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1、银屑病的生物治疗BiologicaltherapiesforpsoriasisChronicPlaquePsoriasisT-cellmediateddiseaseMenandwomenaffectedequallyGeneticcomponentCircumscribed,raised,redplaquesScaly,itchy,cracking,bleedingModeratetoseverecharacterizedby>10%bodysurfaceareainvolvement,butcanbeu
2、pto98%Life-longdiseasewithnocureConceptbasedon:KruegerJG.JAmAcadDermatol.2002;46:1-23.Cytokine productionKeratinocyte hyperproliferationInflammatory responseT-cellActivation,Proliferation,andCytokineProductionActivatedAPCT-cellImmunologicSynapseICAMLFA-1M
3、HCTCRCD4/CD8LFA-3CD2CD40CD40LB7CD28ICAMLFA-1CostimulatoryMoleculesCD3Costimulatory SignalsCD11aAntigen-PeptideT-cell ActivationSignalsT-cellactivationBiologicalTherapiesofPlaquePsoriasisICAMCD11aLFA-3CD2B7CD28anti-CD11aEfalizumabLFA3-IgAlefaceptCTLA4-IgAb
4、ataceptT-cellactivationInhibitorCytokineInhibitorTNFR-IgEternacetAnti-TNFInfliximabHumanizedmAbIgG1 kappahumanframeworkcontainingmurineantibodycomplementarity-determiningregions(CDRs) (MW150kd)GENENTECHBlocksinteractionbetweenLFA-1onT-cellandintracellular
5、adhesionmolecule(ICAM)onAPC,endotheliumandkeratinocytesEfalizumab（Raptiva）CharacteristicsHeavychainLightchainHeavychainCDRLightchainCDRCarbohydratesPhaseIstudy(HU9602)Thisstudyinvestigatedsingleintravenous(IV)doses(0.03,0.1,0.3,0.6,1.0,2.0,3.0or10.0mg/kg)
6、ofefalizumabadministeredinadose-escalationmannerto31subjectsmoderatetosevereplaquepsoriasis.PhaseIstudyConclusionsTheIVdosageof0.6mg/kg/wkwasthelowestIVdosagethatconsistentlyproducedthemaximalPDeffect.TheSCdosagewasexpectedtobe1.0mg/kg/wkbasedontheestimat
7、eofapproximately50%bioavailabilitywiththeSCdosagerelativetoIVadministration.Theaveraget1/2forSCefalizumab1.0mg/kg/wkis5.5daysAlthoughpeakserumconcentrationafterthelastdose(Cmax)washigherforthe2.0mg/kg/wk(30.9μg/mL)thanforthe1.0mg/kg/wkdosage(12.4μg/mL),no
8、additionalchangesinPDeffectswereobservedatthehigherdosagesC-EFF-EfalizumabStudy2390: PivotalPhaseIIIEfficacyStudyRandomizationDay0ScreenPrimaryAnalysisWeek12(Day84)Placebo(n=187)Raptiva1mg/kg(n=369)EntrancecriteriaP
