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TargetedTherapyofCancer
Dr.SharkeyisMemberandDirec-torofClinicalResearch,GardenStateCancerCenterattheCenterforMolecularMedicineandImmunol-ogy,Belleville,NJ.
Dr.GoldenbergisPresident,Gar-denStateCancerCenterattheCen-terforMolecularMedicineandImmunology,Belleville,NJ.
Thisarticleisavailableonlineat
http://CAonline.AmCancerS
TargetedTherapyofCancer:NewProspectsforAntibodiesand
Immunoconjugates1
RobertM.Sharkey,PhD;DavidM.Goldenberg,ScD,MD
ABSTRACTImmunotherapyofcancerhasbeenexploredforoveracentury,butitisonlyinthelastdecadethatvariousantibody-basedproductshavebeenintroducedintothemanagementofpatientswithdiversecancers.Atpresent,thisisoneofthemostactiveareasofclinicalresearch,witheighttherapeuticproductsalreadyapprovedinoncology.Antibodiesagainsttumor-associatedmarkershavebeenapartofmedicalpracticeinimmunohistologyandinvitroimmunoassaysforseveraldecades,haveevenbeenusedasradioconjugatesindiagnosticimaging,andarenowbecomingincreasinglyrecognizedasimportantbiologicalagentsforthedetectionandtreatmentofcancer.Molecularengineeringhasimprovedtheprospectsforsuchantibody-basedtherapeutics,resultingindifferentconstructsandhumanized/humanantibodiesthatcanbeadministeredfre-quently.Consequently,arenewedinterestinthedevelopmentofantibodiesconjugatedwithradio-
nuclides,drugs,andtoxinshasemerged.Wereviewhowantibodiesandimmunoconjugateshaveinfluencedcancerdetectionandtherapy,andalsodescribepromisingnewdevelopmentsandchallengesforbroaderapplications.(CACancerJClin2006;56:226–243.)?AmericanCancerSociety,Inc.,2006.
INTRODUCTION
Thesearchforamechanismtotargetdiseasesselectivelywasfirstrealizedwhenresistancetoinfectiousdiseasecouldbetransferredfromoneanimaltoanotherthroughtheirserum,aprocessknownaspassiveserotherapy.1Fiveyearslater,in1895,HericourtandRichetimmunizeddogswithahumansarcomaandthentransferredtheserumtopatients.2Thisanticipatedthe“magicbullet”conceptofPaulEhrlichin1908,that“toxins”couldbetargetedtocancerandotherdiseases.3Anotherhalf-centurypassedbeforeantibodieswereidentifiedasthesubstanceinserumresponsiblefortheseeffects.
Despitebeingpotentimmunesysteminstigatorsforkillinginfectiousagents,clinicalresearchinitiallyfocusedonimmunoconjugatespreparedwithradionuclides,drugs,ortoxins,sinceunconjugatedor“naked”antibodieshadlittletherapeuticbenefitinoncologycomparedwiththeimmunoconjugates.Earlyimmunotherapytrialsfailedtoshowsubstantialresponses,4–6butantibodiesagainstcarcinoembryonicantigen(CEA)couldselectivelytargetanddisclosesitesofCEA-expressingcancersinpatients,andalsodelivercytotoxicradioactivityinhumancoloniccancerxenograftshavingCEA.7,8Thereafter,DeNardo,etal.9reportedresponsesinlymphomapatientstoradiolabeledantibodies,andsoonothersconfirmedthatradiolabeledantibodieshadantitumoractivityinnon-Hodgkinlym-phoma(NHL),buttherewasalsoearlyevidencethatthenakedantibodiesthemselvesmightbeeffective.10–12Itwasduringthissameperiodthatrituximab(Rituxan,Genentech,andbiogenidec),ananti-CD20IgG,becameofinterestasatherapeuticforNHLwithoutbeingradiolabeled.13TheexperienceandsubsequentintroductionofrituximabintothetreatmentofNHLcanbecreditedfortheexpandedinterestinunconjugatedantibodiesforcancertherapy.
1ThisworkwassupportedinpartbyUSPHSgrantP01-CA103985fromtheNationalCancerInstitute,NIH,andgrant06-1853-FS-N0fromtheNewJerseyDepartmentofHealthandSeniorServices.
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Antibodies(eg,IgG,whichisthemostcom-monlyusedimmunoglobulinform,Figure1)areuniqueproteinswithdualfunctionality.Allnaturallyoccurringantibodiesaremulti-valent,withIgGhavingtwobinding‘a(chǎn)rms.’Antigen-bindingspecificityisencodedbythreecomplementarity-determiningregions(CDRs),whiletheFc-regionisresponsibleforbindingtoserumproteins(eg,complement)orcells.Anantibodyitselfusuallyisnotresponsibleforkillingtargetcells,butinsteadmarksthecellsthatothercomponentsoreffectorcellsofthebody’simmunesystemshouldattack,oritcaninitiatesignalingmechanismsinthetargetedcellthatleadstothecell’sself-destruction(Fig-ure2).Theformertwoattackmechanismsarereferredtoasantibody-dependentcomplement-mediatedcytotoxicity(CMC)andantibody-dependentcellularcytotoxicity(ADCC).ADCCinvolvestherecognitionoftheantibodybyimmunecellsthatengagetheantibody-markedcellsandeitherthroughtheirdirectaction,orthroughtherecruitmentofothercelltypes,leadtothetagged-cell’sdeath.CMCisapro-cesswhereacascadeofdifferentcomplementproteinsbecomeactivated,usuallywhensev-eralIgGsareincloseproximitytoeachother,eitherwithonedirectoutcomebeingcelllysis,oroneindirectoutcomebeingattractingotherimmunecellstothislocationforeffectorcellfunction.
Antibodies,whenboundtokeysubstancesfoundonthecellsurface,alsocaninducecellstoundergoprogrammedcelldeath,orapoptosis(Figure2).Forexample,ifrituximabbindstotwoCD20molecules,thistriggerssignalsin-sidethecellthatcaninduceapoptosis.14Ifrituximabiscross-linkedbyotherantiantibod-ies,theapoptoticsignalisintensified.15Thiscross-linkingcouldalsooccurwhentheanti-bodyisboundbyanotherimmunecellthroughitsFc-gammareceptors(Fc?R).Otheranti-bodies,suchastrastuzumab(anti-HER2/neu;Herceptin,Genentech)andcetuximab(anti-epidermalgrowthfactorreceptor,EGFR;Er-bitux,ImCloneSystemsandBristol-MyersSquibb)alsohavetheabilitytoinhibitcellproliferation.16–18Becausecellsfrequentlyhavealternativepathwaysforcriticalfunctions,interruptingasinglesignalingpathwayalone
mightnotbesufficienttoensurecelldeath.Fromthisperspective,itisnotsurprisingthatantibodiesareoftenbestusedincombinationwithchemotherapyandradiationtherapytoaugmenttheirantitumoreffects.19–21
Bevacizumab(Avastin,Genentech)isyetanotherexampleofhowantibodiescanbeusedtherapeutically.Thisantibodybindstovascularendothelialgrowthfactor(VEGF)thatismadebytumorcellstopromotevesselformation,therebypreventingitfrominter-actingwithendothelialcellstoformnewbloodvessels(Figure2).22Antibodiescanalsobeusedtomodulateimmuneresponse.AntibodiestothecytotoxicT-lymphocyteassociatedantigen-4(CTLA-4)stimulateT-cellimmuneresponsesbyblockingtheinhibitoryeffectsofCTLA-4,whichcanen-hancetumorrejection.23However,releaseofthisinnateinhibitorymechanismcanalsoincreasetheriskofautoimmunity.24Twohumananti-CTLA-4antibodiesarecurrentlyinearlyclinicaltrials(MDX-010,Medarex,andCP-675,206,Pfizer),withevidencethattheymayhaveactivityinmelanoma.24Therearealreadyanumberofantibodiesusedorbe-ingstudiedastherapeuticagentsincanceraswellasautoimmunediseases(eg,alemtuzumab,daclizumab,infliximab,rituximab,epratu-zumab).25–31Antibodiesalsocanblockmoleculesassociatedwithcelladhesion,therebyinhibitingtumormetastasis.32,33Withsuchdiversemecha-nismsofaction,thereareanumberofopportu-nitiesforbuildingantibody-basedtherapeutics.
Antibodiesnaturallyhavelongserumhalf-lives.Forimmunotherapy,thispropertyishelpfulbecausetheantibodyismaintainedinthebodyfluids,whereitcancontinuallyinter-actwithitstarget.Forothertargetingstrategies,mostnotablywithradioconjugates,itcanbeharmfulbecausethehighlyradiosensitivebonemarrowiscontinuallyexposedtoradiation,resultingindose-limitingmyelosuppression.Thelargesizeofanantibodyimpactsitsabilitytomovethroughatumormass.Ahighinter-stitialpressureinhibitsthediffusionoflargermoleculeswithinthetumor.34Migrationwithinthetumorisalsoinhibitedbyabinding-sitebarrier,aprocesswheretheantibodyasitisleavingthetumor’sbloodvesselsbindstothe
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TargetedTherapyofCancer
FIGURE1SchematicrepresentationofanIgGmolecule,itschemicallyproducedfragments,andseveralrecombinantantibodyfragmentswiththeirnominalmolecularweights.Atthebottom,aschematicrepresentationoftheprocessin-
volvedinengineeringmurineMAbstoreducetheirimmunogenicityisprovided.AchimericantibodysplicestheVLandVHportionsofthemurineIgGtoahumanIgG.AhumanizedantibodysplicesonlytheCDRportionsfromthemurine
MAb,alongwithsomeoftheadjacent“framework”regionstohelpmaintaintheconformationalstructureoftheCDRs.AfullyhumanIgGcanbeisolatedfromspecializedtransgenicmicebredtoproducehumanIgGafterimmunizingwithtu-morantigenorbyaspecializedphagedisplaymethod.
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FIGURE2Mechanismsofactionassociatedwithunconjugatedantibodies.Inthisexample,theantigenisshowntobefloatinginlipidraftswithinthetumorcellmembrane.(A)Antibodiescanactivateapoptoticsignalsbycross-linkinganti-gen,particularlyacrossdifferentlipidrafts.Additionalcross-linkingofantibodybyimmunecellscanalsoenhancecellu-larsignaling.(B)Immunecellsthemselvescanattacktheantibody-coatedcell(eg,phagocytosis),and/ortheycan
liberateadditionalfactors,suchascytokinesthatattractothercytotoxiccells.(C)Ifantibodiesarepositionedcloselyto-gether,theycaninitiatethecomplementcascadethatcandisruptthemembrane,butsomeofthecomplementcompo-nentsalsoarechemo-attractantsforimmuneeffectorcellsandstimulatebloodflow.(D)Tumorsalsocanproduce
angiogenicfactorsthatinitiateneovascularization.Antibodiescanneutralizethesesubstancesbybindingtothem,ortheycanbinddirectlytouniqueantigenspresentedinthenewbloodvessels,wheretheycouldexertsimilaractivities.
firstavailableantigen,concentratingtheanti-bodyintheperivascularspace.35High-affinityantibodiesarelesslikelytomigrateintothetumorbed.36Administeringhigherdosesoftheantibodycanreducetheeffectofthebindingsitebarrierandallowtheantibodytodiffusemoredeeplyintothetumorbed.37Forcyto-toxicagentsthatmustbeinternalizedtokillthecell(eg,toxins,cytotoxicdrugs),theabilitytodistributethroughoutthetumorisimportant.Radioconjugatesarelessaffectedbythisbe-causesomeradioactiveparticlescantraverseasmuchas1.0cmfromwheretheyaredeposited(bystanderorcrossfireeffect).
THERAPYWITHUNCONJUGATEDANTIBODIES
Arenewedinterestintheeffectsofun-conjugatedantibodiesincancerbeganintheearly1980s,aftermurinemonoclonalanti-bodies(MAbs)becameavailable.38Theseinitialtrialswereperformedinhematologicalmalignancies,aswellasincolorectalcancerandmelanoma.4–6,39–41Aswithmanyinno-
vativetreatmentapproachesthataresome-timesintroducedbeforethetechnologyhasmaturedsufficientlytoextractmaximumbenefit,onlyoccasionalclinicalresponseswereobserved.WithinsufficientefficacyandtheimmunogenicityoftheforeignmurineMAb,mostofthesestudieswereterminated.Fortunately,someinvestigatorspersevered.Anexcellentlessononthetribulationsofthedevelopmentofanantibodyproductbe-tweenanacademicgroupandindustryisthatofalemtuzumab(Campath,Berlex,andGen-zyme).42Alemtuzumab(anti-CD52)hadoneoftheearliestandprotracteddevelopmentsofanantibodyultimatelycommercialized.Ittookover20yearsfromthedevelopmentofthefirstratimmunoglobulinagainstCD52,changingtheimmunoglobulintype,andfi-nallydevelopingahumanized,recombinantform,andinvolvedseveralcommercialfirmsduringthistime.Chemotherapy-refractivechroniclymphocyticleukemiawastheindi-cationfinallyapprovedin2001.
DueinparttothecontributionsmadebythegroupsledbyMorrison(ColumbiaandStan-
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fordUniversities)andWinter(Cambridge),MAbsnowareengineeredtoremoveasignif-icantportionofthemurinecomponentoftheIgG,substitutinghumanIgGcomponentsbe-foreenteringclinicalstudies.43–45ChimericantibodiesessentiallyspliceVLandVHregionsonthemurineantibodytothehumanIgG,makingamoleculethatis75%humanand25%murineIgG,whereasahumanizedantibodygraftstheCDRregionsfromamurineMAb,alongwithsomeofthesurrounding“frame-work”regionstomaintainCDRconforma-tion,ontoahumanIgG,essentiallymakingamoleculewith5%ofitssequencefromtheparentalMAb(Figure1).45Morerecentad-vanceshavemadeavailable,eitherbygeneticorphage-displaymethods,thedevelopmentoffullyhumanMAbsthathavenowenteredclin-icaltrials.46SuchengineeredMAbsarepostu-latedtogreatlyreducetheimmunogenicityofantibodies,allowingmultipleinjectionstobegiven,andthehumanFcenhancestheinter-actionwithotherimmunesystemelements.
Rituximabisperhapsthemostprominentexampleofahighlysuccessfulparadigmofan-tibodytherapy.Asachimericantibody,notonlydidithavereducedimmunogenicity,butitseffectorfunction(associatedwiththeFc-portion)wasimproved.Forexample,whentestingADCCactivityagainstfollicularlym-phomaisolatedfrom43patients,Weng,etal.reportedthatonlyrituximab,notitsparentmurineanti-CD20IgG(2B8),hadactivityinvitro.47Rituximabwasinitiallyapprovedasasingleagenttherapyforrelapsedorrefractorylow-grade,follicularB-cellNHL,havinganoverallresponserateof48%(10%werecom-pleteresponses,CR)withamediandurationof11.8months.48,49SinceCD20isnotexpressedonprecursorsB-cells,rituximabinducesade-pletionofonlymatureB-cells.Rituximab’smajorsideeffects,whicharethoughttobeassociatedwiththeactivationofcomplementpathways,occurduringorshortlyafteritsin-fusion.Otherlesscommonsideeffectsincludesymptomsassociatedwithtumorlysissyn-drome,severemucotaneousreactions,renaltoxicity,cardiacarrhythmias,hypersensitivityreactions,andreactivationofhepatitisB(pri-
marilywhenusedincombinationwithchemo-therapy).49
Rituximab’sactivityisuniqueamongcancertreatmentsbecause40%ofthepatientsre-treatedwithrituximabcouldagainrespondwithasimilarduration.50Extendingthedura-tionofrituximabtherapycanimprovethere-sponserate,particularlythenumberofcompleteresponses,anditsduration.However,whethergivenasamaintenanceregimenorretreatingatthefirstsignofprogression,thetimetochemotherapywasthesame.51Withbothapproacheshavingequalbenefit,retreat-mentisgenerallyfavoredbecauseofthehigherexpenseofamaintenanceregimen.Despitethesuccessofrituximabasamonotherapy,therearestillanumberofpatientswhodonotre-spondtotheinitialtreatment,andovertime,manyofthosewhodowillrelapse.Inanat-tempttoimproveoutcome,rituximabhasbeencombinedwithchemotherapyregimens,in-cludingCHOP,CVP,andMCP,asfront-linetreatments,withverypromisingresultsinnotonlyfollicularB-celllymphomas,butalsoindiffuselargeB-celllymphomas.52,53Indeed,trialsexaminingfront-linecombinationsofrit-uximabandchemotherapyhavealreadydem-onstratedimprovementsinresponserates,timetoprogression,andevent-freesurvival,andwhiletheoverallresponseratesarepromisingbasedoncurrent2-to3-yearfollow-updata,moretimewillberequiredtofullyappre-ciateitsimpact.52Eveninchroniclymphocyticleukemia(CLL),whereinitialtestingofritux-imabwasdisappointing,doseintensifica-tionandcombinationswithchemotherapyhaveprovidedsignificantimprovementsinresponse.54,55Earlyclinicalstudiescombiningrituximabwithahumanizedanti-CD22,epratuzumab(Immunomedics,Inc.)suggestedthepotentialforadditionalbenefit,particularlyinpatientswithdiffuselargeB-celllympho-mas.56,57Studieshavealsoassessedthepossibleroleofananti-CD80MAb(galiximab,biogenidec)asamonotherapyinNHL,58,59andclin-icaltrialsareinprogresstestingitscombinationwithrituximab.
Considerableattentionhasbeendevotedtounderstandingthemechanismofactionofrit-uximab,particularlywhysomeB-celllympho-
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masareaffectedandwhynotallpatientswithfollicularlymphomasrespond.Asmentionedearlier,rituximabhasbeenshowntohaveCMC,ADCC,andapoptoticactivity,withtheformertwomechanismsbelievedtohavethegreatestimpact,althoughthereareconflictingviewsofwhichofthesetwopathwayscontrib-utesthemosttotheresponse.14,60–66Studiesintransgenicandothermousemodelshavesup-portedtheimportanceoftheFc-receptor-mediatedmechanismofactionforrituximab.67,68TheseeffortshavecontributedinparttoabetterunderstandingoftheroleofvariousFcreceptorsfoundonavarietyofim-muneeffectorcells(eg,B-cells,neutrophils,naturalkillercells,andmonocytes)on(inthecaseofrituximab)theclearanceofB-cells,aswellastheplasmahalf-lifeofantibodies.69NotonlydothevariousFc-receptorsinfluencebinding,buttheabsenceofcertaincarbohy-dratesontheFcportionoftheIgGcanaffectbothADCCandCMCactivities.70,71Cartron,etal.foundthattheexpressionofthehomozy-gousFc-gammaRIIIareceptor(CD16)158Vgenotypecorrelatedwithahigherresponseratetorituximab,butitdidnothaveanimpactontheprogression-freesurvival.72Weng,etal.foundasimilarcorrelationandalsonotedthatthehomozygousexpressionoftheFc-gammaRIIahistidine/histidinegenotypecorrelatedindependentlywithahigherresponserate,par-ticularlywhenassessingtheresponsestatus≥6monthsfromtreatment.47Byunravelingthemolecularbasisforantibodycytotoxicity,notonlycanmoreeffectiveantibodiesbedesigned,butitcouldleadtoamorerationalapproachforcombinationstoenhanceactivity,suchasthefindingthatG-CSFup-regulatesCD64(Fc-gammareceptorI),whichcanenhancethebindingofneutrophilsandmonocytestoB-cellscoatedwithrituximab.73IL-12hasasimilarstimulatoryeffectinmousemodelsandmorerecentlyhasbeenappliedclinicallywithpromisingresults.74,75Thesediscoveriesarealsohavinganimpactonthedevelopmentofantibodiesfortreatingothercancers.76–80
TheapprovedantibodieslistedinTable1in-dicatethatimmunotherapyisnotrestrictedtohematologicalmalignancies,butincludesdiversetargetantigensandreceptorshavingdifferent
biologicalfunctions.Trastuzumabisananti-HER2/neuantibodythathashadamajorimpactonthetherapyofbreastcancerandisusedaloneandincombinationwithdrugs.81–83HER2/neuisoverexpressedonaproportionofbreastandothercancers,andtrastuzumabbindswithanextracellularepitopeofthistargetmolecule.About15%ofwomenwhosetumorsoverexpressHER2/neurespondtotrastuzumab,butitseffi-cacyisclearlybestwhenusedincombinationwithchemotherapy,wherea25%increaseinthemediansurvival(to29months)hasbeenreport-ed.81Further,theadditionofthisantibodytoadjuvantchemotherapyforbreastcancerhasim-provedsurvivalmarkedly.83SinceonlyaportionofbreastcancerpatientsoverexpressHER2/neuandrespondtotrastuzumab,selectionofsuitablepatientsisimportant.Newdataareemergingthatsuggesttrastuzumabtreatmentafteradjuvantche-motherapycanhaveasignificantbenefitcom-paredwithobservation,particularlyinreducingtherateofdistantrecurrence.82
Asamemberofafamilyofreceptortyrosinekinases,thebindingofHER2bytrastuzumabcaninterruptintracellularsignalingandaffecttumorcellgrowth.Izumi,etal.showedthattrastuzumabalsohasantiangiogenicproper-ties.84Whilethismaybeanimportantunder-lyingmechanismofaction,otherevidencesuggeststhattrastuzumab’sactivityisprinci-pallygovernedbyADCC.85However,trastu-zumabcombinedwithchemotherapyimprovesresponserates,despitetheimmunosuppressiveactivityofthechemotherapy,andtrastuzum-ab’sactivityisenhancedwhencombinedwithother,nonantibody,Erbinhibitors,suchasge-fitinibanderlotinib,allofwhichsuggestthatitsabilitytointerferewithsignalingisimpor-tant.86SinceHER2isamemberofafamilyofgrowthfactorsknownastheneuregulins/heregulinandisexpressedinmultipleneuronalandnon-neuronaltissuesinembryosandadultanimals,includingtheheart,itisnotsurprisingthatcardiomyopathyhasbeenassociatedwithtrastuzumab,particularlywhencombinedwithpaclitaxelandanthracyclines.87–90
EGFRisalsooverexpressedinmanysolidcancers,andwhenboundbyitsligand,cellgrowthisstimulated.However,whenengagedbyanEGFR-specificantibody,receptorphos-
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TABLE1FDA-approvedAntibodiesfortheParenteralUseinDetectionandTreatmentofCancer
GenericName
UnconjugatedRituximab
TrastuzumabAlemtuzumabCetuximab
Tradename
Agent/Target
CancerIndication
Approval
1997
1998
2001
2004
2006
Rituxan
Herceptin
Campath-1HErbitux
Chimericanti-CD20IgG1
Humanizedanti-HER2IgG1Humanizedanti-CD52
Chimericanti-EGFR
B-celllymphoma
Breast
CLL?
ColorectalHead/neck
Bevacizumab
Radioconjugates
Satumomabpendetide
NofetumomabmerpentanArcitumomab
CapromabpendetideIbritumomabtiuxetanTositumomab
Avastin
Chimericanti-VEGF
Colorectal
2004
OncoScint*
111In-murineanti-TAG-72IgG
Colorectal,ovarian
1992
Verluma*
99mTc-murineanti-EGP-1Fab’
SCLC?
1996
CEA-Scan*
99mTc-murineanti-CEAFab’
Colorectal
1996
ProstaScint
111In-murineanti-PSMA
Prostate
1996
Zevalin
90Y-murineanti-CD20IgG+rituximab
B-celllymphoma
2002
Bexxar
131I-murineanti-CD20IgG+unlabeledtositumomab
B-celllymphoma
2003
Drugconjugates
Gemtuzumabozogamicin
Mylotarg
Humanizedanti-CD33IgG4conjugatedtocolicheamicin
AML§
2000
*Nolongercommerciallyavailable.
?CLL=chroniclymphocyticleukemia.?SCLC=smallcelllungcancer.
§AML=acutemyelogenousleukemia.
phorylationisdecreasedandcellgrowthisinhib-ited.ThechimericantibodyagainstEGFR,cetuximab,alsohasaneffectonneovasculariza-tion.91,92Cetuximabworksbestincombinationwithchemotherapyincolorectalcancer,forwhichitwasinitiallyapproved,andwithexternalirradiationinheadandneckcancers,whichwasrecentlyFDA-approved.17,93Besidetheusualrisksassociatedwithantibodyinfusions,cetux-imabcausesanacneformrashandotherskinreactionsinmostpatients,with10%ofthesebeingsevere.Thereisevidencesuggestingthattheintensityoftheskinrashisassociatedwithitsantitumorresponseandevensurvival.94OtherEGFRantibodies,particularlyhumanizedandfullyhumanforms,alsoareindevelopment,asindicatedinTable2,andmayinfactbebettertoleratedandshowevidenceofactivitywithoutbeingcombinedwithcytotoxicchemotherapy,whichiscurrentlybeingevaluatedinPhaseIIItrials.Itistooearlytospeculatewhethertheywill,infact,provideanytherapeuticadvantagesovercetuximab.
Bevacizumabtargetsandblocksvascularen-dothelialgrowthfactor(VEGF)andVEGF’sbindingtoitsreceptoronthevascularendo-thelium.SinceVEGFisreleasedbymanycancerstostimulateproliferationofnewbloodvessels,thecombinationofbevacizumabandchemotherapywasfoundtoincreaseobjective
responses,mediantimetoprogression,andsur-vivalinpatientswithmetastaticcolorectalcancer,comparedwithchemotherapyalone,butearlierpreclinicalstudiesindicatedthatanti-VEGFantibodieswereactivealone,aswellasincombinationwithradiation.22,95,96Itiscurrentlybeingstudiedclinicallyinrenalcell,breast,andlungcancers,aswellasinanumberofothernonhematologicalandhematologicalmalignancies.97–99Asmightbeexpected,bev-acizumabmaycausegastrointestinalperfora-tionsanddelayedwou
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