosphodiesterase 4 Inhibitorsapproved by the US FDA in December 2002. These products weredeveloped to treat rheumatoid arthritis and inflammatory bowel Phosphodiesterase 4 (PDE4) inhibitors, although in develop-disease, however, clinical trials are now underway to determine ment as potential therapies for COPD, are now, because of theirtheir effect in patients with severe asthma.[105] Small molecule anti-inflammatory properties combined with bronchodilator activ-inhibitors of TNFα are now being sought in order to avoid some of ity, being considered as potential therapies for asthma. The secondthe problems involved with antibody therapy, and specifically generation PDE4 inhibitors, roflumilast[122] and cilomilast,[123]

with TNFα neutralizing agents, such as the development of tuber- lead the field, although it is probable that the development ofculosis and other such opportunistic infections and an adverse cilomilast for asthma has been discontinued.[124] Roflumilast haseffect on congestive heart failure.[106] A novel approach to reduc- been shown to significantly improve lung function in patients withing TNFα levels could be provided by inhibitors of TNFα-con- exercise-induced asthma,[125] and in a 12-week study in asthma,verting enzyme (TACE).[107] A study with two dual TACE/MMP roflumilast produced a dose-dependent improvement in asthmainhibitors, PKF 242-484 and PKF 241-466, demonstrated com- control and was well tolerated.[126] The latest clinical findings inplete inhibition of TNFα and a reduction in inflammatory cell asthma show that roflumilast improves asthma control to a levelinflux in an animal model of acute lung inflammation,[108] sug- equivalent to beclamethasone dipropionate. Furthermore, roflumi-gesting that these compounds may have therapeutic potential for last significantly and dose-dependently attenuates the late asthmat-the treatment of asthma. ic reaction, indicating that its clinical efficacy in asthma is based

on its anti-inflammatory activity. One other compound worthy of2. General Anti-Inflammatory Therapies mention in this class is AWD12-281, which recently demonstrated

efficacy in animal models of asthma when given by the inhaledroute.[127] It is also claimed that when given orally, intravenously,2.1 Corticosteroidsor intratracheally, AWD12-281 has a lower emetic potential than

Inhaled corticosteroids provide the current maintenance ther- cilomilast or roflumilast, which may confer an advantage on thisapy of choice for asthma and, with the bronchodilator β-agonists compound when it reaches the clinic. Interestingly, recent datafor acute symptom relief, they form the mainstay of current suggests that roflumilast may also inhibit the remodeling processtherapy for the disease. However, steroid treatment, especially if in a chronic asthma model in the mouse.[128]

high or frequent doses are required, is associated with a range ofadverse effects including adrenal suppression and an adverse 2.3 p38 Mitogen-Activated Protein Kinase Inhibitorseffect on growth and bone formation[109,110] including the develop-ment of corticosteroid-induced osteoporosis.[111] These adverse The p38 mitogen-activated protein kinase (MAPK) signalingeffects and many others, such as skin thinning, easy bruising, pathway is common to many pro-inflammatory cytokines andcataracts, oral candidiasis and dysphonia, result from significant chemokines,[129] and thus presents an attractive target for the


220 Belvisi et al.

development of nonpeptide inhibitors.[130] Several p38 MAPK also demonstrated that transgenic expression of human LXA4

inhibitors are being examined for their potential to provide novel receptors in murine leukocytes led to significant inhibition oftherapies for asthma.[131] Two p38 MAPK inhibitors, SB-203580 pulmonary inflammation and eicosanoid-initiated eosinophil tis-and SB-239063, have shown anti-inflammatory activity in animal sue infiltration. These findings suggest that the lipoxin pathwaymodels of airway inflammation.[132,133] It remains to be seen if this may offer a novel multi-pronged therapeutic approach to theactivity will transfer to efficacy in the clinic. An interesting recent treatment of asthma.observation has shown that SB-203580 may have potential in

3. Conclusionreversing glucocorticoid insensitivity and re-establishing the bene-ficial effects of glucocorticoids in patients with severe asthma,[134]

Asthma is a disease of the airways with an inflammatorythus suggesting that a p38 MAPK inhibitor may have potential ascomponent. Asthma has been studied for many years and thean add-on therapy to corticosteroid treatment in asthma. A numberunderstanding of the pathophysiology resulting from this researchof these compounds are about to have their anti-inflammatoryhas led to the development of several effective therapies to treatpotential examined in the clinic: SB-281832 (phase I), SCIO-469the symptoms of the disease. However, the incidence of asthma is(phase II), and the newer compounds VX-702 and VX-850still on the increase and further understanding of the basic mecha-(phase I); and the development of inhaled formulations for thenisms central to the development of the disease has resulted in thetreatment of asthma is also underway.[131]

development of novel therapeutic strategies to improve the treat-ment options for the disease. Improvements to the current therapy2.4 Peroxisome Proliferator-Activated Receptor Agonistsavailable to treat asthma in the form of longer acting β-agonists,safer corticosteroids, and combination therapies, are ongoing butPeroxisome proliferator-activated receptor γ (PPARγ) is aas yet no treatment has been shown to impact significantly on themember of the nuclear hormone family and the development ofdevelopment of asthma. The identification of some of the process-PPARγ agonists has been suggested as a novel anti-inflammatoryes and pathways involved in the inflammatory responses in asthmatarget for asthma.[135] An immunoregulatory role for PPARγ hashas led to the identification of novel targets, and this has allowedbeen proposed in airway epithelial cells, where it has been shownpharmaceutical companies to develop novel therapies, some ofto antagonize pro-inflammatory pathways in the airways.[136] Awhich have progressed to the clinic. It will be interesting torole for PPARγ has also been demonstrated in human asthmaticobserve which of the many and diverse approaches will result inairways, where increased expression has been thought to representsafe, novel treatments, and whether these treatments can effective-a regulatory mechanism aimed at limiting airway inflamma-ly suppress inflammation in the airways and thereby start to impacttion.[137] A recent study employing a murine model of asthmaon the prevalence of asthma worldwide.demonstrated that selective PPARγ but not PPARδ agonists limit-

ed the development of ovalbumin-induced airway inflamma-Acknowledgmentstion.[138] Several pharmaceutical companies are developing newer

and more potent PPARγ agonists for various inflammatory indica-Drs Birrell and Hele were funded by a grant from GlaxoSmithKline.

tions,[139] but whether this approach proves to be beneficial intreating inflammatory disease remains to be seen.

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New Advances and Potential Therapies for the Treatment of Asthma