MonoclonalMonoclonal AntibodiesAntibodies inin AsthmaAsthma TherapyTherapy

YehiaYehia ElEl --GamalGamal MD,MD, PhDPhD ConflictConflict ofof InterestInterest

NothingNothing toto disclosedisclose ObjectivesObjectives FollowingFollowing thisthis presentation,presentation, thethe audienceaudience shouldshould bebe ableable to:to: ••RecognizeRecognize somesome importantimportant monoclonalmonoclonal antibodiesantibodies availableavailable forfor asthmaasthma therapy.therapy. ••IdentifyIdentify candidatescandidates forfor treatmenttreatment withwith monoclonalmonoclonal antibodies.antibodies. ••BeBe awareaware ofof thethe sideside effectseffects andand costcost -- benefitbenefit ofof suchsuch therapy.therapy. SinceSince thethe firstfirst publicationpublication byby KohlerKohler andand MilsteinMilstein onon thethe productionproduction ofof murinemurine monoclonalmonoclonal antibodiesantibodies (MAbs)(MAbs) byby hybridomahybridoma technology,technology, therapeutictherapeutic useuse ofof MAbsMAbs hashas becomebecome aa majormajor partpart ofof treatmentstreatments inin variousvarious diseases.diseases. Köhler G, Milstein C. Nature 1975;256: http://en.wikipedia.org/wiki/Mon 495 -7. oclonal_antibodies SchematicSchematic representationrepresentation ofof MAbMAb productionproduction

Martin -Mateos MA. Allergol Immunopathol (Madr) 2007; 35(4):145 -50. MAbsMAbs inin allergicallergic diseasesdiseases (cont(cont ’’d)d) OmalizumabOmalizumab (anti(anti --IgEIgE ab)ab) •• ItIt isis aa recombinantrecombinant humanizedhumanized monoclonalmonoclonal antibodyantibody (rhuMAb(rhuMAb --E25)E25) developeddeveloped byby immunizingimmunizing micemice withwith humanhuman IgE.IgE. •• Then,Then, aa monoclonalmonoclonal antibodyantibody waswas selectedselected thatthat recognizesrecognizes IgEIgE atat thethe samesame sitesite asas thethe highhigh --affinityaffinity receptorreceptor forfor IgEIgE (Fc(Fc εεRI).RI). Milgrom H, et al. N Engl J Med 1999;341(26):1966 -73. MAbsMAbs inin allergicallergic diseasesdiseases (cont(cont ’’d)d) OmalizumabOmalizumab isis thethe onlyonly MAbMAb toto datedate thatthat hashas beenbeen foundfound toto bebe effectiveeffective andand approvedapproved byby bothboth thethe FDAFDA andand EuropeanEuropean MedicinesMedicines AgencyAgency (EMEA)(EMEA) forfor thethe treatmenttreatment ofof difficultdifficult allergicallergic asthma.asthma. Bousquet J, et al. Expert Opin Biol Ther 2008;8(12):1921 -8. MechanismsMechanisms ofof ActionAction ofof OmalizumabOmalizumab

•• ReducesReduces serumserum levelslevels ofof freefree IgEIgE •• DownDown --regulatesregulates expressionexpression ofof IgEIgE receptorsreceptors (FceRI)(FceRI) onon mastmast cellscells andand basophils.basophils. •• InIn thethe airwaysairways ofof patientspatients withwith allergicallergic asthma,asthma, itit reducesreduces FcFc εεRI+RI+ andand IgE+IgE+ cellscells andand causescauses aa profoundprofound reductionreduction inin tissuetissue eosinophilia,eosinophilia, togethertogether withwith reductionsreductions inin submucosalsubmucosal TT --cellcell andand BB --cellcell numbers.numbers. Holgate S, Casale T, Wenzel S, Bousquet J, Deniz Y, Reisner C. J Allergy Clin Immunol 2005;115(3):459 -65. MechanismsMechanisms ofof actionaction ofof omalizumabomalizumab (cont(cont ’’d)d) •• TheThe reductionsreductions inin circulatingcirculating levelslevels ofof IgEIgE resultingresulting fromfrom omalizumabomalizumab treatmenttreatment leadsleads toto reductionsreductions inin FceRIFceRI expressionexpression onon mastmast cells,cells, basophilsbasophils andand dendriticdendritic cells.cells. •• ThisThis combinedcombined effecteffect resultsresults inin attenuationattenuation ofof severalseveral markersmarkers ofof inflammation,inflammation, includingincluding peripheralperipheral andand bronchialbronchial tissuetissue eosinophilia,eosinophilia, levelslevels ofof GMGM --CSF,CSF, ILIL --2,2, ILIL --4,4, ILIL --55 andand ILIL --13.13. •• ItIt maymay alsoalso reducereduce allergenallergen presentationpresentation toto TT -- cellscells andand thethe productionproduction ofof Th2Th2 cytokines.cytokines. Holgate S, et al. Allergy 2009:64(12):1728 –36. Fig 2

ProposedProposed MechanismsMechanisms ofof ActionAction ofof OmalizumabOmalizumab

Source: Journal Holgateof Allergy and ClinOI:10.1016/j.jac S, et al.i.2004.11.053 J Allergy ) Clin Immunol 2005;115(3):459 -65. TreatmentTreatment ofof allergicallergic asthmaasthma withwith monoclonalmonoclonal antianti --IgEIgE antibody:antibody: rhuMAbrhuMAb --E25E25 StudyStudy Group.Group.

Serum concentrations of total and free IgE in subjects given a low dose of rhuMAb -E25 for 20 weeks Milgrom H, et al. N Engl J Med. 1999 Dec 23;341(26):1966 -73. Fig 1

ImmunohistochemicalImmunohistochemical stainingstaining ofof bronchialbronchial biopsybiopsy specimensspecimens beforebefore (( leftleft )) andand afterafter (( rightright )) 1616 weeksweeks ofof omalizumabomalizumab treatment.treatment. RepresentativeRepresentative sectionssections showshow stainingstaining withwith antibodyantibody against:against: ECPECP (A(A andand B)B) CellCell --surfacesurface IgEIgE (C(C andand D)D) HighHigh --affinityaffinity IgEIgE RR (E(E andand F)F) ILIL --44 (G(G andand H)H) Djukanovi ć R, et al. Am J Respir Crit Care Med 2004;170:583 -93. Fig 1 EosinophilEosinophil apoptosisapoptosis atat baselinebaseline andand weekweek 1212 ofof omalizumabomalizumab therapy:therapy: TheThe omalizumabomalizumab groupgroup (n(n == 9)9) demonstrateddemonstrated aa significantsignificant increaseincrease inin AnnexinAnnexin --positivepositive eosinophilseosinophils comparedcompared withwith placeboplacebo (n(n == 10).10). ∗∗ ∗∗∗∗ ∗∗∗∗pp << 0.010.01

Noga O,et al. J Allergy Clin Immunol 2006;117:1493 –9. Individual eosinophil counts at baseline and after 12 weeks of treatment with omalizumab or placebo. Horizontal bars represent median values van Rensen E, et al. Allergy 2009;64:72 –80. ForcedForced expiratoryexpiratory volumevolume inin 11 secondsecond asas aa percentagepercentage ofof baselinebaseline inin thethe placeboplacebo (A)(A) andand omalizumabomalizumab (B)(B) groups.groups.

van Rensen E, et al. Allergy 2009;64:72 –80. EffectEffect ofof addadd --onon therapytherapy withwith omalizumabomalizumab inin patientspatients withwith severesevere persistentpersistent asthmaasthma whosewhose asthmaasthma waswas inadequatelyinadequately controlledcontrolled byby therapytherapy withwith highhigh --dosedose ICSsICSs plusplus aa LABALABA

Humbert M, et al. Allergy 2005; 60:309 –16 AntiAnti --IgEIgE TherapyTherapy inin ChildrenChildren •• OmalizumabOmalizumab isis approvedapproved forfor thethe treatmenttreatment ofof adultsadults andand adolescentsadolescents (12(12 years)years) withwith inadequatelyinadequately controlledcontrolled moderatemoderate --toto --severesevere (United(United States)States) oror severesevere (Europe)(Europe) allergicallergic (IgE(IgE -- mediated)mediated) asthma.asthma. http://www.xolair.com/prescribing_information.html. http://www.emea.europa.eu/humandocs/Humans/EPAR/xolair/xolair.ht m. •• AA randomizedrandomized DBPCDBPC studystudy inin 334334 childrenchildren (6(6 toto 1212 years)years) withwith moderatemoderate --toto --severesevere allergicallergic asthma,asthma, omalizumabomalizumab significantlysignificantly reducedreduced asthmaasthma exacerbationsexacerbations andand enabledenabled reductionsreductions inin ICSICS dose.dose. Milgrom H, et al. Pediatrics 2001;108:E36. AntiAnti --IgEIgE TherapyTherapy inin ChildrenChildren (cont(cont ’’d)d) MoreMore recently,recently, LanierLanier etet al.al. demonstrated,demonstrated, inin aa RDBPCRDBPC trial,trial, thatthat addadd --onon therapytherapy withwith omalizumabomalizumab hashas aa reassuringreassuring safetysafety profile,profile, withwith nono increasedincreased riskrisk ofof adverseadverse events,events, andand reducesreduces asthmaasthma exacerbationsexacerbations inin childrenchildren ((66 toto <12<12 yearsyears )) withwith inadequatelyinadequately controlledcontrolled moderatemoderate --toto -- severesevere allergicallergic asthma.asthma. Lanier B, et al. J Allergy Clin Immunol 2009;124:1210 -6. Fig 2

ClinicallyClinically significantsignificant asthmaasthma exacerbationexacerbation ratesrates overover aa periodperiod ofof 2424 weeksweeks (primary(primary outcome;outcome; A)A) andand 5252 weeksweeks (B)(B) inin patientspatients withwith moderatemoderate --toto -- severesevere asthmaasthma treatedtreated withwith addadd --onon omalizumabomalizumab

Lanier B , et al. J Allergy Clin Immunol 2009;124(6):1210 -6. AsthmaAsthma symptomsymptom rere --emergenceemergence afterafter omalizumabomalizumab withdrawalwithdrawal

•• TheThe reasonreason forfor omalizumabomalizumab beingbeing ineffectiveineffective inin somesome patientspatients isis unknown,unknown, butbut itit isis reasonablereasonable toto askask whetherwhether thethe ‘‘‘‘ failuresfailures ’’’’ resultresult fromfrom ineffectiveineffective reductionsreductions inin IgEIgE levels.levels. •• QuestionsQuestions areare beingbeing askedasked aboutabout whetherwhether thethe dosedose cancan bebe reducedreduced afterafter monthsmonths ofof treatmenttreatment oror whetherwhether offoff --tabletable regimensregimens cancan bebe used.used. •• ReducingReducing omalizumabomalizumab dosesdoses maymay resultresult inin increaseincrease inin freefree IgEIgE causingcausing deteriorationdeterioration inin asthmaasthma control.control. Salvin RG, et al. J Allergy Clin Immunol 2009;123(1):107 -13. MacGlashan D. J Allergy Clin Immunol 2009;123(1):114 -5. OmalizumabOmalizumab SafetySafety

•• OmalizumabOmalizumab isis consideredconsidered generallygenerally safe.safe. •• TheThe mostmost commoncommon adverseadverse reactionreaction fromfrom omalizumabomalizumab isis injectioninjection -- sitesite painpain andand bruisingbruising butbut thethe packagepackage insertinsert containscontains warningswarnings regardingregarding malignancies,malignancies, geohelminthgeohelminth infectionsinfections andand aa "black"black box"box" warningwarning aboutabout anaphylaxis.anaphylaxis. Cox LS, et al. Allergy Asthma Clin Immunol 2009;5(1):4. OmalizumabOmalizumab inin allergicallergic patientspatients atat riskrisk ofof geohelminthgeohelminth infectioninfection

•• A RDBPC trial from Brazil, conducted in 137 subjects (12 – 30 years), revealed that 50% of the omalizumab group experienced at least one intestinal geohelminth infection compared with 41% of the placebo subjects. •• This provides some evidence for a potential increased risk of geohelminth infection in subjects receiving omalizumab. •• Omalizumab therapy did not appear to be associated with increased morbidity attributable to intestinal helminthes or to affect response to anithelmintics. Cruz AA, et al. Clin Exp Allergy 2007; 37 : 197 –207. ValueValue ofof screeningscreening forfor helminthhelminth infectionsinfections inin patientspatients receivingreceiving longlong --termterm omalizumabomalizumab therapytherapy

TheThe usefulnessusefulness ofof screeningscreening forfor helminthhelminth infectionsinfections beforebefore consideringconsidering omalizumabomalizumab therapytherapy variesvaries widelywidely betweenbetween differentdifferent exposureexposure riskrisk groups,groups, andand isis generallygenerally notnot necessarynecessary exceptexcept inin individualsindividuals withwith continuingcontinuing exposure,exposure, aa pastpast historyhistory ofof filarialfilarial oror schistosomalschistosomal infection,infection, andand individualsindividuals withwith aa historyhistory oror highhigh riskrisk ofof infectioinfectionn withwith Strongyloides.Strongyloides. Cooper PJ, et al. Allergy 2008;63:409 –17. OmalizumabOmalizumab andand AnaphylaxisAnaphylaxis •• A review of post -marketing adverse events suggested that at least 0.2% of patients who received omalizumab experienced anaphylaxis between June 2003 and December 2006. Limb SL, et al. J Allergy Clin Immunol 2007;120:1378 –81. •• An Omalizumab Joint Task Force of the AAAAI and the ACAAI concluded that the anaphylaxis -reporting rate was 0.09% .It recommended an observation period of 2 hours for the first 3 injections and 30 minutes for subsequent injections as well as patient education regarding anaphylaxis. Cox L, et al. AAAAI/ACAAI Joint Task Force Report on omalizumab - associated anaphylaxis. J Allergy Clin Immunol 2007;120:1373 –7. •• Another reported incidence of anaphylaxis was 0.14% in omalizumab -treated patients and 0.07% in control patients. Corren J, et al. Clin Exp Allergy 2009;39:788 -97. OmalizumabOmalizumab andand MalignancyMalignancy

•• Current clinical trial data do not support an increased risk of malignant neoplasia or thrombocytopenia with omalizumab. Corren J, et al. Clin Exp Allergy 2009;39(6):788 -97. •• No cases were considered drug -related by a panel of blinded independent oncologists. The majority of cases (60%) were diagnosed within 6 months of treatment Cox LS, et al. Allergy Asthma Clin Immunol 2009;5(1):4. •• A multicenter, prospective, observational cohort study designed to evaluate the long term safety of Xolair® (omalizumab) is currently in progress. http://clinicaltrials.gov/ct2/show/NCT00252135?term=omalizumab ChurgChurg --StraussStrauss syndromesyndrome inin patientspatients treatedtreated withwith omalizumabomalizumab

OmalizumabOmalizumab treatmenttreatment maymay unmaskunmask CSSCSS inin patientspatients whowho havehave anan underlyingunderlying eosinophiliceosinophilic disorderdisorder duedue toto withdrawalwithdrawal ofof corticosteroidscorticosteroids inin favorfavor ofof omalizumab,omalizumab, oror maymay delaydelay corticosteroidcorticosteroid treatmenttreatment allowingallowing forfor CSSCSS toto manifest.manifest. Wechsler ME, et al. Chest 2009;136;507 -18.http://chestjournal.chestpubs. org/ content/136/2/507.full.html AntibodiesAntibodies specificspecific forfor aa segmentsegment ofof humanhuman membranemembrane IgEIgE depletedeplete IgEIgE --producingproducing BB cellscells inin humanizedhumanized micemice •• Although efficacious, current therapeutic IgE - specific antibodies do not appear to affect IgE production and therefore must be given frequently and chronically to maintain sufficient suppression of serum IgE. •• Recently, a strategy was developed to disrupt IgE production by generating MAbs that target a segment of membrane IgE on human IgE -switched B cells that is not present in serum IgE. •• This may provide a novel treatment for asthma and allergy Brightbill HD, et al. J Clin Invest 2010;120(6):2218 –29. MepolizumabMepolizumab (anti(anti --ILIL --55 ab)ab) •• ILIL --55 isis believedbelieved toto bebe aa keykey cytokinecytokine inin eosinophileosinophil functionfunction atat sitessites ofof allergicallergic inflammation.inflammation. •• HumanizedHumanized monoclonalmonoclonal antibodiesantibodies againstagainst ILIL --55 havehave beenbeen synthesized.synthesized. •• OneOne suchsuch antibody,antibody, mepolizumabmepolizumab ,, isis aa highhigh -- affinityaffinity humanized,humanized, nonnon ––complementcomplement --fixingfixing monoclonalmonoclonal antibodyantibody (IgG1)(IgG1) specificspecific forfor humanhuman ILIL --5.5. Flood -Page P, et al. Am J Respir Crit Care Med 2007;176:1062 –71. MepolizumabMepolizumab (cont(cont ’’d)d) •• PilotPilot studiesstudies ofof antianti ––ILIL --55 therapytherapy showedshowed profoundprofound reductionreduction inin bothboth circulatingcirculating andand sputumsputum eosinophils.eosinophils. •• However,However, inin contrastcontrast toto thethe resultsresults ofof animalanimal studies,studies, therethere waswas nono significantsignificant effecteffect ofof ILIL --55 blockadeblockade onon eithereither AHRAHR oror thethe latelate asthmaticasthmatic responseresponse afterafter allergenallergen challenge,challenge, oror sustainedsustained effecteffect onon lunglung function.function. Leckie MJ, et al. Lancet 2000; 356:2144 –8. Kips JC, et al. Am J Respir Crit Care Med 2003;167:1655 –9. Flood -Page PT, et al. Am J Respir Crit Care Med 2003;167:199 – 204. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma

Mean values for blood eosinophils

Flood -Page P, et al. Am J Respir Crit Care Med 2007;176:1062 –71. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma

AA higherhigher proportionproportion ofof patientspatients inin thethe placeboplacebo andand mepolizumabmepolizumab 250250 -- mgmg treatmenttreatment groupsgroups hadhad anan exacerbationexacerbation ofof anyany levellevel ofof severityseverity duringduring thethe study,study, comparedcompared withwith thethe mepolizumabmepolizumab 750750 --mgmg treatmenttreatment group.group.

Flood -Page P, et al. Am J Respir Crit Care Med 2007;176:1062 –71. TheThe DemiseDemise ofof AntiAnti ––ILIL --55 forfor Asthma,Asthma, oror Not!Not! •• AntiAnti ––ILIL --55 hashas provenproven toto bebe usefuluseful inin managingmanaging hyperhyper --eosinophiliceosinophilic syndromessyndromes .. •• TheThe resultsresults ofof clinicalclinical trialstrials inin patientspatients withwith asthmaasthma withwith airwayairway eosinophiliaeosinophilia andand poorpoor controlcontrol ,, whichwhich areare underway,underway, areare eagerlyeagerly awaited,awaited, becausebecause theythey havehave implicationsimplications notnot onlyonly forfor thethe possiblepossible rolerole ofof antianti ––ILIL --55 asas aa therapytherapy forfor asthmaasthma butbut alsoalso inin clarifyingclarifying thethe rolerole ofof airwayairway eosinophilseosinophils inin itsits pathopatho --biology.biology. O’Byrne PM . Am J Respir Crit Care Med 2007;176:1059 –61. RECENTRECENT DATADATA MepolizumabMepolizumab andand ExacerbationsExacerbations ofof RefractoryRefractory EosinophilicEosinophilic AsthmaAsthma Severe Exacerbations during the Course of the Study. Panel A shows the cumulative number of severe exacerbations that occurred in each study group over the course of 50 weeks. Panel B shows the distribution of the number of exacerbations among subjects in each group duringHaldar the P, ettreatment al. N Engl period. J Med 2009;360:973 -84. RECENTRECENT DATADATA MepolizumabMepolizumab forfor PrednisonePrednisone --DependentDependent AsthmaAsthma withwith SputumSputum EosinophiliaEosinophilia

Proportion of Patients without an Asthma Exacerbation during the Study Nair P, et al. N Engl J Med 2009;360:985 -93. EosinophilsEosinophils inin AsthmaAsthma —— ClosingClosing thethe LoopLoop oror OpeningOpening thethe Door?Door? •• OverOver thethe years,years, eosinophilseosinophils werewere identifiedidentified asas aa prominentprominent cellcell typetype inin asthma,asthma, yetyet theirtheir rolerole asas eieitherther anan ““effectoreffector ”” oror ““innocentinnocent bystanderbystander ”” waswas notnot confirmed.confirmed. •• RecentRecent studiesstudies confirmconfirm thatthat inin aa subgroupsubgroup ofof patienpatientsts withwith eosinophiliceosinophilic asthma,asthma, mepolizumabmepolizumab therapytherapy hadhad somesome clinicalclinical benefitbenefit .. •• However,However, manymany patientspatients withwith asthmaasthma dodo notnot havehave eosinophiliaeosinophilia ,, andand eveneven inin patientspatients withwith eosinophiliceosinophilic asthma,asthma, mepolizumabmepolizumab hadhad nono effecteffect onon otherother physiologicalphysiological andand clinicalclinical factorsfactors .. Wenzel SE. N Engl J Med 2009;360;1026 -8. AntiAnti ––TumorTumor NecrosisNecrosis FactorFactor --alphaalpha inin AsthmaAsthma TherapyTherapy •• PositivePositive resultsresults inin treatingtreating asthmaasthma patientspatients werewere challengedchallenged byby otherother researches.researches. •• ThereThere isis alsoalso concernconcern aboutabout seriousserious problemsproblems andand adverseadverse eventsevents relatedrelated toto thatthat kindkind ofof treatmenttreatment especiallyespecially inin children.children. •• However,However, researchresearch onon antianti --TNFTNF --alphaalpha andand asthmaasthma underlinedunderlined aa significantsignificant polymorphismpolymorphism inin asthmaasthma phenotypes.phenotypes. •• TherapyTherapy withwith antianti --TNFTNF --alphaalpha shouldshould bebe limitedlimited toto aa smallsmall subgroupsubgroup ofof patientspatients withwith aa specificspecific phenotypephenotype manifestedmanifested byby anan increasedincreased TNFTNF axis.axis. Gjurow D, et al. Recent Pat Inflamm Allergy Drug Discov 2009;3(2 ):143 -8. The Effects of a Monoclonal Antibody Directed against TNF -alpha in Asthma (Infliximab)

Exacerbations of Asthma The authors concluded that infliximab caused a decrease in the number of exacerbations in symptomatic moderate asthma. Erin EM, et al. Am J Respir Crit Care Med 2006;174:735 –62. AA randomizedrandomized DBPCDBPC studystudy ofof TNFTNF --alphaalpha blockadeblockade inin severesevere persistentpersistent asthmaasthma (Golimumab)(Golimumab)

Change from baseline in pre -bronchodilator percent -predicted FEV1. The authors concluded that treatment with golimumab did not demonstrate a favorable risk –benefit profile. Wenzel SE, et al. Am J Respir Crit Care Med 2009;179:549 –58. Correspondence:Correspondence: AntiAnti ––TNFTNF --alphaalpha inin AsthmaAsthma

•• The incidence of anti –TNF - induced tuberculosis can be as high as 224/100,000 treated patients. Manifestations are often extra -pulmonary, and in 24% of the cases there is disseminated disease with a significant risk of death. •• The risk -benefit should be carefully considered as the protective effect of such treatment is estimated not to be higher than 60% . •• Therefore, studies on the therapeutic value of anti-TNF in asthma should be focused on patients with severe debilitating disease. Krouwels FH. Am J Respir Crit Care Med 2007;175(3):288. Correspondence:Correspondence: StudyStudy ofof infliximabinfliximab treatmenttreatment inin asthmaasthma •• TheThe occurrenceoccurrence ofof neutralizingneutralizing antibodiesantibodies againstagainst infliximabinfliximab isis aa commoncommon event,event, andand thisthis maymay compromisecompromise drugdrug efficacy.efficacy. •• LargeLarge multicenter,multicenter, placeboplacebo --controlled,controlled, randomized,randomized, controlledcontrolled trialstrials inin patientspatients withwith severesevere chronicchronic asthmaasthma areare requiredrequired beforebefore settingsetting anyany recommendations.recommendations. Edwards CJ, Polosa R. Am J Respir Crit Care Med 2007;175(2 ):196. AntiAnti --TGFTGF betabeta MAbMAb •• NeutralizationNeutralization ofof TGFTGF --b1b1 withwith specificspecific antibodyantibody hadhad nono significantsignificant effecteffect onon airwayairway inflammationinflammation andand eosinophiliaeosinophilia •• ItIt alsoalso enhancedenhanced ovalbuminovalbumin inducedinduced AHRAHR •• ItIt suppressedsuppressed pulmonarypulmonary fibrosis.fibrosis.

Alcorn JF, et al. Am J Respir Crit Care Med 2007;176:974 –82. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a RDBPC trial

The use of daclizumab, an anti -CD25 antibody, was associated with some improvement in lung function and asthma control along with a red uction in blood eosinophils. Busse WW, et al. Am J Respir Crit Care Med 2008;178:1002 –8. OtherOther PotentialPotential MAbsMAbs inin AsthmaAsthma TherapyTherapy •• AA mutatedmutated interleukininterleukin --44 (pitrakinra)(pitrakinra) thatthat bindsbinds thethe ILIL --4R4R αα andand blocksblocks thethe effectseffects ofof bothboth ILIL --44 andand ILIL --1313 hashas beenbeen developed.developed. •• AA smallsmall RDBPCRDBPC phasephase IIII trialtrial inin mildmild --toto -- moderatemoderate asthmaticsasthmatics showedshowed thatthat inhaledinhaled pitrakinrapitrakinra reducedreduced thethe latelate phasephase declinedecline inin lunglung functionfunction inin responseresponse toto inhalationalinhalational allergenallergen challengechallenge withwith nono seriousserious adverseadverse events.events. Wenzel SE, et al. Lancet 2007;370:1422 –31. Other potential MAbs in asthma therapy (cont ’d) •• AA phasephase 11 studystudy evaluatingevaluating thethe pharmacokinetics,pharmacokinetics, safetysafety andand tolerabilitytolerability ofof aa humanhuman ILIL --1313 antibodyantibody (CAT(CAT --354)354) inin asthmaasthma revealedrevealed anan acceptableacceptable safetysafety profile.profile. Singh D, et al. BMC Pulm Med 2010;10:3. •• SpecificSpecific inhibitioninhibition ofof tissuetissue kallikreinkallikrein 11 withwith aa humanhuman monoclonalmonoclonal antibodyantibody (DX(DX --23002300 )) revealedrevealed aa potentialpotential inin vitrovitro andand inin vivovivo rolerole inin airwayairway diseases.diseases. Sexton DJ, et al. Biochem J 2009;422(2):383 -92. Other potential MAbs in asthma therapy (cont ’d) •• THTH --1717 cellscells maymay contributecontribute toto thethe pathogenesispathogenesis ofof TH2TH2 --mediatedmediated allergicallergic diseases,diseases, increaseincrease neutrophilneutrophil infiltrationinfiltration andand mucusmucus proteins,proteins, andand isis associatedassociated withwith aa steroidsteroid --resistantresistant asthmaasthma phenotype.phenotype. TargetingTargeting THTH --1717 cellscells maymay bebe ofof valuevalue inin severesevere neutrophilicneutrophilic asthma.asthma. •• InIn animalanimal studies,studies, aa neutralizingneutralizing antibodyantibody againstagainst ILIL --2525 abrogatesabrogates AHR,AHR, reducesreduces ILIL --55 andand ILIL --1313 production,production, reducesreduces tissuetissue eosinophileosinophil infiltration,infiltration, andand serumserum IgE.IgE. Long AA. MAbs 2009; 1(3):237 -46. Other potential MAbs in asthma therapy (cont ’d) •• InIn vivovivo treatmenttreatment withwith anan antianti --CD147CD147 MAbMAb significantlysignificantly reducedreduced thethe accumulationaccumulation ofof eosinophilseosinophils andand antigenantigen --specificspecific Th2Th2 cytokinecytokine secretionsecretion inin lunglung tissues,tissues, airwayairway epithelialepithelial mucinmucin production,production, andand AHRAHR toto methacholinemethacholine challenge.challenge. Gwinn WM, et al. J Immunol 2006;177(7):4870 –9. •• ComplexesComplexes ofof ILIL --22 // antianti --ILIL --22 MAbMAb ,, inin aa murinemurine asthmaasthma model,model, reducedreduced thethe severityseverity ofof allergenallergen --inducedinduced inflammationinflammation inin thethe lunglung byby expandingexpanding Tregs.Tregs. Wilson MS, et al. J Immunol 2008;181(10):6942 –54. Other potential MAbs in asthma therapy (cont ’d) •• TT cell,cell, immunoglobulin,immunoglobulin, mucinmucin (TIM)(TIM) genesgenes areare associatedassociated withwith severalseveral atopicatopic diseases.diseases. •• AA MAbMAb againstagainst TIMTIM --11 proteinprotein influencedinfluenced activatedactivated TT cellscells andand blockedblocked thethe developmentdevelopment ofof diseasedisease inin aa humanizedhumanized mousemouse modelmodel ofof allergicallergic asthmaasthma suggestingsuggesting thatthat itit maymay provideprovide potentpotent therapeutictherapeutic benefitbenefit inin asthmaasthma Sonar SS. J Clin Invest 2010;120(8):2767 -81. LimitationsLimitations ofof UseUse ofof MAbsMAbs inin AsthmaAsthma

•• ExpenseExpense •• ParenteralParenteral administrationadministration •• AdverseAdverse effectseffects •• HostHost antianti --drugdrug responsesresponses limitinglimiting ongoingongoing therapytherapy •• LimitationsLimitations inin currentcurrent conceptsconcepts ofof molecularmolecular pathogenesispathogenesis ofof diseasedisease TakeTake HomeHome MessageMessage •• TheThe costcost --effectivenesseffectiveness andand adverseadverse eventsevents associatedassociated withwith thethe useuse ofof eacheach monoclonalmonoclonal antibodyantibody shouldshould bebe considered.considered. •• ThisThis couldcould bebe achievedachieved byby carefullycarefully revisingrevising thethe existingexisting clinicalclinical trialstrials inin lightlight ofof solidsolid evidenceevidence --basedbased criteria.criteria. •• PediatricPediatric datadata onon cytokinecytokine --specificspecific monoclonalmonoclonal antibodyantibody therapiestherapies areare stillstill needed.needed.

ThankThank YouYou

YehiaYehia ElEl --GamalGamal