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New anti-inflammatory approaches in COPD
Vol. 1, No. 3 2004
Drug Discovery Today: Therapeutic Strategies Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Respiratory diseases
New anti-inflammatory approaches in COPD Maria Gabriella Matera1, Mario Cazzola2* 1 2
Unit of Pharmacology, Department of Experimental Medicine, School of Medicine, Second University, Piazza Miraglia 4, 80123 Naples, Italy Unit of Pneumology and Allergology, Department of Respiratory Medicine, A. Cardarelli Hospital, Via A. Cardarelli 9, 80131 Naples, Italy
Inflammation in chronic obstructive pulmonary disease (COPD) is characterised by increased numbers of neutrophils, macrophages and CD8+ T-lymphocytes, and the release of multiple inflammatory mediators (leukotrienes, chemokines, cytokines). It appears to be resistant to corticosteroids. This circumstance is stimulating a search for novel anti-inflammatory therapies that might prevent the relentless progression of the disease. For this reason, attention has largely been focused on inhibition of recruitment and activation of inflammatory cells, and on antagonism of their products.
Section Editors: Roy Goldie – University of Western Australia, Western Australian Institute for Medical Research, Australia Duncan Stewart – Terrence Donnelly Research Laboratories, Division of Cardiology, St Michael’s Hospital and University of Toronto, Toronto, Ontario, Canada Chronic obstructive pulmonary disease (COPD) is a degenerative inflammatory lung disease often associated with long-term cigarette smoking. Despite the inflammatory nature of COPD, currently available anti-inflammatory therapies such as those used in asthma and rheumatoid arthritis for example, are not clinically very effective in blunting either the symptoms or the progression of COPD. Accordingly, there is an urgent need to discover novel, effective antiinflammatory treatments for this disease. Matera and Cazzola have been leading researchers in the COPD field for many years and have put together a very useful summary of the state-of-the-art development of clearly and potentially useful anti-inflammatory strategies in COPD.
Introduction Chronic inflammation plays a central role in chronic obstructive pulmonary disease (COPD). It is characterised by an increase in neutrophils, macrophages and CD8+ T-lymphocytes in small and large airways as well as in lung parenchyma and pulmonary vasculature [1]. Alveolar macrophages play a crucial part in orchestrating this inflammation through the release of proteases such as matrix metalloproteinase (MMP) 9, inflammatory cytokines such as tumour necrosis factor (TNF)-a and chemokines such as interleukin (IL)-8 that attract neutrophils into the airways. Corticosteroids are highly effective as an anti-inflammatory treatment in a wide range of chronic inflammatory diseases, but patients with COPD are poorly responsive to these drugs. This probably happens because cigarette smok*Corresponding author: (M. Cazzola) [email protected] 1740-6773/$ ß 2004 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddstr.2004.11.013
ing and oxidative stress impair histone deacetylase 2 function [2]. Nonetheless, in severe COPD patients, combinations of inhaled corticosteroids and long-acting b2-agonists show an additive effect, suggesting an interaction between the two moieties that can have a positive effect [3].
Emerging anti-inflammatory strategies Suppression of the inflammatory response is a logical approach to the treatment of COPD and might improve symptoms such as cough and mucus secretion, improve health status and reduce exacerbations. In the long-term, such treatments should reduce disease progression. However, hitherto, no therapeutic agent has been shown to reduce the numbers of the important inflammatory cells, macrophages, neutrophils and CD8+ lymphocytes in COPD [4]. For this reason, attention has largely been focused on inhibition of www.drugdiscoverytoday.com
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Glossary CXC: chemokine ligand. GAG: glycosaminoglycan. ICAM: intercellular adhesion molecule that mediates attachment, spreading and migration of polymorphonuclear leukocytes. IL: interleukin; mediator of inflammatory and immune reactions. LFA: lymphocyte function antigen, an adhesion molecule that appears to play a major role in T-lymphocyte adhesion to vascular endothelium, cytotoxic function, and activation. LTB4: leukotriene B4, an extremely potent lipid inflammatory mediator, derived from membrane phospholipids by the sequential actions of cytosolic phospholipase A2, which recruits and activates leukocytes. MAPK: mitogen-activated protein kinase. NF-kB: nuclear factor-kB, a protein transcription factor necessary for maximal transcription of several pro-inflammatory molecules associated with an inflammatory response. PDE4: phosphodiesterase 4 enzyme that catalyses the breakdown of adenosine 30 :50 -cyclic monophosphate. PI3K: phosphatidylinositol 3-kinase enzymes that are characterised by their ability to phosphorylate the 3-OH position of the inositol ring of several different phosphoinositides and are key signalling targets downstream of a variety of chemokine receptors. SLex, sialyl Lewisx, the carbohydrate ligands for E-selectin. TNF-a: tumour necrosis factor-a, primary pro-inflammatory cytokine that provides cell signals resulting in the activation of redox-sensitive transcription factors, such as NF-kB and activator protein-1. VCAM: vascular cell adhesion molecule that contributes preferentially to adhesion and migration of lymphocytes and monocyte-macrophages. VLA: very late antigen, the a1b1 integrin that is the major receptor for collagen molecules in the extracellular matrix and plays an important role in inflammatory responses involving T cells, macrophages, angiogenesis and fibrosis.
recruitment and activation of these cells, and on antagonism of their products. To do it, we can try to directly influence the cellular components of inflammation, or interfere with inflammatory mediators that regulate migration and activation of inflammatory cells.
How to influence directly the cellular components of inflammation At present, some new therapeutic strategies allow us to try to influence directly the cellular components of inflammation, although there are concerns about their use for a chronic disease, as an impaired neutrophilic response can increase the susceptibility to infection in patients with COPD, who are often already at risk [4]. The therapies explored include: (a) drugs that interfere with adhesion-molecules; (b) adenosine A2a-receptor agonists; and (c) phosphodiesterase 4 (PDE4) inhibitors (Table 1). Drugs that interfere with adhesion-molecules
The sequential interaction between specific adhesion molecules on inflammatory cells and the pulmonary endothelium mediates the recruitment of monocytes, CD8+ lymphocytes and neutrophils into the lung of patients with COPD. Specific binding of lymphocytes to bronchial endothelium has been observed which was significantly inhibited by antibodies against P-selectin, P-selectin glycoprotein (PSGL)-1, lymphocyte function-associated antigen (LFA)-1, L-selectin, intercel336
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lular adhesion molecule (ICAM)-1 and ICAM-2 but not Eselectin, very late antigen (VLA)-4, vascular cell adhesion molecule (VCAM)-1 or Mac-1 (CD11b+/CD18+) [5]. However, the expression of Mac-1 is increased on neutrophils of patients with COPD [6]. It has been postulated that targeting these molecules might reduce the inflammation in COPD [4,6]. In any case, monoclonal antibodies to CD18, ICAM-1 and E-selectin inhibit neutrophil accumulation in animal models of lung inflammation. Carbohydrates, recombinant soluble ligands, antibodies and small-molecule inhibitors have all entered clinical development as potential therapeutic agents targeting selectins. Sialyl Lewisx (SLex), Lewisx or Lewisa-containing carbohydrates are major ligands of the selectin family. SLex antagonists, such as bimosiamose (TBC1269, Revotar Biopharmaceuticals AG), a small non-oligosaccharide molecule, could be used as an inhibitor of selectin binding to their ligand. Unfortunately, the preliminary clinical data show that this agent is not active, at least in asthmatic patients [7]. It would be intriguing to test a selectin antagonist such as bimosiamose in the clinical setting of COPD, considering that pre-clinical studies have shown that bimosiamose is particularly active in models involving neutrophils. Humanised monoclonal antibody (hu 1124, efalizumab, Genentech) against the CD11a component of LFA-1 inhibits the interaction of CD11a with various ICAM molecules [8]. Therefore, a possible role of this drug in COPD might be postulated. Adenosine A2a-receptor agonists
Adenosine receptors exist on human monocytes and neutrophils; their activation inhibits neutrophil aggregation, and neutrophil adherence to endothelial cells. Adenosine reduces the expression of adhesion molecules and release of proinflammatory mediators (e.g. reactive oxygen species, elastase and TNF-a) [9]. To date, four subtypes (A1, A2a, A2b, A3) of adenosine receptors have been cloned each with a unique pattern of tissue distribution and signal transduction. In experimental systems, activation of adenosine A2a receptors mediates marked anti-inflammatory activity, both in vitro and in vivo. Highly potent A2a-receptor agonists are in development, and can be ‘tailored’ to target neutrophils, although several compounds such as binodenoson (Aderis Pharmaceuticals) and WRC-0470 (Discovery Therapeutics Inc) have been developed only for cardiac pharmacologic stress-imaging. In a rat model of asthma, an A2a-receptor agonist, CGS 21680 (Novartis Pharma AG), exhibited broad-spectrum antiinflammatory activity. Reports on the effect of these compounds in models of COPD are awaited with interest [10]. PDE4 inhibitors
A large body of evidence documents that inhibition of PDE4 in inflammatory cells influences various specific responses, such
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Table 1. Drugs that directly influence the cellular components of inflammation Pros
Cons
Latest developments
Who is working on this strategy
Refs
Drugs that interfere with adhesion molecules
Monoclonal antibodies to CD18, ICAM-1a, and E-selectin inhibit neutrophil accumulation in animal models of lung inflammation
SLexb antagonists not active, at least in asthmatic patients
- Bimosiamose (TBC1269) - Efalizumab
-Revotar Biopharmaceuticals AG: http://www.lifescience-bavaria.de/ portal/news_detail,6647,31234,detail.html - Genentech: http://www.gene.com/gene/products/ information/immunological/raptiva/index.jsp
[5,6]
Adenosine A2a-receptor agonists
- Activation of adenosine A2a-receptors mediates marked anti-inflammatory activity, both in vitro and in vivo
Adenosine A2a receptors have a wide tissue distribution, and mediate inhibition of platelet activation, vasorelaxation and a variety of effects on the central nervous system
- CGS 21680 - Regadenoson (CVT-3146) - Binodenoson (MRE-0470) - WRC-0470
- Novartis Pharma AG - CV Therapeutics: http://www.prnewswire.com/ cgi-bin/stories.pl?ACCT =105&STORY=/www/story/ 04-26-2004/0002159213 - King Pharmaceuticals: http://www.kingpharm.com/ news_details.asp?id_news=247
[9]
PDE4 inhibitors
- Reduction in airway tissue inflammatory cells characteristic of COPDc - Stabilisation of FEV1d over time - Fewer exacerbations
- Vomiting - Some anti-inflammatory effects reported in vitro might not be expressed at plasma levels that are attained in humans - Delayed apoptosis of neutrophils
-
- GSK: http://www.gsk.com/ media/archive-03.htm - Altana: http://www.altanapharma. com/home/site.nsf/files/e_2_news. 04-05-25.html - Bayer - Elbion: http://www.elbion.de/ pipelinechart/awd12281.html - Schering-Plough - Inflazyme Pharmaceuticals: http://www.inflazyme.com/ PDE4_body.htm - Glenmark
[11–18]
Cilomilast Roflumilast BAY 19-8004 AWD 12-281 Sch-351591 IPL4088 GRC-3015
a
ICAM, intercellular adhesion molecule. SLex, sialyl Lewisx. COPD, chronic obstructive pulmonary disease. d FEV1, forced expiratory volume in 1 s. b c
as the production and/or release of proinflammatory mediators including cytokines and active oxygen species [11]. In fact, selective PDE4 inhibitors, such as cilomilast (GSK), roflumilast (Altana), BAY 19-8004 (Bayer), AWD 12-281 (Elbion), GRC3015 (Glenmark), SCH 351591 (Schering-Plough) are active in animal models of neutrophil inflammation and also in patients with COPD [12,13], in which they exert some anti-inflammatory effects, measurable in airway biopsies, with a reduction of levels of inflammatory markers, that is, CD8+ T cells and CD68+ macrophages. [14]. These results represent the first demonstration for any agent of a reduction in airway tissue inflammatory cells characteristic of COPD. However, some inflammatory cells are less sensitive to PDE4 inhibition than others. Within the same cell type, different functions display different sensitivities to cyclic adenosine monophosphate (cAMP) elevation. In the neutrophil, degranulation is relatively insensitive compared to superoxide production and leukotriene (LT)B4 generation. Thus, some anti-inflammatory effects reported in vitro might not be expressed at plasma levels that are attained in humans [11]. Moreover, elevation of cAMP, at least in normal circu-
lating cells, results in delayed apoptosis, which could have proinflammatory consequences [15]. PDE4 inhibitors have been limited by side effects, but the development of more-selective inhibitors might be feasible in the future. It now seems probable that vomiting is because of inhibition of a particular subtype of PDE4, the PDE4D [16], whereas PDE4B is more important than PDE4D in inflammatory cells [17]. Thus, theoretically, PDE4B-selective inhibitors might have a greater therapeutic ratio. Alternatively, the PDE4 inhibitor with low oral bioavailability could be administered by inhalation [18]. In any case, although the observed efficacy of PDE4 inhibitors in COPD patients is encouraging, it is not clear whether the demonstrable effects on lung function and symptoms are a manifestation of their bronchodilator activity or are a consequence of anti-inflammatory effects.
How to interfere with inflammatory mediators that regulate migration and activation of inflammatory cells Several inflammatory mediators are probable to be involved in COPD as many inflammatory cells and structural cells are www.drugdiscoverytoday.com
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activated in the disease. In particular, cytokines and chemokines regulate migration and activation of these inflammatory cells. There is now an intensive search for compounds able to interact with these inflammatory mediators. However, because an imbalance between proinflammatory and antiinflammatory mediators might underlie the appearance of pulmonary chronic inflammation, the administration or stimulated production of anti-inflammatory mediators is considered a further therapeutic possibility. Therapies under investigation mainly consist of: (a) IL-10; (b) TNF-a inhibitors; (c) chemokine inhibitors; (d) nuclear factor (NF)-kB inhibitors; (e) p38 mitogen-activated protein kinase (MAPK) inhibitors; (f) phosphoinositide 3-kinase (PI3K) inhibitors; and (g) LTB4 inhibitors (Table 2). IL-10
IL-10, a regulatory cytokine that decreases inflammatory responses, is reduced in COPD [19]. It is currently under study in clinical trials for chronic inflammatory diseases, such as inflammatory bowel disease, psoriasis and rheumatoid arthritis [20]. Although IL-10 itself might have limited therapeutic potential in COPD, a selective activator of IL-10 receptors or signal transduction pathways might have therapeutic potential. The new strategies of IL-10 treatment include recombinant human IL-10 (ilodecakin, ScheringPlough), the use of genetically modified bacteria, gelatine microsphere containing IL-10 (GM-IL-10), adenoviral vectors encoding IL-10 (AdvmuIL-10) and combining regulatory T cells. TNF-a inhibitors
Studies have shown that TNF-a levels in COPD might be higher than in the general population, and other researches have reported TNF-a gene polymorphisms in COPD patients. It is not surprising, therefore, that TNF-a might mediate several the pulmonary and systemic manifestations of COPD [21]. Consequently, inhibition of the effects of TNF-a could have considerable benefit in COPD. Humanised monoclonal antibodies to TNF-a [e.g. infliximab (Centocor), adalimumab (D2E7) (Abbott Laboratories, Cambridge Antibody Technology, Eisai Co Ltd/GTC Biotherapeutics Inc), CDP 571 (Celltech Chiroscience), CDP 870 (Celltech Chiroscience)] and soluble TNF-a receptors (e.g. etanercept, Amgen Inc and Wyeth Pharmaceuticals) are effective in the treatment of inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, and their use could be extended to COPD [10]. However, clinical studies evaluating this concept are yet to be published, although a recent exploratory study presented as an abstract did not show a short-term effect of infliximab on respiratory symptoms FEV1 and sputum cell counts in patients with mild COPD [22]. It also seems possible to reduce TNF-a levels by inhibition of TNF-a-converting enzyme (TACE). Targeting 338
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TACE can result in similar efficacy to that seen with antiTNF antibodies and soluble receptors. In an animal model of airway inflammation, PKF 242–484 (Novartis Pharma AG) and PKF 241–466 (Novartis Pharma AG), two TACE inhibitors, blocked TNF-a release into the airways and inflammatory cell influx [23]. The treatment of patients with inhibitors of TNF-a production such as SB210313 (GSK) [24], CJ14877 (Pfizer), CJ 14897 (Ono), or with antisense oligonucleotides directed against the mRNA molecules encoding TNF-a such as ISIS 104838 and ISIS 25302 (Isis Pharmaceuticals) can be alternative strategies [25]. Chemokine inhibitors
Chemokines regulate increased inflammatory cell migration and activation in the lung. Consequently, one strategy in the treatment of COPD would be to inhibit the effect of chemokines to recruit and activate leucocytes [10]. Chemokines are divided into four main classes based on the number and spacing of conserved cysteines at the amino terminus: CXC, CC, C and CX3C families. Several chemokines shown to be associated with COPD belong to the CXC family and include IL-8, RANTES (regulated on activation, normal T-cell expressed and secreted) and growth-regulated oncogene-a (GRO-a). Both IL-8 and GRO-a play an important role in the accumulation of neutrophils, monocytes and macrophages in the lungs of patients with COPD. In consideration of the documentation that a monoclonal antibody to IL-8 significantly inhibited the chemotactic activity in COPD patients’ sputum, but not in induced sputum from healthy subjects, a phase II trial of ABX-IL-8 (Abgenix), a human monoclonal antibody to IL-8, in COPD patients is currently under way [4]. IL-8 activates neutrophils via a specific receptor (CXCR1) coupled to activation and degranulation, and via a highaffinity receptor (CXCR2), which is important in chemotaxis. Therefore, a CXCR2 antagonist is probable to be more useful, particularly as CXCR2 is also expressed on monocytes. Thus, treatment with CXCR2 antagonist GRO-a (8–73) reduced the neutrophilic inflammation and alveolar damage and decreased mortality associated with endotoxinemia, acid aspiration and in a skin air pouch model [26]. Several CXCR2 antagonists, such as nicotinamide N-oxides (Celltech R&D, Inc), nicotinanilides (Celltech R&D Inc), SB 225002 (GSK) and SB 265610 (GSK), two small-molecule inhibitors, are under development [10]. However, the effects on many actions of IL-8 and related chemokines acting upon CXCR2 would have to be monitored carefully as neutrophils are essential for host defence against microbial pathogens, and undesired immunosuppression is surely the most worrying potential adverse effect of administration of these compounds to humans [27]. The action of CC-chemokines at the CCR2-receptor has also been shown to be involved in COPD [28]. The anti-CCR2
Pros a
b
Cons
Latest developments
Who is working on this strategy
Refs [19–21]
IL-10
It not only inhibits TNF and chemokines, but also certain matrix metalloproteinases, such as MMP-9c
Hematological side effects
Recombinant IL-10 (ilodecakin)
Schering-Plough
TNF-a inhibitors
They reduce the systemic effects of TNF-a and induction of IL-8 and other chemokines in airway cells
Effective inhibitors might cause immune suppression and impair host defences
- Humanised monoclonal antibodies to TNF-a: infliximab, adalimumab (D2E7), CDP 571 CDP 870 - Humanised monoclonal antibodies to soluble TNF-a receptors: etanercept - TACEd inhibitors: PKF 242–484, PKF 241–466 - Inhibitors of TNF-a production: SB210313, CJ14877, CJ 14897 - Antisense oligonucleotides directed against the mRNA molecules encoding TNF-a: ISIS 104838, ISIS 25302
- Centocor: http://www.clinicaltrials. gov/ct/gui/show/NCT00056264 - Abbott: http://abbott.com/news/ press_release.cfm?id=506 - Celltech: http://www.celltechpharma.de/ueber_celltech_forschung.html - Amgen Inc/Wyeth Pharmaceuticals - Novartis Pharma AG - GlaxoSmithKline - Pfizer - Ono - Isis Pharmaceuticals: http:// www.isispharm.com/antisense_pipeline.html
- Human anti-CXCL8 antibody: ABX-IL-8, GAG - CXCR2 inhibitors: SB225002, SB 265610, 4-fluoronicotinanilides - Anti-CCR2 monoclonal antibody: MLN-1202 - Antagonists for CCR2 receptors: RS504393
-
339
They inhibit the effect of chemokines to recruit and activate leucocytes
Inhibition of a single receptor or chemokine might not be sufficient to block the inflammatory response due to the redundancy in the chemokine network. Moreover, CXCR2 antagonists might inhibit epithelial repair
NF-kBe inhibitors
They can efficiently inhibit the production of several proinflammatory cytokines
Effective inhibitors might cause immune suppression and impair host defences
p38 MAPKh inhibitors
There is a much greater dependence on the p38 MAPK cascade in the neutrophil when compared with other leukocytes
- Several reports have identified conditions in which p38 MAPK inhibitors enhance inflammatory responses - p38 MAPK inhibitors have effects on various cell types, thereby possibly enhancing the therapeutic effects but also increasing the risk of side effects
PI3Ki inhibitors
PI3K signalling cascade plays a pivotal role in the activation of inflammatory cells
Abgenix Sigma-Aldrich GSK Celltech Millennium Roche
[21–25]
[10,26–31]
- NF-kB specific decoy oligonucleotides
- Corgentech
- IKKgf (NEMO)g binding peptide
- Imgenex: http://www.imgenex. com/inhibit_list.php?id=4
-
- GSK - R.W. Johnson Pharmaceutical Research Institute - Signal Pharmaceuticals, Inc: http://www.signalpharm.com/spr_ikk.html - Boehringer Ingelheim - Fujisawa - Scios
[34,35]
Eli Lilly & Company
[4,36,37]
SB 203580 SB 239063 SB 242235 RWJ 67657 BIRB796BS FR167653 SCIO469 SCIO323
LY294002
[32,33]
(Cont.)
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Table 2. Drugs able to interfere with inflammatory mediators that regulate migration and activation of inflammatory cells
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Pros LTB4j
inhibitors
They might have some effect on sputum neutrophil content and/or activation in patients with stable COPDk - They might therefore protect the airways from neutrophil-mediated damage and from the effects of an acute exacerbation
Cons
Latest developments l
Side effects with 5-LO inhibitors
-
BLT1m
antagonists: LY29311, SC53228, CP105696, amelubant (BIIL284), SB201146, LTB019 - 5-LO inhibitors: BAYx1005, BWA4C, ZD4407, CJ-13,610 - FLAPn inhibitors: MK886
Who is working on this strategy
Refs
- Novartis: http://www.novartis.com/ annualreport2000/cid_respiratory.html - AstraZeneca: http://www.astrazeneca. com/AnnualRep2000/inbrief/ randdpipelinetable.asp
[38–43]
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Table 2. (Continued)
a
IL, interleukin. TNF, tumour necrosis factor. c MMP, matrix metalloproteinase. d TACE, TNF-a-converting enzyme. e NF-kB, nuclear factor-kB. f IKK, inhibitor kB kinase. g NEMO, NF-kB essential modulator. h MAPK, mitogen-activated protein kinase. i PI3K, phosphatidylinositol 3-kinase. j LTB4, leukotriene B4. k COPD, chronic obstructive pulmonary disease. l 5-LO, 50 -lipoxygenase. m BLT1, LTB4 receptor-1. n FLAP, 5-LO activating protein. b
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monoclonal antibody MLN-1202 (Millennium) reduces both monocyte and neutrophil influx into airways in experimental models of airway inflammation [29]. Small-molecule antagonists for CCR2 receptors, including RS-504393 (Sanwa Kagaku Kenkyusho Co) are under development as well [30]. Also CXCR3, which is expressed on T cells and mediates CD8+ lymphocyte migration and activation, is a potential target for small-molecule antagonists or antibodies because its expression is elevated in peripheral airways of smokers and patients with COPD [31]. One potential general problem in targeting chemokines in COPD is the redundancy in the chemokine network such that inhibition of a single receptor or chemokine might not be sufficient to block the inflammatory response [10]. NF-kB inhibitors
NF-kB regulates the expression of IL-8 and other chemokines, TNF-a and other inflammatory cytokines, and some MMPs. Consequently, inhibition of NF-kB activity might be a therapeutic option. NF-kB is sequestered in the cytoplasm by the inhibitor of NF-kB (IkB) family of inhibitory proteins that mask the nuclear localisation signal of NF-kB thereby preventing translocation of NF-kB to the nucleus. External stimuli such as TNF or other cytokines result in phosphorylation and degradation of IkB resulting in the release of NF-kB dimers. IkB proteins are phosphorylated by IkB kinase complex consisting of at least three proteins, inhibitors of kB kinase (IKK)a, IKKb and IKKg. There are several possible approaches to the inhibition of NF-kB. They include gene transfer of IkB, IKK, NF-kB-inducing kinase (NIK) and IkB ubiquitin ligase, which regulate the activity of NF-kB and drugs that inhibit the degradation of IkB [32]. Several these drugs are in development. The most promising approach can be the inhibition of IKK-2 by smallmolecule inhibitors, which suppress the release of inflammatory cytokines and chemokines from alveolar macrophages. Hypoestoxide, a naturally occurring diterpene from Hypoestes rosea, and ()-epigallocatechin-3-gallate, a green tea polyphenol, are IKK inhibitors, which could act as prototypic molecules for development of potent and selective synthetic compounds [10]. Further developments include NF-kB ‘decoy’ oligonucleotides (Corgentech) that inhibit nuclear translocation of NF-kB [33]. One concern about long-term inhibition of NF-kB, however, is that effective inhibitors might cause immune suppression and impair host defences. However, there are alternative pathways of NF-kB activation, via kinases other than IKK, which might be more important in inflammatory disease [4]. p38 MAPK inhibitors
MAPKs play a key role in chronic inflammation. One of these, the p38 MAPK, is activated by cellular stress. p38 MAPK in
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turn phosphorylates and activates downstream substrates, such as other protein kinases and transcriptional factors, and ultimately results in significant transcriptional up-regulation of the pro-inflammatory cytokines TNF-a, IL-1b IL-6 and IL-8, as well as the pro-inflammatory prostaglandin pathway via cyclooxygenase-2 (COX-2) [34]. Small-molecule inhibitors of p38 MAPK, such as SB 203580 (GSK), SB 239063 (GSK) and RWJ 67657 (Johnson & Johnson Pharmaceutical), have been developed, offering a broad range of anti-inflammatory effects that might be beneficial in COPD [35]. In lipopolysaccharide (LPS) and bleomycin models of inflammation and pulmonary fibrosis, SB 239063 reduced neutrophil infiltration, IL-6 expression, and MMP9 activity in the airways. Oral administration of RWJ 67657, a pyrindinyl imidazole inhibitor of p38 MAPK, inhibited LPSinduced increases in plasma IL-6, IL-8 and TNF-a in healthy human volunteers. More recently, another p38 MAPK inhibitor, doramapimod (BIRB796BS, Boehringer Ingelheim), inhibited several LPS-induced inflammatory responses in healthy volunteers. Such a broad-spectrum anti-inflammatory drug is probable to infer some toxicity, but inhalation might be a feasible therapeutic approach [4]. SCIO469 and SCIO323 (Scios) are antisense p38 MAPK oligonucleotides not tested in COPD yet. PI3K inhibitors
PI3K catalyses the production of phosphatidylinositol-3,4,5triphosphate which initiates several cytosolic events leading to cell growth, entry into the cell cycle, cell migration and cell survival [36]. Several these events are proinflammatory. There are four members of the class I PI3Ks, all of which are expressed in neutrophils, PI3Ka, b, g and d. PI3Kg regulates their migration and respiratory burst [37], as well as impaired T-lymphocyte and macrophage function. Consequently, selective PI3K inhibitors could suppress neutrophil- and MMP-derived lung damage in COPD. Small-molecule inhibitors of PI3Kg and d are in development [4]. Wortmannin, a fungal metabolite (Penicillium fumiculosum), and LY294002 (Eli Lilly & Company) are non-selective inhibitors. At present, LY294002 is only been tested in a mouse model of asthma. LTB4 inhibitors
LTB4 contributes to neutrophil chemotaxis [38]. Moreover, it induces retardation of neutrophil apoptosis [38]. Because persistent neutrophilia is a feature of COPD, antagonism of leukotriene LTB4 receptors is being considered as a mode of treating this disease. Two subtypes of receptor for LTB4 have been described. The LTB4 receptors-1 (BLT1) are expressed mainly on granulocytes and monocytes, whereas BLT2 receptors are expressed on Tlymphocytes [39]. BLT1 antagonists, such as LY 29311 (Eli Lilly & Company), SB 225002 (GSK), SC 53228 (Pfizer, formerly Searle), CP 105696 (Pfizer), amelubant (BIIL284), LY www.drugdiscoverytoday.com
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29311 (Eli Lilly & Company), and SB 201146 (GSK), have now been developed for the treatment of neutrophilic inflammation [40,41]. LTB4 is synthesised by 50 -lipoxygenase (5-LO). Members of the 5-LO inhibitor, 5-LO activating protein (FLAP) inhibitor, and dual 5-LO/COX inhibitor classes, together with LTB4receptor antagonists have all demonstrated the inhibition of neutrophil influx and tissue oedema when administered orally to animals [42]. This has been associated with a reduction in tissue LTB4 levels and LTB4 synthesis ex vivo from circulating neutrophils [42]. A recent small study suggests that a leukotriene synthesis inhibitor, BAYx1005, can produce modest reductions in some measures of neutrophilic bronchial inflammation in patients with COPD [43]. The incidence of adverse effects is, in any case, limiting development of 5-LO inhibitors [42].
Conclusions The recently published American Thoracic Society/European Respiratory Society guidelines [44] identify a pressing need to develop agents that suppress the inflammation associated with COPD and prevent disease progression. As illustrated in this review (which is not exhaustive because of the ongoing identification of new targets that might allow the development of novel approaches by the pharmaceutical industry), there are some interesting therapeutic attempts, which are under pharmacological or clinical development. We do not know if all these new therapies will reach the market. In effect, the therapeutic rationale behind many of these treatments is mainly speculative and, in any case, they are fraught with important safety issues. Nonetheless, although we think that there is still much to be learned about the mechanisms involved in the inflammatory component of COPD, findings from pre-clinical studies reveal promising avenues for the design of better therapeutics. Looking at a rather near future, we believe that PDE4 inhibitors and LTB4 inhibitors will provide interesting opportunities for novel anti-inflammatory therapeutic interventions that will slow or halt disease progression in this debilitating respiratory disease. Obviously, full knowledge of the therapeutic value of these novel compound classes awaits the outcome of longer-term clinical trials.
References 1 Gan, W.Q. et al. (2004) Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a metaanalysis. Thorax 59, 574–580 2 Barnes, P.J. et al. (2004) Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase. Lancet 363, 731– 733 3 Cazzola, M. and Dahl, R. (2004) Inhaled combination therapy with longacting ß2-agonists and corticosteroids in stable COPD. Chest 126, 220–237 4 Barnes, P.J. (2004) COPD: is there light at the end of the tunnel? Curr. Opin. Pharmacol. 4, 263–272
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5 Ainslie, M.P. et al. (2002) Characterisation of adhesion receptors mediating lymphocyte adhesion to bronchial endothelium provides evidence for a distinct lung homing pathway. Thorax 57, 1054–1059 6 Noguera, A. et al. (1998) Expression of adhesion molecules and G proteins in circulating neutrophils in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 158, 1664–1668 7 Avila, P.C. et al. (2004) Effect of a single dose of the selectin inhibitor TBC1269 on early and late asthmatic responses. Clin. Exp. Allergy 34, 77– 84 8 Pietrzak, A. et al. (2003) Efaluzimab in the treatment of psoriasis. Ann. Univ. Mariae Curie Sklodowska [Med.] 58, 174–178 9 Sullivan, G.W. (2003) Adenosine A2A receptor agonists as anti-inflammatory agents. Curr. Opin. Investig. Drugs 4, 1313–1319 10 Donnelly, L.E. and Rogers, D.F. (2003) Therapy for chronic obstructive pulmonary disease in the 21st century. Drugs 63, 1973–1998 11 Spina, D. (2003) Phosphodiesterase-4 inhibitors in the treatment of inflammatory lung disease. Drugs 63, 2575–2594 12 Compton, C.H. et al. (2001) Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study. Lancet 358, 265–270 13 Gamble, E. et al. (2003) Anti-inflammatory effects of the phosphodiesterase 4 inhibitor cilomilast (Ariflo) in COPD. Am. J. Respir. Crit. Care Med. 168, 976–982 14 Leitchl, S. et al. (2002) Efficacy of once-daily roflumilast, a new, orally active, selective phosphodiesterase 4 inhibitor, in chromic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 165 (Suppl.), A229 (abstract) 15 Sturton, G. and Fitzgerald, M. (2002) Phosphodiesterase 4 inhibitors for the treatment of COPD. Chest 121 (5 Suppl.), 192S–196S 16 Lamontagne, S. et al. (2001) Localization of phosphodiesterase-4 isoforms in the medulla and nodose ganglion of the squirrel monkey. Brain Res. 920, 84–96 17 Jin, S.L. and Conti, M. (2002) Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-a responses. Proc. Natl. Acad. Sci. USA 99, 7628–7633 18 Kuss, H. et al. (2003) In vivo efficacy in airway disease models of N-(3,5dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyo xylic acid amide (AWD 12-281), a selective phosphodiesterase 4 inhibitor for inhaled administration. J. Pharmacol. Exp. Ther. 307, 373–385 19 Takanashi, S. et al. (1999) Interleukin-10 level in sputum is reduced in bronchial asthma COPD and in smokers. Eur. Respir. J. 14, 309– 314 20 Li, M.C. and He, S.H. (2004) IL-10 and its related cytokines for treatment of inflammatory bowel disease. World J. Gastroenterol. 10, 620–625 21 De Boer, W.I. (2002) Cytokines and therapy in COPD: a promising combination? Chest 121 (Suppl. 5), 209s–218s 22 van der Vaart, H. et al. (2004) The effect of infliximab in patients with chronic obstructive pulmonary disease. Chest 126 (Suppl.), 840S (abstract) 23 Trifilieff, A. et al. (2002) Pharmacological profile of PKF242-484 and PKF241-466, novel dual inhibitors of TNF-a converting enzyme and matrix metalloproteinases, in models of airway inflammation. Br. J. Pharmacol. 135, 1655–1664 24 Boehm, J.C. et al. (1996) 1-substituted 4-aryl-5-pyridinylimidazoles: a new class of cytokine suppressive drugs with low 5-lipoxygenase and cyclooxygenase inhibitory potency. J. Med. Chem. 39, 3929–3937 25 Nyce, J. (2002) Respirable antisense oligonucleotides: a new, third drug class targeting respiratory disease. Curr. Opin. Allergy Clin. Immunol. 2, 533–536 26 McColl, S.R. and Clark-Lewis, I. (1999) Inhibition of murine neutrophil recruitment in vivo by CXC chemokine receptor antagonists. J. Immunol. 163, 2829–2835 27 Pease, J.E. and Sabroe, I. (2002) The role of interleukin-8 and its receptors in inflammatory lung disease. Implications for therapy. Am. J. Respir. Med. 1, 19–25 28 Owen, C. (2001) Chemokine receptors in airway disease: which receptors to target? Pulm. Pharmacol. Ther. 14, 193–202
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29 Horvath, C. et al. (2002) Targeting CCR2 or CD18 inhibits experimental in-stent restenosis in primates: inhibitory potential depends on type of injury and leukocytes targeted. Circ. Res. 90, 488–494 30 Witherington, J. et al. (2001) Conformationally restricted indolopiperidine derivatives as potent CCR2B receptor antagonists. Bioorg. Med. Chem. Lett. 11, 2177–2180 31 Saetta, M. et al. (2002) Increased expression of the chemokine receptor CXCR3 and its ligand CXCL10 in peripheral airways of smokers with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 165, 1404–1409 32 Delhase, M. et al. (2000) Kinase regulation in inflammatory response. Nature 406, 367–368 33 Gill, J.S. et al. (2002) Effects of NFkB decoy oligonucleotides released from biodegradable polymer microparticles on a glioblastoma cell line. Biomaterials 23, 2773–2781 34 Bukhtiyarova, M. et al. (2004) Improved expression, purification, and crystallization of p38a MAP kinase. Protein Expr. Purif. 37, 154–161 35 Kumar, S. et al. (2003) p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat. Rev. Drug Discov. 2, 717–726 36 Cantley, L.C. (2002) The phosphoinositide 3-kinase pathway. Science 296, 1655–1657
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37 Yoon, S.O. et al. (2002) Sustained production of H2O2 activates proMMP-2 through receptor tyrosine kinases/PI3-K/NF-kB pathway. J. Biol. Chem. 277, 30271–30282 38 Crooks, S.W. and Stockley, R.A. (1998) Leukotriene B4. Int. J. Biochem. Cell Biol. 30, 173–178 39 Yokomizo, T. et al. (2000) A second leukotriene B4 receptor BLT2. A new therapeutic target in inflammation and immunological disorders. J. Exp. Med. 192, 421–432 40 Beeh, K.M. et al. (2003) Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4. Chest 123, 1240–1247 41 Donnelly, L.E. and Rogers, D.F. (2003) Therapy for chronic obstructive pulmonary disease in the 21st century. Drugs 63, 1973–1998 42 Kilfeather, S. (2002) 5-Lipoxygenase inhibitors for the treatment of COPD. Chest 121 (5 Suppl.), 197S–200S 43 Gompertz, S. and Stockley, R.A. (2002) A randomized, placebo-controlled trial of a leukotriene synthesis inhibitor in patients with COPD. Chest 122, 289–294 44 Celli, B.R. and MacNee, W. (2004) Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur. Respir. J. 23, 932–946
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Drug Discovery Today: Therapeutic Strategies Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Respiratory diseases
New anti-inflammatory approaches in COPD Maria Gabriella Matera1, Mario Cazzola2* 1 2
Unit of Pharmacology, Department of Experimental Medicine, School of Medicine, Second University, Piazza Miraglia 4, 80123 Naples, Italy Unit of Pneumology and Allergology, Department of Respiratory Medicine, A. Cardarelli Hospital, Via A. Cardarelli 9, 80131 Naples, Italy
Inflammation in chronic obstructive pulmonary disease (COPD) is characterised by increased numbers of neutrophils, macrophages and CD8+ T-lymphocytes, and the release of multiple inflammatory mediators (leukotrienes, chemokines, cytokines). It appears to be resistant to corticosteroids. This circumstance is stimulating a search for novel anti-inflammatory therapies that might prevent the relentless progression of the disease. For this reason, attention has largely been focused on inhibition of recruitment and activation of inflammatory cells, and on antagonism of their products.
Section Editors: Roy Goldie – University of Western Australia, Western Australian Institute for Medical Research, Australia Duncan Stewart – Terrence Donnelly Research Laboratories, Division of Cardiology, St Michael’s Hospital and University of Toronto, Toronto, Ontario, Canada Chronic obstructive pulmonary disease (COPD) is a degenerative inflammatory lung disease often associated with long-term cigarette smoking. Despite the inflammatory nature of COPD, currently available anti-inflammatory therapies such as those used in asthma and rheumatoid arthritis for example, are not clinically very effective in blunting either the symptoms or the progression of COPD. Accordingly, there is an urgent need to discover novel, effective antiinflammatory treatments for this disease. Matera and Cazzola have been leading researchers in the COPD field for many years and have put together a very useful summary of the state-of-the-art development of clearly and potentially useful anti-inflammatory strategies in COPD.
Introduction Chronic inflammation plays a central role in chronic obstructive pulmonary disease (COPD). It is characterised by an increase in neutrophils, macrophages and CD8+ T-lymphocytes in small and large airways as well as in lung parenchyma and pulmonary vasculature [1]. Alveolar macrophages play a crucial part in orchestrating this inflammation through the release of proteases such as matrix metalloproteinase (MMP) 9, inflammatory cytokines such as tumour necrosis factor (TNF)-a and chemokines such as interleukin (IL)-8 that attract neutrophils into the airways. Corticosteroids are highly effective as an anti-inflammatory treatment in a wide range of chronic inflammatory diseases, but patients with COPD are poorly responsive to these drugs. This probably happens because cigarette smok*Corresponding author: (M. Cazzola) [email protected] 1740-6773/$ ß 2004 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddstr.2004.11.013
ing and oxidative stress impair histone deacetylase 2 function [2]. Nonetheless, in severe COPD patients, combinations of inhaled corticosteroids and long-acting b2-agonists show an additive effect, suggesting an interaction between the two moieties that can have a positive effect [3].
Emerging anti-inflammatory strategies Suppression of the inflammatory response is a logical approach to the treatment of COPD and might improve symptoms such as cough and mucus secretion, improve health status and reduce exacerbations. In the long-term, such treatments should reduce disease progression. However, hitherto, no therapeutic agent has been shown to reduce the numbers of the important inflammatory cells, macrophages, neutrophils and CD8+ lymphocytes in COPD [4]. For this reason, attention has largely been focused on inhibition of www.drugdiscoverytoday.com
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Glossary CXC: chemokine ligand. GAG: glycosaminoglycan. ICAM: intercellular adhesion molecule that mediates attachment, spreading and migration of polymorphonuclear leukocytes. IL: interleukin; mediator of inflammatory and immune reactions. LFA: lymphocyte function antigen, an adhesion molecule that appears to play a major role in T-lymphocyte adhesion to vascular endothelium, cytotoxic function, and activation. LTB4: leukotriene B4, an extremely potent lipid inflammatory mediator, derived from membrane phospholipids by the sequential actions of cytosolic phospholipase A2, which recruits and activates leukocytes. MAPK: mitogen-activated protein kinase. NF-kB: nuclear factor-kB, a protein transcription factor necessary for maximal transcription of several pro-inflammatory molecules associated with an inflammatory response. PDE4: phosphodiesterase 4 enzyme that catalyses the breakdown of adenosine 30 :50 -cyclic monophosphate. PI3K: phosphatidylinositol 3-kinase enzymes that are characterised by their ability to phosphorylate the 3-OH position of the inositol ring of several different phosphoinositides and are key signalling targets downstream of a variety of chemokine receptors. SLex, sialyl Lewisx, the carbohydrate ligands for E-selectin. TNF-a: tumour necrosis factor-a, primary pro-inflammatory cytokine that provides cell signals resulting in the activation of redox-sensitive transcription factors, such as NF-kB and activator protein-1. VCAM: vascular cell adhesion molecule that contributes preferentially to adhesion and migration of lymphocytes and monocyte-macrophages. VLA: very late antigen, the a1b1 integrin that is the major receptor for collagen molecules in the extracellular matrix and plays an important role in inflammatory responses involving T cells, macrophages, angiogenesis and fibrosis.
recruitment and activation of these cells, and on antagonism of their products. To do it, we can try to directly influence the cellular components of inflammation, or interfere with inflammatory mediators that regulate migration and activation of inflammatory cells.
How to influence directly the cellular components of inflammation At present, some new therapeutic strategies allow us to try to influence directly the cellular components of inflammation, although there are concerns about their use for a chronic disease, as an impaired neutrophilic response can increase the susceptibility to infection in patients with COPD, who are often already at risk [4]. The therapies explored include: (a) drugs that interfere with adhesion-molecules; (b) adenosine A2a-receptor agonists; and (c) phosphodiesterase 4 (PDE4) inhibitors (Table 1). Drugs that interfere with adhesion-molecules
The sequential interaction between specific adhesion molecules on inflammatory cells and the pulmonary endothelium mediates the recruitment of monocytes, CD8+ lymphocytes and neutrophils into the lung of patients with COPD. Specific binding of lymphocytes to bronchial endothelium has been observed which was significantly inhibited by antibodies against P-selectin, P-selectin glycoprotein (PSGL)-1, lymphocyte function-associated antigen (LFA)-1, L-selectin, intercel336
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lular adhesion molecule (ICAM)-1 and ICAM-2 but not Eselectin, very late antigen (VLA)-4, vascular cell adhesion molecule (VCAM)-1 or Mac-1 (CD11b+/CD18+) [5]. However, the expression of Mac-1 is increased on neutrophils of patients with COPD [6]. It has been postulated that targeting these molecules might reduce the inflammation in COPD [4,6]. In any case, monoclonal antibodies to CD18, ICAM-1 and E-selectin inhibit neutrophil accumulation in animal models of lung inflammation. Carbohydrates, recombinant soluble ligands, antibodies and small-molecule inhibitors have all entered clinical development as potential therapeutic agents targeting selectins. Sialyl Lewisx (SLex), Lewisx or Lewisa-containing carbohydrates are major ligands of the selectin family. SLex antagonists, such as bimosiamose (TBC1269, Revotar Biopharmaceuticals AG), a small non-oligosaccharide molecule, could be used as an inhibitor of selectin binding to their ligand. Unfortunately, the preliminary clinical data show that this agent is not active, at least in asthmatic patients [7]. It would be intriguing to test a selectin antagonist such as bimosiamose in the clinical setting of COPD, considering that pre-clinical studies have shown that bimosiamose is particularly active in models involving neutrophils. Humanised monoclonal antibody (hu 1124, efalizumab, Genentech) against the CD11a component of LFA-1 inhibits the interaction of CD11a with various ICAM molecules [8]. Therefore, a possible role of this drug in COPD might be postulated. Adenosine A2a-receptor agonists
Adenosine receptors exist on human monocytes and neutrophils; their activation inhibits neutrophil aggregation, and neutrophil adherence to endothelial cells. Adenosine reduces the expression of adhesion molecules and release of proinflammatory mediators (e.g. reactive oxygen species, elastase and TNF-a) [9]. To date, four subtypes (A1, A2a, A2b, A3) of adenosine receptors have been cloned each with a unique pattern of tissue distribution and signal transduction. In experimental systems, activation of adenosine A2a receptors mediates marked anti-inflammatory activity, both in vitro and in vivo. Highly potent A2a-receptor agonists are in development, and can be ‘tailored’ to target neutrophils, although several compounds such as binodenoson (Aderis Pharmaceuticals) and WRC-0470 (Discovery Therapeutics Inc) have been developed only for cardiac pharmacologic stress-imaging. In a rat model of asthma, an A2a-receptor agonist, CGS 21680 (Novartis Pharma AG), exhibited broad-spectrum antiinflammatory activity. Reports on the effect of these compounds in models of COPD are awaited with interest [10]. PDE4 inhibitors
A large body of evidence documents that inhibition of PDE4 in inflammatory cells influences various specific responses, such
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Table 1. Drugs that directly influence the cellular components of inflammation Pros
Cons
Latest developments
Who is working on this strategy
Refs
Drugs that interfere with adhesion molecules
Monoclonal antibodies to CD18, ICAM-1a, and E-selectin inhibit neutrophil accumulation in animal models of lung inflammation
SLexb antagonists not active, at least in asthmatic patients
- Bimosiamose (TBC1269) - Efalizumab
-Revotar Biopharmaceuticals AG: http://www.lifescience-bavaria.de/ portal/news_detail,6647,31234,detail.html - Genentech: http://www.gene.com/gene/products/ information/immunological/raptiva/index.jsp
[5,6]
Adenosine A2a-receptor agonists
- Activation of adenosine A2a-receptors mediates marked anti-inflammatory activity, both in vitro and in vivo
Adenosine A2a receptors have a wide tissue distribution, and mediate inhibition of platelet activation, vasorelaxation and a variety of effects on the central nervous system
- CGS 21680 - Regadenoson (CVT-3146) - Binodenoson (MRE-0470) - WRC-0470
- Novartis Pharma AG - CV Therapeutics: http://www.prnewswire.com/ cgi-bin/stories.pl?ACCT =105&STORY=/www/story/ 04-26-2004/0002159213 - King Pharmaceuticals: http://www.kingpharm.com/ news_details.asp?id_news=247
[9]
PDE4 inhibitors
- Reduction in airway tissue inflammatory cells characteristic of COPDc - Stabilisation of FEV1d over time - Fewer exacerbations
- Vomiting - Some anti-inflammatory effects reported in vitro might not be expressed at plasma levels that are attained in humans - Delayed apoptosis of neutrophils
-
- GSK: http://www.gsk.com/ media/archive-03.htm - Altana: http://www.altanapharma. com/home/site.nsf/files/e_2_news. 04-05-25.html - Bayer - Elbion: http://www.elbion.de/ pipelinechart/awd12281.html - Schering-Plough - Inflazyme Pharmaceuticals: http://www.inflazyme.com/ PDE4_body.htm - Glenmark
[11–18]
Cilomilast Roflumilast BAY 19-8004 AWD 12-281 Sch-351591 IPL4088 GRC-3015
a
ICAM, intercellular adhesion molecule. SLex, sialyl Lewisx. COPD, chronic obstructive pulmonary disease. d FEV1, forced expiratory volume in 1 s. b c
as the production and/or release of proinflammatory mediators including cytokines and active oxygen species [11]. In fact, selective PDE4 inhibitors, such as cilomilast (GSK), roflumilast (Altana), BAY 19-8004 (Bayer), AWD 12-281 (Elbion), GRC3015 (Glenmark), SCH 351591 (Schering-Plough) are active in animal models of neutrophil inflammation and also in patients with COPD [12,13], in which they exert some anti-inflammatory effects, measurable in airway biopsies, with a reduction of levels of inflammatory markers, that is, CD8+ T cells and CD68+ macrophages. [14]. These results represent the first demonstration for any agent of a reduction in airway tissue inflammatory cells characteristic of COPD. However, some inflammatory cells are less sensitive to PDE4 inhibition than others. Within the same cell type, different functions display different sensitivities to cyclic adenosine monophosphate (cAMP) elevation. In the neutrophil, degranulation is relatively insensitive compared to superoxide production and leukotriene (LT)B4 generation. Thus, some anti-inflammatory effects reported in vitro might not be expressed at plasma levels that are attained in humans [11]. Moreover, elevation of cAMP, at least in normal circu-
lating cells, results in delayed apoptosis, which could have proinflammatory consequences [15]. PDE4 inhibitors have been limited by side effects, but the development of more-selective inhibitors might be feasible in the future. It now seems probable that vomiting is because of inhibition of a particular subtype of PDE4, the PDE4D [16], whereas PDE4B is more important than PDE4D in inflammatory cells [17]. Thus, theoretically, PDE4B-selective inhibitors might have a greater therapeutic ratio. Alternatively, the PDE4 inhibitor with low oral bioavailability could be administered by inhalation [18]. In any case, although the observed efficacy of PDE4 inhibitors in COPD patients is encouraging, it is not clear whether the demonstrable effects on lung function and symptoms are a manifestation of their bronchodilator activity or are a consequence of anti-inflammatory effects.
How to interfere with inflammatory mediators that regulate migration and activation of inflammatory cells Several inflammatory mediators are probable to be involved in COPD as many inflammatory cells and structural cells are www.drugdiscoverytoday.com
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activated in the disease. In particular, cytokines and chemokines regulate migration and activation of these inflammatory cells. There is now an intensive search for compounds able to interact with these inflammatory mediators. However, because an imbalance between proinflammatory and antiinflammatory mediators might underlie the appearance of pulmonary chronic inflammation, the administration or stimulated production of anti-inflammatory mediators is considered a further therapeutic possibility. Therapies under investigation mainly consist of: (a) IL-10; (b) TNF-a inhibitors; (c) chemokine inhibitors; (d) nuclear factor (NF)-kB inhibitors; (e) p38 mitogen-activated protein kinase (MAPK) inhibitors; (f) phosphoinositide 3-kinase (PI3K) inhibitors; and (g) LTB4 inhibitors (Table 2). IL-10
IL-10, a regulatory cytokine that decreases inflammatory responses, is reduced in COPD [19]. It is currently under study in clinical trials for chronic inflammatory diseases, such as inflammatory bowel disease, psoriasis and rheumatoid arthritis [20]. Although IL-10 itself might have limited therapeutic potential in COPD, a selective activator of IL-10 receptors or signal transduction pathways might have therapeutic potential. The new strategies of IL-10 treatment include recombinant human IL-10 (ilodecakin, ScheringPlough), the use of genetically modified bacteria, gelatine microsphere containing IL-10 (GM-IL-10), adenoviral vectors encoding IL-10 (AdvmuIL-10) and combining regulatory T cells. TNF-a inhibitors
Studies have shown that TNF-a levels in COPD might be higher than in the general population, and other researches have reported TNF-a gene polymorphisms in COPD patients. It is not surprising, therefore, that TNF-a might mediate several the pulmonary and systemic manifestations of COPD [21]. Consequently, inhibition of the effects of TNF-a could have considerable benefit in COPD. Humanised monoclonal antibodies to TNF-a [e.g. infliximab (Centocor), adalimumab (D2E7) (Abbott Laboratories, Cambridge Antibody Technology, Eisai Co Ltd/GTC Biotherapeutics Inc), CDP 571 (Celltech Chiroscience), CDP 870 (Celltech Chiroscience)] and soluble TNF-a receptors (e.g. etanercept, Amgen Inc and Wyeth Pharmaceuticals) are effective in the treatment of inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, and their use could be extended to COPD [10]. However, clinical studies evaluating this concept are yet to be published, although a recent exploratory study presented as an abstract did not show a short-term effect of infliximab on respiratory symptoms FEV1 and sputum cell counts in patients with mild COPD [22]. It also seems possible to reduce TNF-a levels by inhibition of TNF-a-converting enzyme (TACE). Targeting 338
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TACE can result in similar efficacy to that seen with antiTNF antibodies and soluble receptors. In an animal model of airway inflammation, PKF 242–484 (Novartis Pharma AG) and PKF 241–466 (Novartis Pharma AG), two TACE inhibitors, blocked TNF-a release into the airways and inflammatory cell influx [23]. The treatment of patients with inhibitors of TNF-a production such as SB210313 (GSK) [24], CJ14877 (Pfizer), CJ 14897 (Ono), or with antisense oligonucleotides directed against the mRNA molecules encoding TNF-a such as ISIS 104838 and ISIS 25302 (Isis Pharmaceuticals) can be alternative strategies [25]. Chemokine inhibitors
Chemokines regulate increased inflammatory cell migration and activation in the lung. Consequently, one strategy in the treatment of COPD would be to inhibit the effect of chemokines to recruit and activate leucocytes [10]. Chemokines are divided into four main classes based on the number and spacing of conserved cysteines at the amino terminus: CXC, CC, C and CX3C families. Several chemokines shown to be associated with COPD belong to the CXC family and include IL-8, RANTES (regulated on activation, normal T-cell expressed and secreted) and growth-regulated oncogene-a (GRO-a). Both IL-8 and GRO-a play an important role in the accumulation of neutrophils, monocytes and macrophages in the lungs of patients with COPD. In consideration of the documentation that a monoclonal antibody to IL-8 significantly inhibited the chemotactic activity in COPD patients’ sputum, but not in induced sputum from healthy subjects, a phase II trial of ABX-IL-8 (Abgenix), a human monoclonal antibody to IL-8, in COPD patients is currently under way [4]. IL-8 activates neutrophils via a specific receptor (CXCR1) coupled to activation and degranulation, and via a highaffinity receptor (CXCR2), which is important in chemotaxis. Therefore, a CXCR2 antagonist is probable to be more useful, particularly as CXCR2 is also expressed on monocytes. Thus, treatment with CXCR2 antagonist GRO-a (8–73) reduced the neutrophilic inflammation and alveolar damage and decreased mortality associated with endotoxinemia, acid aspiration and in a skin air pouch model [26]. Several CXCR2 antagonists, such as nicotinamide N-oxides (Celltech R&D, Inc), nicotinanilides (Celltech R&D Inc), SB 225002 (GSK) and SB 265610 (GSK), two small-molecule inhibitors, are under development [10]. However, the effects on many actions of IL-8 and related chemokines acting upon CXCR2 would have to be monitored carefully as neutrophils are essential for host defence against microbial pathogens, and undesired immunosuppression is surely the most worrying potential adverse effect of administration of these compounds to humans [27]. The action of CC-chemokines at the CCR2-receptor has also been shown to be involved in COPD [28]. The anti-CCR2
Pros a
b
Cons
Latest developments
Who is working on this strategy
Refs [19–21]
IL-10
It not only inhibits TNF and chemokines, but also certain matrix metalloproteinases, such as MMP-9c
Hematological side effects
Recombinant IL-10 (ilodecakin)
Schering-Plough
TNF-a inhibitors
They reduce the systemic effects of TNF-a and induction of IL-8 and other chemokines in airway cells
Effective inhibitors might cause immune suppression and impair host defences
- Humanised monoclonal antibodies to TNF-a: infliximab, adalimumab (D2E7), CDP 571 CDP 870 - Humanised monoclonal antibodies to soluble TNF-a receptors: etanercept - TACEd inhibitors: PKF 242–484, PKF 241–466 - Inhibitors of TNF-a production: SB210313, CJ14877, CJ 14897 - Antisense oligonucleotides directed against the mRNA molecules encoding TNF-a: ISIS 104838, ISIS 25302
- Centocor: http://www.clinicaltrials. gov/ct/gui/show/NCT00056264 - Abbott: http://abbott.com/news/ press_release.cfm?id=506 - Celltech: http://www.celltechpharma.de/ueber_celltech_forschung.html - Amgen Inc/Wyeth Pharmaceuticals - Novartis Pharma AG - GlaxoSmithKline - Pfizer - Ono - Isis Pharmaceuticals: http:// www.isispharm.com/antisense_pipeline.html
- Human anti-CXCL8 antibody: ABX-IL-8, GAG - CXCR2 inhibitors: SB225002, SB 265610, 4-fluoronicotinanilides - Anti-CCR2 monoclonal antibody: MLN-1202 - Antagonists for CCR2 receptors: RS504393
-
339
They inhibit the effect of chemokines to recruit and activate leucocytes
Inhibition of a single receptor or chemokine might not be sufficient to block the inflammatory response due to the redundancy in the chemokine network. Moreover, CXCR2 antagonists might inhibit epithelial repair
NF-kBe inhibitors
They can efficiently inhibit the production of several proinflammatory cytokines
Effective inhibitors might cause immune suppression and impair host defences
p38 MAPKh inhibitors
There is a much greater dependence on the p38 MAPK cascade in the neutrophil when compared with other leukocytes
- Several reports have identified conditions in which p38 MAPK inhibitors enhance inflammatory responses - p38 MAPK inhibitors have effects on various cell types, thereby possibly enhancing the therapeutic effects but also increasing the risk of side effects
PI3Ki inhibitors
PI3K signalling cascade plays a pivotal role in the activation of inflammatory cells
Abgenix Sigma-Aldrich GSK Celltech Millennium Roche
[21–25]
[10,26–31]
- NF-kB specific decoy oligonucleotides
- Corgentech
- IKKgf (NEMO)g binding peptide
- Imgenex: http://www.imgenex. com/inhibit_list.php?id=4
-
- GSK - R.W. Johnson Pharmaceutical Research Institute - Signal Pharmaceuticals, Inc: http://www.signalpharm.com/spr_ikk.html - Boehringer Ingelheim - Fujisawa - Scios
[34,35]
Eli Lilly & Company
[4,36,37]
SB 203580 SB 239063 SB 242235 RWJ 67657 BIRB796BS FR167653 SCIO469 SCIO323
LY294002
[32,33]
(Cont.)
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Table 2. Drugs able to interfere with inflammatory mediators that regulate migration and activation of inflammatory cells
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Pros LTB4j
inhibitors
They might have some effect on sputum neutrophil content and/or activation in patients with stable COPDk - They might therefore protect the airways from neutrophil-mediated damage and from the effects of an acute exacerbation
Cons
Latest developments l
Side effects with 5-LO inhibitors
-
BLT1m
antagonists: LY29311, SC53228, CP105696, amelubant (BIIL284), SB201146, LTB019 - 5-LO inhibitors: BAYx1005, BWA4C, ZD4407, CJ-13,610 - FLAPn inhibitors: MK886
Who is working on this strategy
Refs
- Novartis: http://www.novartis.com/ annualreport2000/cid_respiratory.html - AstraZeneca: http://www.astrazeneca. com/AnnualRep2000/inbrief/ randdpipelinetable.asp
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Table 2. (Continued)
a
IL, interleukin. TNF, tumour necrosis factor. c MMP, matrix metalloproteinase. d TACE, TNF-a-converting enzyme. e NF-kB, nuclear factor-kB. f IKK, inhibitor kB kinase. g NEMO, NF-kB essential modulator. h MAPK, mitogen-activated protein kinase. i PI3K, phosphatidylinositol 3-kinase. j LTB4, leukotriene B4. k COPD, chronic obstructive pulmonary disease. l 5-LO, 50 -lipoxygenase. m BLT1, LTB4 receptor-1. n FLAP, 5-LO activating protein. b
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monoclonal antibody MLN-1202 (Millennium) reduces both monocyte and neutrophil influx into airways in experimental models of airway inflammation [29]. Small-molecule antagonists for CCR2 receptors, including RS-504393 (Sanwa Kagaku Kenkyusho Co) are under development as well [30]. Also CXCR3, which is expressed on T cells and mediates CD8+ lymphocyte migration and activation, is a potential target for small-molecule antagonists or antibodies because its expression is elevated in peripheral airways of smokers and patients with COPD [31]. One potential general problem in targeting chemokines in COPD is the redundancy in the chemokine network such that inhibition of a single receptor or chemokine might not be sufficient to block the inflammatory response [10]. NF-kB inhibitors
NF-kB regulates the expression of IL-8 and other chemokines, TNF-a and other inflammatory cytokines, and some MMPs. Consequently, inhibition of NF-kB activity might be a therapeutic option. NF-kB is sequestered in the cytoplasm by the inhibitor of NF-kB (IkB) family of inhibitory proteins that mask the nuclear localisation signal of NF-kB thereby preventing translocation of NF-kB to the nucleus. External stimuli such as TNF or other cytokines result in phosphorylation and degradation of IkB resulting in the release of NF-kB dimers. IkB proteins are phosphorylated by IkB kinase complex consisting of at least three proteins, inhibitors of kB kinase (IKK)a, IKKb and IKKg. There are several possible approaches to the inhibition of NF-kB. They include gene transfer of IkB, IKK, NF-kB-inducing kinase (NIK) and IkB ubiquitin ligase, which regulate the activity of NF-kB and drugs that inhibit the degradation of IkB [32]. Several these drugs are in development. The most promising approach can be the inhibition of IKK-2 by smallmolecule inhibitors, which suppress the release of inflammatory cytokines and chemokines from alveolar macrophages. Hypoestoxide, a naturally occurring diterpene from Hypoestes rosea, and ()-epigallocatechin-3-gallate, a green tea polyphenol, are IKK inhibitors, which could act as prototypic molecules for development of potent and selective synthetic compounds [10]. Further developments include NF-kB ‘decoy’ oligonucleotides (Corgentech) that inhibit nuclear translocation of NF-kB [33]. One concern about long-term inhibition of NF-kB, however, is that effective inhibitors might cause immune suppression and impair host defences. However, there are alternative pathways of NF-kB activation, via kinases other than IKK, which might be more important in inflammatory disease [4]. p38 MAPK inhibitors
MAPKs play a key role in chronic inflammation. One of these, the p38 MAPK, is activated by cellular stress. p38 MAPK in
Drug Discovery Today: Therapeutic Strategies | Respiratory diseases
turn phosphorylates and activates downstream substrates, such as other protein kinases and transcriptional factors, and ultimately results in significant transcriptional up-regulation of the pro-inflammatory cytokines TNF-a, IL-1b IL-6 and IL-8, as well as the pro-inflammatory prostaglandin pathway via cyclooxygenase-2 (COX-2) [34]. Small-molecule inhibitors of p38 MAPK, such as SB 203580 (GSK), SB 239063 (GSK) and RWJ 67657 (Johnson & Johnson Pharmaceutical), have been developed, offering a broad range of anti-inflammatory effects that might be beneficial in COPD [35]. In lipopolysaccharide (LPS) and bleomycin models of inflammation and pulmonary fibrosis, SB 239063 reduced neutrophil infiltration, IL-6 expression, and MMP9 activity in the airways. Oral administration of RWJ 67657, a pyrindinyl imidazole inhibitor of p38 MAPK, inhibited LPSinduced increases in plasma IL-6, IL-8 and TNF-a in healthy human volunteers. More recently, another p38 MAPK inhibitor, doramapimod (BIRB796BS, Boehringer Ingelheim), inhibited several LPS-induced inflammatory responses in healthy volunteers. Such a broad-spectrum anti-inflammatory drug is probable to infer some toxicity, but inhalation might be a feasible therapeutic approach [4]. SCIO469 and SCIO323 (Scios) are antisense p38 MAPK oligonucleotides not tested in COPD yet. PI3K inhibitors
PI3K catalyses the production of phosphatidylinositol-3,4,5triphosphate which initiates several cytosolic events leading to cell growth, entry into the cell cycle, cell migration and cell survival [36]. Several these events are proinflammatory. There are four members of the class I PI3Ks, all of which are expressed in neutrophils, PI3Ka, b, g and d. PI3Kg regulates their migration and respiratory burst [37], as well as impaired T-lymphocyte and macrophage function. Consequently, selective PI3K inhibitors could suppress neutrophil- and MMP-derived lung damage in COPD. Small-molecule inhibitors of PI3Kg and d are in development [4]. Wortmannin, a fungal metabolite (Penicillium fumiculosum), and LY294002 (Eli Lilly & Company) are non-selective inhibitors. At present, LY294002 is only been tested in a mouse model of asthma. LTB4 inhibitors
LTB4 contributes to neutrophil chemotaxis [38]. Moreover, it induces retardation of neutrophil apoptosis [38]. Because persistent neutrophilia is a feature of COPD, antagonism of leukotriene LTB4 receptors is being considered as a mode of treating this disease. Two subtypes of receptor for LTB4 have been described. The LTB4 receptors-1 (BLT1) are expressed mainly on granulocytes and monocytes, whereas BLT2 receptors are expressed on Tlymphocytes [39]. BLT1 antagonists, such as LY 29311 (Eli Lilly & Company), SB 225002 (GSK), SC 53228 (Pfizer, formerly Searle), CP 105696 (Pfizer), amelubant (BIIL284), LY www.drugdiscoverytoday.com
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29311 (Eli Lilly & Company), and SB 201146 (GSK), have now been developed for the treatment of neutrophilic inflammation [40,41]. LTB4 is synthesised by 50 -lipoxygenase (5-LO). Members of the 5-LO inhibitor, 5-LO activating protein (FLAP) inhibitor, and dual 5-LO/COX inhibitor classes, together with LTB4receptor antagonists have all demonstrated the inhibition of neutrophil influx and tissue oedema when administered orally to animals [42]. This has been associated with a reduction in tissue LTB4 levels and LTB4 synthesis ex vivo from circulating neutrophils [42]. A recent small study suggests that a leukotriene synthesis inhibitor, BAYx1005, can produce modest reductions in some measures of neutrophilic bronchial inflammation in patients with COPD [43]. The incidence of adverse effects is, in any case, limiting development of 5-LO inhibitors [42].
Conclusions The recently published American Thoracic Society/European Respiratory Society guidelines [44] identify a pressing need to develop agents that suppress the inflammation associated with COPD and prevent disease progression. As illustrated in this review (which is not exhaustive because of the ongoing identification of new targets that might allow the development of novel approaches by the pharmaceutical industry), there are some interesting therapeutic attempts, which are under pharmacological or clinical development. We do not know if all these new therapies will reach the market. In effect, the therapeutic rationale behind many of these treatments is mainly speculative and, in any case, they are fraught with important safety issues. Nonetheless, although we think that there is still much to be learned about the mechanisms involved in the inflammatory component of COPD, findings from pre-clinical studies reveal promising avenues for the design of better therapeutics. Looking at a rather near future, we believe that PDE4 inhibitors and LTB4 inhibitors will provide interesting opportunities for novel anti-inflammatory therapeutic interventions that will slow or halt disease progression in this debilitating respiratory disease. Obviously, full knowledge of the therapeutic value of these novel compound classes awaits the outcome of longer-term clinical trials.
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