key: cord-0006769-bdr8ofs6
authors: Romano, Suzanne J.
title: Selectin Antagonists: Therapeutic Potential in Asthma and COPD
date: 2012-08-23
journal: Treat Respir Med
DOI: 10.2165/00151829-200504020-00002
sha: 4a14374b4cc52924cfe67845c94d97f118f43856
doc_id: 6769
cord_uid: bdr8ofs6

Asthma and COPD are chronic inflammatory conditions that affect hundreds of millions of patients worldwide. New therapeutics are desperately needed, especially those that target the underlying causes and prevent disease progression. Although asthma and COPD have distinct etiologies, both are associated with reduced airflow caused by excess infiltration of inflammatory cells into healthy lung tissues. As selectin-mediated adhesion of leukocytes to the vascular endothelium is a key early event in the initiation of the inflammatory response, selectin inhibition is thought to be a good target for therapeutic intervention. Three known selectins are expressed in distinct subsets of cells: P-selectin is presented on the surface of activated platelets and endothelial cells, L-selectin is constitutively expressed on leukocytes, and E-selectin synthesis is upregulated in activated endothelial cells. They mediate cell-cell adhesion in the shear flow of the bloodstream via specialized interactions with clusters of oligosaccharides presented on cell surface glycopeptide ligands. The role of selectin-ligand interactions in the inflammatory response has been demonstrated in various animal models, prompting considerable attention from the pharmaceutical industry. Drug discovery efforts have yielded many different classes of selectin inhibitors, including soluble protein ligands, antibodies, oligosaccharides and small molecules. Although many selectin inhibitors have shown activity in preclinical models, clinical progress of selectin-directed therapies has been slow. Early approaches employed carbohydrate-based inhibitors to mimic the natural ligand sialyl Lewis X; however, these compounds proved challenging to develop. Cytel’s CY 1503, a complex oligosaccharide, progressed to phase II/III trials for reperfusion injury, but further development was halted when it failed to demonstrate clinical efficacy. Two protein-based selectin inhibitors have reached phase II development. These included Wyeth’s recombinant soluble P-selectin ligand, TSI (PSGL-1), which was discontinued after disappointing results in myocardial infarction trials and Protein Design Labs’ humanized anti-L-selectin monoclonal antibody, which is currently in development for trauma. Bimosiamose, discovered by Encysive Pharmaceutical and presently being developed by Revotar Biopharmaceuticals, is an 863 g/mol molecular weight dimer with minimal carbohydrate content and is, to date, the leading selectin inhibitor in clinical development. This compound has shown promise in a phase Ha ‘proof of concept’ trial in patients with asthma, reducing airway recruitment of eosinophils after intravenous administration. Further clinical development of an inhaled formulation is underway. Despite a significant need for new therapeutics, selectin inhibitors have not yet been explored for the treatment of COPD. Bimosiamose represents an important proof of principle, and hopefully continued success will spark renewed interest in selectin-directed therapeutics for respiratory diseases.

lungs. While asthma and COPD have distinct etiologies and differ-mation by activating second messenger pathways, including members of the mitogen-activated protein (MAP) kinase cascade. [7] ent inflammatory mediators are responsible for pathogenesis of the Because of their critical role in the earliest stages of the immune two diseases, it is thought that intervening at the initial stages of response, the selectins are potential targets for novel therapeutics the inflammatory process may provide the best opportunity for to treat inflammatory conditions such as asthma and COPD. [3, 8] halting the progress of both diseases. [3] However, most available treatments address the downstream consequences of excess leukocyte infiltration into pulmonary tissue (figure 1). For example, 1. The Structure and Function of Selectins bronchodilators relax smooth muscle in the airways and alleviate bronchoconstriction, while leukotriene inhibitors counteract the The selectins are a small family of transmembrane glycoprorelease of pro-inflammatory mediators from invading inflammatoteins that mediate cell-cell adhesion by binding to cell surface ry cells. Corticosteroids have broader anti-inflammatory activity, carbohydrate ligands. [9] [10] [11] To date, three members have been idenbut cause a number of adverse effects that limit long-term use.

tified, each expressed in a distinct subset of cells: P-selectin (platelets and endothelial cells), L-selectin (leukocytes), and E-To provide safer and more effective therapeutic agents for selectin (endothelial cells). They are also known by their cluster of chronic respiratory diseases, pharmaceutical and biotechnology differentiation (CD) antigen designations CD62P, CD62E and companies are making concerted efforts to discover drugs that CD62L. The three selectin proteins share similar structural feaspecifically target the upstream triggers and mediators of these tures, including a calcium-dependent (C-type) lectin binding dodiseases. [4] One such strategy is to interfere with the 'leukocyte main, an epidermal growth factor (EGF)-like domain, a series of adhesion cascade', a key early process in inflammation during short consensus 'complement regulatory (CR) protein' repeat sewhich a series of chemoattractants, cytokines, and cell adhesion quences, and a transmembrane anchor segment. The number of molecules (CAMs) work in a programmed, sequential manner to CR repeats and the size of their cytoplasmic domains vary. direct inflammatory cells to inflamed tissue (figure 2). [5] By inhib-

The ligands for the selectins are cell surface glycoproteins that iting this process it may be possible to reduce tissue damage present clusters of specialized oligosaccharides. [7, 12] Key motifs caused by excess cellular infiltration and stop the feedback loop recognized by all three selectins include sialylated and fucosylated that amplifies the inflammatory response.

tetrasaccharide sialyl Lewis X (sLe X ; figure 3) and the related Three known families of CAMs participate in the leukocyte sialyl Lewis a (sLe a ); [12] [13] [14] however, there is considerable variabiladhesion cascade: selectins, integrins, and members of the immuity in the ligands' glycoprotein scaffolds and how they present noglobulin superfamily. The initial event of this cascade, the their carbohydrate moieties. L-selectin is known to bind Glytethering and rolling of leukocytes (including lymphocytes) along CAM-1, CD34 and MAdCAM-1; each is expressed on different the blood vessel wall, is mediated by the selectins. Selectin-ligand tissues and each presents many L-selectin binding sites distributed interactions act like 'Velcro' reducing the flow of inflammatory over the length of the scaffold. In comparison, TSI, the P-selectin cells through the blood vessels and slowing them sufficiently to ligand, is a dimer that presents a single binding site at the tip of allow firm adhesion and extravasation via the integrin and immueach subunit. (P-selectin also binds CD24, the smallest of the noglobulin family members. Selectins may also enhance inflamligands; this interaction may be involved in migration of cancer cells. [15] ) The functional E-selectin ligands have not yet been clearly identified, but candidates include the E-selectin-specific ESL-1 and the shared ligand, TSI. The various selectin-ligand pairs interact with distinct binding affinities and kinetics, allowing the selectins to mediate tethering, rolling and adhesion between various cell types in a wide range of in vivo settings. Specialized interactions allow them to perform their functions in the shear flow forces of the bloodstream, including rapid association/dissociation (on/off) rates, ligand clustering and dimerization, and multivalent oligosaccharide binding sites. [16] Remarkably, selectin-mediated adhesion is actually enhanced by shear stress. [17] The unique properties of the selectin-ligand interaction have made it difficult to measure selectin activity using in vitro assays, and may have hindered progress in the field. The need for shear down-regulated from the surface by protease-mediated cleavage flow, complex ligands and multivalent interactions do not lend known as 'shedding'. themselves to the high throughput methods currently used in most

The role of selectins in the inflammatory response has been drug discovery programs. Some groups have successfully estabwell established. Mouse knockouts of the selectins alone and in lished binding assays and identified inhibitors using synthetic various combinations have been useful tools to elucidate their ligands and recombinant selectin proteins, [18, 19] for example using roles in vivo. [28] It has been demonstrated that P-selectin mediates the system developed by Foxall et al. [20] or modified versions rolling in the basal state, while L-selectin is critical for lymphocyte using cultured cell lines. [21] However, static adhesion assays often homing to peripheral lymph nodes. All three selectins mediate give inaccurate estimations of the activity of a compound and leukocyte rolling during inflammation, with P-selectin appearing make it difficult to obtain an accurate measurement of the ability early in the inflammatory cascade and E-and L-selectin involved of a compound to block selectin-mediated rolling in shear later. Importantly, the knockout data also suggest that it may be flow. [8, 22, 23] To address this concern, mechanistic assays that meanecessary to inhibit more than one of the selectins to have a sure cell-cell adhesion and rolling under flow conditions in vitro significant impact on the inflammatory response. and in vivo have been used to determine the intrinsic selectin-Inhibitors such as antibodies, soluble protein ligands, and variinhibiting potential of test compounds. [22, [24] [25] [26] These mechanistic ous sLe X mimetics have been used to further confirm that blocking assays can serve as important proof of principle to demonstrate the selectins can reduce the inflammatory response in a variety of mechanism of action and support further testing using in vivo animal models (see reviews by Lowe and Ward [8] and Rosen and models of inflammation.

Bertozzi [12] ). Proof of concept in humans comes from the study of a very rare genetic disease termed type II leukocyte adhesion 2. The Role of Selectins in the deficiency (LAD II), which has been described in only a few

The three selectins are expressed in unique temporal and spatial patterns, allowing significant flexibility in the modulation of the inflammatory response. [7, 27] Furthermore, the expression of each selectin is regulated via a different mechanism, providing several opportunities for blockade. P-Selectin is stored in secretory vesicles of endothelial cells (Weibel-Palade bodies) and platelets (αgranules), and is rapidly transported to the cell surface upon activation by mediators such as histamine or thrombin. E-Selectin is regulated at the transcriptional level, and thus appears on the surface more slowly. It is expressed on endothelial cells in response to pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α or interleukin (IL)-1β. L-Selectin is constitutively expressed on all leukocytes, and upon cell activation it can be patients to date. [29, 30] The LAD II mutation causes a defect in carbohydrate inhibitors. [37, 38] Murine models of antigen-induced fucose metabolism, resulting in a complete lack of the selectin airway inflammation have also provided useful data. Mouse ligand sLe X . Because of this, selectin-mediated events such as knockouts suggest that both P-selectin and L-selectin are imporleukocyte rolling and neutrophil chemotaxis are greatly reduced in tant. Antigen-challenged P-selectin-deficient mice had reduced these patients. [31, 32] Clinically, LAD II patients experience chronic, airway hyperresponsiveness (AHR) and decreased pulmonary severe periodontitis as well as mental and growth retardation; eosinophilia in comparison with wild-type controls. [39, 40] In Lhowever, their developmental abnormalities are likely attributed to selectin knockout mice, cellular infiltration was not significantly the general defect in fucose metabolism rather than a defect in reduced but the population of invading cells was slightly different leukocyte adhesion. [30] and AHR was remarkably reduced. [41, 42] While the murine models In addition to acting at sites of inflammation, selectins are do not reproduce human asthma or COPD with complete accuracy, important components of the normal immune response. The they demonstrate that selectins participate in the recruitment of body's surveillance system relies on selectins for directing blood leukocytes to the lung and suggest that each of the selectins is leukocytes to sites of tissue damage or infection, and for traffickresponsible for a different aspect of the inflammatory response. ing of circulating lymphocytes through lymphoid tissues. One

Perhaps the most compelling preclinical data come from sheep concern is that blocking selectins would make already weakened and monkey studies, where anti-selectin monoclonal antibodies patients more susceptible to infection. This theory was supported (mAbs) have shown efficacy. These models are attractive because by observations in E-, P-, and E/P-selectin double-knockout mice, they most closely approximate the two key manifestations of the which had a higher frequency of opportunistic bacterial infection human asthmatic response: bronchoconstriction, which comprises and higher morbidity when challenged with Streptococcus an acute early airway response (EAR), a late airway response pneumoniae. [33, 34] However, clinical experience suggests that (LAR), and prolonged AHR. In fact, the sheep model has become selectin blockade may not create significant problems in human a 'gold standard' for preclinical efficacy studies, and nearly every patients. Adults with LAD II are perhaps the best approximation of new asthma drug that has progressed to clinical trials has been a patient treated long-term with a highly effective selectin inhibitested in this system. An L-selectin mAb reduces all phases of the tor. Aside from chronic periodontitis, LAD II patients do not show airway response in antigen-challenged sheep. [43] In the monkey greater incidence of systemic infection, nor do they require promodel, an E-selectin antibody reduced neutrophil influx and attenphylactic antibacterials. [30] Mice deficient for α-1,3-fucosyltransuated the LAR. [44] ferase Fuc-TVII, a mutation that closely mimics human LAD II, were also resistant to opportunistic infections. [35] This is a less 3. Selectin Inhibitors severe phenotype than what has been observed in the knockout mice, as described above. The apparent differences in susceptibili-Because of their role in inflammatory disease, selectins have ty may be attributed to the fact that the knockouts completely lack been the target of drug discovery programs at many pharmaceutiselectin proteins, while the fucose metabolism mutants may retain cal and biotechnology companies over the past several years. As some selectin binding function due to non-fucosylated ligands. [30] described above, expression of the selectins is regulated via sever-It may also reflect differences in laboratory settings and mouse al different mechanisms, providing a number of potential therastrains.

peutic opportunities. [45, 46] For example, cell-surface expression of selectins can be blocked by small molecules [47] or antisense nucle-

otides. [48] Alternatively, it may be possible to identify compounds that induce cleavage or shedding of the selectins from the cell Data from the LAD II patients, knockout mice, and other surface. [49] This mechanism may already be the target of existing animal models strongly suggest that inhibiting selectins can safely treatments: some NSAIDs, including indometacin, ketoprofen and reduce an inappropriate immune response by attenuating cellular aspirin (acetylsalicylic acid), induce the release of L-selectin from infiltration. Thus, it seems reasonable to postulate that selectin neutrophils. [50] inhibitors could effectively treat airway diseases such as asthma

The most common and straightforward approach for blocking and COPD, where accumulation of inflammatory cells in the lung selectin action is to inhibit the selectin-ligand interaction directly. tissue causes reduced lung function. [36] Data from animal models Over the past decade, more than 20 pharmaceutical companies of airway inflammation have been promising. Ward and colhave reported selectin inhibitors and a number of these have been leagues have demonstrated the role of selectins in several models validated in animal models (see recent reviews [45, 46, 51, 52] ); unfortuof acute lung injury using blocking antibodies, soluble ligands and [53] reported Wyeth TS-1 (PSGL-1) [54] Glycoprotein P Phase II (discontinued) Myocardial infarction Cytel Cylexin ® (CY 1503) [55, 56] Oligosaccharide P, E Phase III (discontinued) Reperfusion injury ARDS = acute respiratory distress syndrome; E = E-selectin; L = L-selectin; P = P-selectin.

nately, only a few of these have been tested in patients, and clinical summarily dismissed. The recent success of the anti-TNFα protein drugs etanercept and infliximab suggest that this may be a viable success has been elusive (table I) .

approach for the treatment of some chronic inflammatory dis-The first-generation selectin inhibitors, represented by Cytel's ease [61] . (now Epimmune) CY 1503 (Cylexin ® 1 ; figure 4), [55, 56] were com-For asthma and COPD, however, patients and clinicians are in plex oligosaccharides that competed with ligand binding by mimneed of new drugs that can be administered orally or, if necessary, icking the natural ligand, sLe X (figure 3). Of the selectin inhibitors via inhalation. Thus, the search continues for potent, small molethat have been nominated for clinical development, Cylexin ® has cule selectin inhibitors with minimal carbohydrate content. A progressed furthest. Unfortunately, it showed no benefit in greater understanding of the selectin structures [62, 63] and the key placebo-controlled phase II/III trials for reperfusion injury, and interactions between selectins and their ligands [7, 13, 64] has aided the development was discontinued in early 1999. [57, 58] This result can search. Several groups have reported non-oligosaccharide inhibilikely be attributed to the carbohydrate nature of the drug. Pharmators with better properties, [65] [66] [67] but few have succeeded in identiceutical development of oligosaccharide-based compounds has fying compounds with potent in vivo activity. proven difficult for several reasons, and clinical success has been

The leading 'second-generation' selectin inhibitor is bimolimited. [57, 59] These compounds often have poor potency and are siamose, which was discovered by Encysive Pharmaceuticals and metabolically unstable in vivo; they also tend to be technically is currently being developed by Revotar Biopharmaceuticals. challenging and expensive to synthesize. Furthermore, because Bimosiamose, shown in figure 5, is an 863 g/mol molecular weight they require parenteral administration, the therapeutic applications dimer with minimal carbohydrate content. This approach miniof such compounds are limited. mizes carbohydrate content of the inhibitor while maintaining the Although they share some of the same problems, protein drugs have, in general, met with better clinical success. Unfortunately, this has not been the case for protein-based selectin inhibitors. Protein Design Labs licensed its humanized anti-L-selectin mAb, aselizumab, to Scil Technology for development in Europe, and planned to use Scil's trial data to aid internal clinical efforts. Recently, however, published results reveal that aselizumab failed to demonstrate statistically significant efficacy in a phase II evaluation in trauma pateients, and as a result the future of this drug is uncertain.

[60] Wyeth's recombinant soluble P-selectin ligand, TSI, [54] was discontinued after disappointing phase II results in myocardial infarction, but may be examined for other indications. Like cytexin, the glycoprotein and antibody drugs are difficult to manufacture and require parenteral administration. Despite these concerns, protein-based anti-selectin approaches should not be Fig. 4 . The chemical structure of a first-generation oligosaccharide inhibitor, Cylexin ® CY 1503. [55, 56] Clinical development of this compound was discontinued due to poor efficacy in phase III clinical trials.

Asthma is a well studied condition, and much is known about its immunology and cell biology. Reversible airway obstruction and hyperreactivity are the hallmarks of this chronic inflammatory disease. It is generally thought that asthma is an innate, IgEmediated allergic response triggered by airborne allergens. However, a closer examination of the clinical data suggests that there may be multiple phenotypes of asthma or 'wheezing illness', each with distinct causes and mediators. [72] This variability may explain some of the clinical failures seen in the past few years -most recently, the anti-IL-5 monoclonal antibodies. [73] These new find- Fig. 5 . The chemical structure of bimosiamose [21] (TBC-1269), the most promising selectin inhibitor undergoing clinical development for asthma and other indications.

ings also raise important questions about future diagnosis and treatment of patients with asthma, and highlight the need for new, multivalent presentation of sugar moieties thought to be required targeted therapeutics that are directed at specific mediators. Many for potency. Bimosiamose has been reported to have IC 50 values such drugs are in clinical trials as pharmaceutical companies seek (concentration producing 50% inhibition) of 500, 70 and 560 alternatives to the current standard of care consisting of the broadμmol/L against E-, P-, and L-selectin, respectively, in cell adhely acting corticosteroids. [74] [75] [76] [77] sion assays and 105, 17 and 87 μmol/L against E-, P-, and L-One of those new drug candidates is the pan-selectin inhibitor selectin, respectively, in ELISA. [21, 68] It has efficacy in several bimosiamose (figure 4), currently in phase II clinical trials for animal models of inflammation [68] and has shown promise in a asthma. [21, 68] In preclinical testing, the compound reduced the phase IIa clinical trial for allergic asthma [52, 69] (see section 4.1).

EAR, LAR and AHR in a sheep model after intravenous and There have been few reports of small molecule selectin inhibiinhaled administration. [43] Some may question why a selectin tors that completely lack carbohydrate content, yet maintain poteninhibitor, which targets a vascular target, would be effective via cy and in vivo activity. One such molecule at the preclinical stage the inhaled route; however, inhaled formulations of both selectin is Ontogen Corporation's OC 229648 (figure 6). The lead comand integrin antagonists have proven efficacious in animal models pound in a series of potent, pan-selectin inhibitors, OC 229648 has of asthma. [78] The simplest explanation for these results is that the IC50 values of 300 nmol/L and 3 μmol/L in P-and L-selectin drug is absorbed into the systemic circulation through the lung epithelium, but it is also possible that the compounds work on ELISAs, respectively, and 10-50 μmol/L IC50s in P-, L-and Eresident cell-cell interactions directly in the lung tissue. Encysive selectin cell adhesion assays; this compound reduces selectin-Pharmaceuticals circumvented potential bioavailability issues in mediated leukocyte rolling in inflamed vessels, and exhibits activity in animal models of cutaneous and peritoneal inflammation. [18, 70, 71] It remains to be seen whether such 'third-generation' selectin inhibitors will be successful in the clinic.

As described above, many different selectin inhibitors have been identified and a number of these have been validated in animal models. These compounds span a broad range of physical properties, selectivity and potencies. However, with one notable exception (bimosiamose), these early-stage successes have not translated to the clinic. [36] Carbohydrate-based and protein inhibitors have proved technically challenging to develop for respiratory diseases, where inhaled administration is common and an oral formulation is preferred. While COPD is often mentioned together with asthma, the two in asthma patients. [36] Toxicity data indicate that bimosiamose is are very different diseases. COPD includes chronic bronchitis and safe and suggest that this compound may have an advantage over emphysema, and is characterized by obstructed airflow without the corticosteroids. [68, 79] airway hyperreactivity seen in asthma. Approximately 80-90% of The clinical development of bimosiamose continues with COPD cases are caused by smoking, and 15% of all cigarette Revotar Biopharmaceuticals. Two phase I, double-blind trials of smokers develop COPD. This chronic respiratory condition can the inhaled formulation were completed in early 2002. [52] In an also be due to exposure to other lung irritants. In rare cases (<5%), escalating single-dose study, the drug was well tolerated and no hereditary, early onset COPD is caused by a deficiency in α1-antiserious adverse events were observed. Plasma levels were trypsin, a protective protease inhibitor. achieved at the higher doses, demonstrating that the drug can, in COPD is six times more prevalent than asthma and is responsifact, enter the bloodstream via the inhaled route. [52] The second ble for more than 100 000 deaths annually in the US; it was the trial examined the effects of various dose levels given twice per fourth leading cause of death in 1999. [80] Despite the large patient day over a 7-day period. Again, the drug was well tolerated. Based population and the severe unmet medical need, COPD drugs on these trials, the maximum tolerated dose and the dose required comprise only 17% of the respiratory disease market and new to achieve systemic drug levels were established. Revotar treatments are desperately needed.

[2] The lack of a predictive Biopharmaceuticals has completed a double-blind, placebo-conanimal model that incorporates all of the key aspects of COPD trolled, randomized, cross-over study to evaluate the effects of may have slowed progress towards new therapies. [81] Currently, inhaled bimosiamose on LAR following inhaled allergen chalthe most effective way to manage COPD is smoking cessation lenge in patients with mild allergic asthma. The results of this therapy that may include nicotine replacement or treatment with proof of concept study demonstrated positive clinical results of the buproprion. Other available therapies include corticosteroids and pan-selectin antagonist, bimosiamose, where pre-treatment with bronchodilators. In addition, antibacterials and vaccines against nebulized bimosiamose decreased the allergen challenge-induced the influenza virus are used to reduce the threat of respiratory LAR in patients by 50% compared to placebo. [69] Bimosiamose is infection in patients with COPD. Lung transplant and lung reducalso in clinical devleopment for psoriasis, COPD, and ARDS. The tion surgery are more invasive options. Unfortunately, these treatcontinued success of bimosiamose represents an important proof ments only attempt to treat the symptoms, and none affect the of principle and suggests that a selectin inhibitor will have use in progression of the disease; even corticosteroids are largely ineffecthe treatment of asthma and other inflammatory diseases.

tive. [82] In fact, most of the drugs currently used to treat COPD Next-generation selectin inhibitors -smaller molecules that were originally developed for asthma. [83] Given the mechanistic lack carbohydrate moieties and are amenable to oral administradifferences between the two diseases, their lack of efficacy is not tion -are under investigation by several groups, but are likely surprising. years away. The structures of the three key selectin inhibitors While asthma and COPD are both associated with an excessive shown in figure 4, figure 5 and figure 6 illustrate the progression influx of inflammatory cells and airway obstruction, the etiology towards smaller compounds with minimal carbohydrate content.

of the two conditions is quite different. [84] COPD is associated Ontogen's OC 229648 (figure 4), which has no sugar moieties, with the infiltration of CD8-positive lymphocytes, neutrophils and was active in mouse models of inflammation but did not show macrophages into lung tissues; in contrast, the invading cells in the efficacy in preliminary sheep airway studies. [46] This result is lungs of asthmatic patients are primarily CD4+ T cells and eosinoprobably not due to insufficient potency, since OC 229648 is more phils. Selectins are key molecules that direct leukocytes to the active than bimosiamose in in vitro P-, E-and L-selectin assays. It lung, [43, 55, 85, 86] and there is evidence that the expression of selectins is possible that bimosiamose has multiple functions in vivo which and their ligands are elevated in the lung tissue and on the enhance its efficacy in asthma. In addition to reducing leukocyte peripheral leukocytes of COPD patients. [87, 88] Thus, it would seem trafficking to the lung, it may inhibit selectin-mediated signaling reasonable to target selectins for the treatment of COPD. Selectin between resident leukocytes in the lung. [36] Indeed, in the sheep antagonists have not yet been pursued for the treatment of COPD model, it reduced mast cell histamine release during the EAR. [43] in the clinic, but the successful use of bimosiamose in asthma may Taking these characteristics into account, future drug discovery well generate greater interest in this area. In fact, preclinical efforts may lead to selectin inhibitors with improved in vivo studies with bimosiamose suggest that it has preferential effects on properties.

neutrophils, [89] so it may be a good candidate for reducing cellular asthma, rather than the classic form. If information such as this can infiltration in the lung tissue of COPD patients.

be built into clinical trials, the chances of success may be greaterand clinical success will be necessary to revive pharmaceutical company interest in selectin blockade as a therapeutic approach.

New treatments for asthma, and especially COPD, are desperately needed. Hopefully, selectin inhibitors will someday be a part of the Selectin-mediated tethering of leukocytes to the vascular endopulmonary physician's arsenal. thelium is a key, early event in the pathogenesis of acute inflammation, and many agree that it is a reasonable target for therapeutic Acknowledgments intervention. Animal data strongly suggest that blocking selectins can prevent excessive infiltration of inflammatory cells associated have developed a novel approach to link dexamethasone to an E-6 (5): 663-73 selectin antibody, in order to target the drug to inflamed tissue. [90] 13 to the appropriate patient population. The fact that bimosiamose 19 . Ohmoto H, Nakamura K, Inoue T, et al. Studies on selectin blocker 1. structureappears to have preferential effects on neutrophils [89] suggests that activity relationships of sialyl Lewis X analogs. J Med Chem 1996; 39 (6):

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The three members of the selectin

Endothelial leukocyte adhesion receptor family recognize a common carbohydrate epitope, the sialyl Lewis X molecule-1 mediates antigen-induced acute airway inflammation and lateoligosaccharide

Selectin antagonists

cell adhesion: synthesis of 1,6-bis[3-(3-carboxymethylphenyl)-4-(2-α-D-mannopyranosyloxy)phenyl]hexane (TBC1269)

Targeting selectins for the treatment of respiratory diseases

molecule expression in human endothelial cells: 1. Selective inhibition of ICAM-1 and E-selectin expression

Inhibition of L-selectin-mediated leukocyte rolling by synthetic glycoprotein mimics

Inhibition of endothelial cell adhesion molecule expression with antisense oligonucleotides

Differential leukocyte recruitment from whole blood via

endothelial adhesion molecules under shear conditions

Mouse bone marrow-derived mast cells roll on P-selectin under conditions of flow in vivo

Prevention of in vitro (3): 634-43 neutrophil-endothelial attachment through shedding of L-selectin by non-steroidal antiinflammatory drugs

Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins

Functional role for selectins in the pathogenesis of cerebral

Selectin synthesis and inflammation

Development of synthetic pan-selectin antagonists: a new 65-9 treatment strategy for chronic inflammation in asthma

Insights into selectin function from knockout mice

Anti-L-selectin antibody treatment of hemorrhagictraumatic shock in baboons

Leukocyte adhesion deficiency II-from A to almost Z

Recombinant soluble form of PSGL-1 accelerates thrombolysis and prevents reocclusion in a porcine model

Of man and mouse: leukocyte and endothelial tion

In vivo behavior of neutrophils from oligosaccharide in sepsis-induced acute lung injury

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Cytel Corporation halts clinical trial of Cylexin

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hematopoiesis in mice deficient in both P-and E-selectins

The effect of anti-L-selectin Streptococcus pneumoniae is impaired in E-, P-, and E/P-selectin deficient (aseulizumab) in multiple traumatized patients: results of a phase II clinical mice

Perspectives for TNF-a-targeting therapies. Arthritis Res controls leukocyte trafficking through an essential role in L-, E-, and P-selectin

Insight into E-selectin/ligand interac

Selectin antagonists: therapeutics for tion from the crystal structure and mutagenesis of the Lec/EGF domains

Insights into the molecular basis of leukocyte

Adhesion molecules in experimental tethering and rolling revealed by structures of P-and E-selectin bound to sLe X lung inflammatory injury

Conformation of sLe X tetrasaccharide

Adhesion molecules in inflammatory lung injury

Adhesion molecules in health and disease

Sialyl Lewis X (sLe X ) and an sLe X

Reduction of allergic airway mimetic, CGP69669A, disrupt E-selectin-dependent leukocyte rolling in vivo. responses in P-selectin-deficient mice

BMS-190394, a selectin inhibitor, prevents rat selectin and ICAM-1-deficient mice

Studies on selectin blockers. 7. airway hyperresponsiveness but not airway inflammation in a murine model of Structure-activity relationships of sialyl Lewis X mimetics based on modified asthma

Curr Opin Anti-Inflamm of allergic airway inflammation in asthma

Selectin blockade prevents antigensynthetic pan-selectin antagonist, on the allergen-induced late asthmatic reinduced late bronchial responses and airway hyperresponsiveness in allergic sponse (LAR) in patients with mild allergic asthma

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2: S90 selectin-dependent lung injury

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Asthma therapy for the 21st century

Comparative analysis of P-selectin

glycoprotein ligand-1 (PSGL-1) expression on leukocytes from patients with allergic asthma, COPD, and smokers

57th AAAAI: novel drugs

SMi Conference

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Severe asthma and COPD: the good, the bad and the ugly