癌症的靶向治疗：抗体和免疫偶联物的新前景Targeted Therapy of Cancer - New Prospects for Antibodies and Immunoconjugates

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‘arms.’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