34

Abstract

Numerous recombinant therapies are being inves-tigated for the treatment of asthma. This reportreviews the current status of several of thesenovel agents. Anti–immunoglobulin (Ig)E (omal-izumab, Xolair) markedly inhibits all aspects of theallergen challenge in subjects who have reductionof free serum IgE to undetectable levels. Severalclinical studies in atopic asthma have demon-strated benefit by improved symptoms and lungfunction and a reduction in corticosteroid require-ments. Early use in atopic asthmatics may beeven more effective. Several approaches targetinterleukin (IL)-4. Soluble IL-4 receptor has beenshown to effectively replace inhaled corticosteroid;further studies are under way. Recombinant anti-IL-5 and recombinant IL-12 inhibit blood and spu-tum eosinophils and allergen-induced eosinophiliawithout any effect on airway responsiveness, aller-gen-induced airway responses, or allergen-inducedairway hyperresponsiveness. Efalizumab, a recom-binant antibody that inhibits lymphocyte trafficking,is effective in psoriasis. A bronchoprovocationstudy showed a reduction in allergen-induced lateasthmatic response and allergen-inducedeosinophilia, which suggests that it should beeffective in clinical asthma. These exciting noveltherapies provide not only promise of new thera-pies for asthma but also valuable tools for inves-tigation of asthma mechanisms.

History

As previously reviewed,1 pharmacotherapy forasthma has changed dramatically in the past 100years. At the turn of the century, therapy foracute asthma included mainly narcotics (eg,heroin, morphine) and sedatives (chloral hydrate),agents now considered contraindicated in acuteasthma. Inhalants were also advocated for acuteasthma, including amyl nitrate, ether, turpentine,ammonia, stramonium smoke, and even tobacco!The only pharmaceutical acting directly on theairways was atropine. Epinephrine, a nonselec-tive � and � agonist, identified early in the 1900sand synthesized shortly thereafter, rapidly becamethe standard therapy for acute asthma adminis-tered subcutaneously at the rate of a minim aminute. Ephedrine, an old nonselective � and �agonist extracted from a Chinese herb, ma huang,was not widely used until well into the twenti-eth century, when it was usually combined withtheophylline and barbiturates. Isoproterenol, aselective � (mixed �1-�2) agonist, proved to bean effective bronchodilator2 and was used byinhalation (nebulization), as was racemic epi-nephrine. The introduction of the pressurizedmetered-dose inhaler (MDI) about 40 years agorevolutionized the management of asthma. Epi-nephrine and isoproterenol soon became avail-able in an MDI, the latter most widely prescribed.Modifications to sympathomimetics resulted inincreasingly long-acting increasingly selective �2

agonists, the most widely prescribed of which wassalbutamol, introduced in 1967. Further modifi-cations have resulted in the ultra–long-actinginhaled �2 agonists salmeterol and formoterol.Anticholinergics also have a long history of usein the Far East; atropine-containing tobaccosmade from Datura stramonium were used forthousands of years in India. This remarkable

Asthma and Therapeutics

Recombinant Therapies in AsthmaDonald W. Cockcroft, MD, FRCPC

D. W. Cockcroft — Department of Medicine, Universityof Saskatchewan, Royal University Hospital, Saskatoon,Saskatchewan

Correspondence to: Dr. Donald W. Cockcroft, RoyalUniversity Hospital, Division of Respiratory Medicine,103 Hospital Drive, Ellis Hall, 5th Floor, Saskatoon, SKS7N 0W8

Recombinant Therapies in Asthma — Cockcroft 35

remedy was brought from India to the UnitedKingdom about 200 years ago. Atropine has beenavailable for over 150 years and was mentionedin Osler’s textbook 100 years ago; however,atropine seems never to have been very widelyused for asthma.3 In contrast, for the first half ofthe twentieth century, many different brands ofasthma cigarettes and asthma burning powderswere available for outpatient management ofasthma. The development of topically activemedium- and long-acting antimuscarinic agents(ipratropium and tiatropium, respectively) haveresulted in useful pharmacologic therapy that ismore valuable in chronic obstructive pulmonarydisease than in asthma. Theophylline is a com-pound extracted from tea, another herbal remedyused for millennia as a stimulant in Asia. Theo-phylline first became widely available as a phar-maceutical in the form of the ethylene diaminesalt known as aminophylline. It was initiallyused as a stimulant and diuretic but later was usedintravenously and rectally as a bronchodilator.Oral preparations became available a little over50 years ago and were often used alone or in com-bination with ephedrine and barbiturates. Yetanother herbal remedy, khellin, extracted fromAmmi visnaga, was a widely used Middle East-ern antispasmodic. The cromones sodium cro-moglycate and nedocromil were modifications ofthis herbal remedy. Corticosteroids, the currentcornerstone of asthma therapy, arrived on thescene relatively recently, having been availablefor a little over 50 years. Topically active corti-costeroids have been available for inhalationtherapy of asthma for almost 30 years now.

The five main classes of asthma drugs up tothe late 1990s were all developed and modifiedfrom plant (ephedrine, atropine, theophylline,khellin) or animal (epinephrine, cortisone) sources.In the late 1990s, the first designer drugs for themanagement of asthma appeared in the form ofvarious leukotriene modifiers, including lipoxy-genase inhibitors and the more successful oralleukotriene receptor antagonists, such as mon-telukast. The currently available pharmaceuticalarmamentarium for the management of asthma isactually quite good. Appropriate and particularlyearly use of anti-inflammatory strategies (in addi-

tion to education and environmental control) isstressed by clinical practice guidelines.4

Nevertheless, numerous new pharmaceuticaldevelopments continue to be designed for asthmatreatment, as summarized in a recent review.5 Sev-eral of these pharmacotherapies have been devel-oped using genetic recombinant technologies,including recombinant antibodies, interleukins(ILs), IL receptors, and IL receptor blockers. Thisreview article covers several of these recombinanttherapies, which involve immunoglobulin (Ig)E,IL-4, IL-5, IL-12, and lymphocytes. These excit-ing new agents provide potentially new thera-peutic options for asthma and valuable tools forinvestigation of mechanisms in asthma.

Immunoglobulin E

Background

IgE antibody was identified as the cause of atopicsensitization and atopic allergic reactions about 35years ago.6 In the last 25 years, laboratory inves-tigations identifying allergen inhalation as a causeof both airway hyperresponsiveness7 and airwayinflammation8 have allowed the reclassification ofallergens as important inducers of asthma.9 Thisinformation has been supplemented by numerousepidemiologic studies, which now confirm thatatopy is the most important single risk factor forthe development of asthma,10–12 and, thus, thatIgE-mediated allergic airway inflammation is themost important cause of asthma. It is therefore log-ical to direct therapeutic strategies towards this end.Indeed, environmental control, where possible,is one of the cornerstones of asthma therapy and,for a single and completely avoidable allergen orsensitizer, such as in the occupational setting, can,in fact, be curative.13 Sodium cromoglycate prob-ably has its major effect in chronic asthma man-agement as a prophylactically anti-inflammatoryasthma therapy by preventing all aspects of theallergen-induced asthmatic response.14 A numberof approaches are available to address IgE and itsinteraction with effector cells. At this point, themost promising therapy, and that nearest market-ing, is a monoclonal anti-IgE antibody, omal-izumab (Xolair).

Anti-IgE Development

The development of anti-IgE antibodies is brieflyoutlined as a general background to the prepara-tion of such agents. Initially, a series of clonalmurine IgG antibodies directed against humanIgE were developed. The clone demonstratingthe ideal characteristics, namely reacting with orat least hiding the Fc component of the IgE mol-ecule (ie, that area of the molecule that bindswith the Fc� receptor on mast cells), was selected.The majority (about 95%) of this murine IgGantibody was then replaced with human IgG,leaving only a small amount of the antibody-spe-cific variable area of the antibody as murine in ori-gin.15 The twenty-fifth antibody in the series,recombinant humanized murine monoclonal anti-body E25 (rhuMAb-E25 [E25 for short], omal-izumab, Xolair) had the desired characteristics,which included good tolerability, a reduction infree serum IgE to undetectable levels, inhibitionof allergic reactions, a lack of mast cell degran-ulation (unlike polyclonal anti-IgE, which servesas a model to mimic allergic reactions), and a lackof immunogenicity (the latter the result of the95% humanization).16 Additionally, Fc� recep-tors are up-regulated in the presence of highserum IgE and down-regulated in the presence oflow serum IgE17; therefore, omalizumab resultsin reduction in Fc� receptors, which may lead toreduced IgE synthesis16; this may allow at leastthe possibility of being able to lower the effectivedose of omalizumab.

Laboratory Studies

The allergen challenge model is a useful methodto study asthma pharmaceutical agents.18 Thiswould be particularly true for an agent designedto prevent IgE-mediated airway allergic responses.Omalizumab administered intravenously at a stan-dard dose of 0.5 mg/kg/wk proved to be veryeffective in inhibition of the early asthmaticresponse (EAR) and the late asthmatic response(LAR).19,20 Fahy and colleagues demonstrated a63% reduction of the allergen-induced LAR after10 weeks of intravenous therapy of omalizumab0.5 mg/kg/wk.19 The results are even more impres-sive when one takes into account that subjects

receiving omalizumab actually received approx-imately twice as much allergen post-treatment asdid those who received placebo. The second aller-gen challenge study involved an EAR model withthe EAR reported as the allergen PC15. The advan-tages of this model are that it allows study in alarger number of subjects and studies in subjectswho are less severe and consequently more stable,and it allows better quantitation of therapeuticeffect, particularly where the therapeutic effect islarge. The disadvantage of this model is the inabil-ity to study the more important late consequences,including the LAR, allergen-induced increase inairway responsiveness, and allergen-induced air-way inflammation. We demonstrated a markedand early shift of the allergen PC15 as early as 4weeks.20 After 10 weeks of treatment with 1 mg/kgfor 2 weeks (the same total dose used in the Fahyand colleagues’ study19 but administered every 2weeks), there was a 6.5-fold improvement in aller-gen PC15.

20 In both allergen challenge studies, thedrug was well tolerated, with the only importantevent being a single episode of first-dose urticaria,which is occasionally seen and does not recur onrepeat exposure. No antiomalizumab antibodiesdeveloped. We observed that those subjects whowere not protected against the antigen challengewere those in whom free serum IgE was not com-pletely reduced to undetectable levels. Subse-quently, studies have dosed E25 based not only onweight but also on total baseline serum IgE lev-els.21 A third study investigated nebulized omal-izumab in high dose (10 mg/d) and moderate dose(1 mg/d) for 8 weeks. Nebulized omalizumab hadno effect on serum IgE levels and no effect on aller-gen challenge.21 There was a single case ofantiomalizumab antibodies developing via theinhaled route.

Clinical Studies

An early clinical study in ragweed allergic rhini-tis served primarily to underscore the need for ade-quate omalizumab dosing based on serum IgE.22

The first clinical asthma study examined twodoses, 2.5 �g and 5.8 �g/kg/ng IgE, adminis-tered intravenously at two-weekly intervals.23

There was improvement in lung function andsymptoms in the active groups and, after

Recombinant Therapies in Asthma — Cockcroft 36

12 weeks, subjects on active therapy were able toreduce their corticosteroids by a larger amountthan were those on placebo. These results wereinterpreted very optimistically. Recently, twolarge omalizumab trials of apparently identicaldesign have been reported.24,25 These parallelstudies have involved more than 500 subjectsreceiving omalizumab compared with approxi-mately the same number on placebo. The activepatients received omalizumab 0.016 mg/kg IgE(IU/mL) every 4 weeks administered subcuta-neously with doses administered every 2 or 4weeks depending on the volume. During the 16-week steroid-stable phase, these asthmatic sub-jects, with a mean duration of asthma over 20years, demonstrated reduced exacerbations,reduced symptoms, and improved lung function.In the subsequent corticosteroid reduction phase,over the next 12 weeks, the subjects on omal-izumab were able to reduce their inhaled corti-costeroids by a larger amount than were those onplacebo. In all studies, omalizumab has been welltolerated, and there have been no instances ofthe development of antiomalizumab antibodies inany subject receiving parenteral omalizumab.

Hypothesis

Omalizumab has demonstrated statistically sig-nificant and clinically relevant improvement inallergic asthma in several studies. The markedsuccess of omalizumab in the bronchoprovocationstudies, however, suggested that omalizumabmight have worked even better.

There are increasing data to support the viewthat early use of anti-inflammatory therapeuticstrategies may improve the natural history of asthma.It was first shown that the late introduction of cor-ticosteroids, even in a survival population treatedwith �2 agonist alone for the first 2 years of asthma,did not allow catch-up to those individuals whostarted on corticosteroids early.26 This has beenconfirmed by other studies.27 This issue related toearly therapy is likely more relevant for prophylacticanti-inflammatory therapies such as environmen-tal control, as has been best demonstrated withoccupational asthma in which early environmentalcontrol frequently resulted in a cure, whereasdelayed environmental control, although helpful,

was associated with persistent asthma airway hyper-responsiveness and airway inflammation.13 Theanti-inflammatory effects of omalizumab should be,to a large extent (perhaps completely), analogousto environmental control. One could hypothesizethat omalizumab might be particularly effective,therefore, when introduced early in subjects withallergic asthma. This testable hypothesis wouldrequire studies of omalizumab targeting children andadolescents with recent-onset atopic asthma.

Interleukin-4

Background

IL-4 is regarded as the most important cytokineunderlying the development of the allergic type ofinflammation by a number of mechanisms, includ-ing IgE production, up-regulation of Fc� receptors,induction of adhesion molecules, and differenti-ation of lymphocytes towards the T helper 2 (Th2)phenotype, which favours maintenance of theallergic type of airway inflammation.28 Thera-peutic strategies designed to block the effect of IL-4 should therefore be effective in asthma and otheratopic allergic disorders. Recombinant pharma-ceutical agents targeting IL-4 include soluble IL-4 receptor (IL-4R),29 an IL-4/13 receptor blocker,30

and anti–IL-4 antibodies.31 All of these are in var-ious stages of investigation. Soluble IL-4R, effec-tive in a murine allergen challenge model,29 hasthe most reported data in humans.

Soluble IL-4R

Recombinant soluble IL-4R is a relatively low-mol-ecular-weight protein representing the extracellu-lar component of the cell membrane IL-4R. Solu-ble IL-4R reduces the effect of IL-4 in tissues bycompeting with membrane-bound IL-4Rs, thusreducing the biologic activity of IL-4. There are twoclinical studies in humans in which nebulized IL-4 was shown to have some effect.32,33 In a prelim-inary small placebo-controlled study,32 two dif-ferent doses of nebulized IL-4R (500 and 1,500 �g)were administered in a single dose on day 1. Inhaledcorticosteroids were stopped on day 0, and thesubjects were followed closely. The drug was well

Recombinant Therapies in Asthma — Cockcroft 37

38 Allergy, Asthma, and Clinical Immunology / Volume 1, Number 1, October 2004

tolerated; this was primarily a safety study. Noantibodies developed. The nine subjects receivingthe high dose of IL-4 demonstrated stable symp-toms, quality of life, and lung function comparedwith significant deterioration in the eight subjectsreceiving placebo and the eight subjects receivingthe low dose. A subsequent double-blind, placebo-controlled, dose-ranging study was carried outover 12 weeks assessing weekly nebulized dosesof 750, 1,500 and 3,000 �g in approximately 15subjects each.33 All subjects were demonstratedto be dependent on inhaled corticosteroids, whichwere stopped abruptly at the beginning of the trial.Once again, efficacy was demonstrated for solu-ble IL-4R, particularly in the highest-dose group,who demonstrated less decline in lung function, lessincrease in symptoms, and less requirement for res-cue medications. IL-4R was demonstrated to besafe, although one subject in this study did developnon-neutralizing antibodies to IL-4R.33 Much aswas hypothesized for omalizumab, the maximumbenefit from this (or any other anti-IL-4) strategyshould occur with early use.

Interleukin-5

Airway eosinophilia is a ubiquitous feature inasthma, and eosinophil levels correlate with dis-ease activity. Airway eosinophilia, along with theLAR and airway hyperresponsiveness, can beinduced by exposure to allergen.7,8 Eosinophilia,LARs, and airway hyperresponsiveness are allinhibited by inhaled corticosteroids.34 Conse-quently, it has been assumed that airway hyper-responsiveness and the LAR may somehow becaused by the eosinophilia or other airway inflam-matory cells. IL-5 is the major cytokine respon-sible for the differentiation and production ofeosinophils.35 Consequently, IL-5 has become apotential target for new asthma therapies.

There is one double-blind, randomized,placebo-controlled study in which two differentsingle doses of intravenous humanized anti–IL-5 antibody (2.5 and 10 mg/kg) were comparedwith placebo.36 The eight subjects with asthma ineach group were then followed for 16 weeks.

As expected, there was a marked effect on bothblood and sputum eosinophils. The suppressiveeffect was greater and longer lasting for the highdose. The anti-IL-5 antibody suppressed allergen-induced eosinophilia in allergen challenges done9 and 30 days after the dose. There was no effect,however, on airway responsiveness to histamine,the allergen-induced EAR, the allergen-inducedLAR, or the allergen-induced increase in airwayresponsiveness to histamine. Although this par-allel study was not adequately powered to detectsmall differences in allergen-induced airwayresponses, examination of the data confirms thatthere was not even a trend for a difference.

These results have been interpreted as sur-prising by many. They provide convincing evi-dence that airway eosinophilia and airway hyper-responsiveness may not be as closely linked as hadbeen previously assumed. This is one way inwhich these new recombinant therapies have givenus some remarkable and unsuspected insight intomechanisms. This, of course, raises importantquestions as to the relevance of eosinophils in thepathogenesis of clinical asthma. Further studieswith this novel therapy, if pursued, may providevaluable answers.

Interleukin-12

IL-12 is a cytokine involved in the Th1-Th2 balance.IL-12 has been reported to favour the Th1 as opposedto the Th2 phenotype. IL-12 is effective in animalallergen challenge models in inhibiting airwayeosinophilia and airway hyperresponsiveness.37

Recombinant IL-12 was administered subcu-taneously in increasing doses (0.1, 0.25, and 0.5�g/kg) weekly in 19 individuals compared withplacebo in 20 individuals.38 IL-12, like anti-IL-5,had a profound effect on eosinophils but no effecton airway responsiveness or the allergen-inducedLAR. There was a marked reduction in blood andsputum eosinophilia and a reduction in the mag-nitude of allergen-induced eosinophilia. IL-12does not appear to have been terribly well toler-ated because flu-like symptoms were reported inthe majority of individuals.

Recombinant Therapies in Asthma — Cockcroft 39

Lymphocytes

Lymphocytes play an important role in the patho-genesis of allergic inflammation. Efalizumab isa humanized murine monoclonal antibodydirected against CD11a. This antibody interfereswith lymphocyte integrin 1 and intercellularadhesion molecule and blocks T-lymphocyteactivation and trafficking.39 Efalizumab is effec-tive in the treatment of psoriasis.40 Efalizumabwas investigated in the human allergen chal-lenge model in a double-blind, parallel studywith 2:1 randomization active:placebo and 2:1randomization dual asthmatic:early asthmaticresponders. After a conditioning dose, sevenweekly doses of 2 mg/kg were administered sub-cutaneously. Allergen challenges were donebefore and 4 and 8 weeks after starting treat-ment. The allergen-induced EAR was notaffected. There was a reduction in the allergen-induced LAR expressed as the maximum percentfall in forced expiratory volume in 1 second (p = .09) and the area under the curve (p = .06)when compared with placebo.41 In a subset ofpatients, we did demonstrate a significant (p <.05) reduction in allergen-induced sputumeosinophilia.41 There was a significant preva-lence of flu-like syndromes with early dosing.Although not severe, this drug was not as welltolerated as, for example, omalizumab.

The trend towards inhibition of the allergen-induced LAR and the definite reduction in eosinophilspoints to the importance of lymphocytes and thepathogenesis of the clinically important late allergen-induced sequelae. This is another example of the valueof these new recombinant medications in furtherclarifying mechanisms of allergen-induced asthma.The potential role of efalizumab in the therapy ofasthma remains to be determined.

Conclusion

Recombinant therapies that inhibit IgE, whichinhibit (IL-4, IL-5) or mimic (IL-12) ILs andwhich block lymphocyte trafficking, are currentlybeing investigated in asthma. Undoubtedly, otherrecombinant approaches are in developmental

stages. These exciting new agents hold promise forthe treatment of asthma and provide valuable toolsfor the understanding of mechanisms in asthma.

Acknowledgement

Jacquie Bramley is thanked for assisting in thepreparation of the manuscript.

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