Safety, pharmacokinetics, and biologic activity of pateclizumab, a novel monoclonal antibody targeting lymphotoxin α results of a phase I randomized, placebo-controlled trial 英文参考文献.docVIP

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Safety, pharmacokinetics, and biologic activity of pateclizumab, a novel monoclonal antibody targeting lymphotoxin α results of a phase I randomized, placebo-controlled trial 英文参考文献.doc

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Safety, pharmacokinetics, and biologic activity of pateclizumab, a novel monoclonal antibody targeting lymphotoxin α results of a phase I randomized, placebo-controlled trial 英文参考文献

Emuetal.ArthritisResearchTherapy2012,14:R6 /content/14/1/R6 RESEARCH ARTICLE OpenAccess Safety,pharmacokinetics,andbiologicactivityof pateclizumab,anovelmonoclonalantibody targetinglymphotoxina:resultsofaphaseI randomized,placebo-controlledtrial BrindaEmu1,DianaLuca1,CarolynOffutt1,JaneLGrogan1,BernadetteRojkovich2,MarnaBWilliams1, MeinaTTang1,JimXiao1,JuneHLee3andJohnCDavis1* Abstract Introduction:Pateclizumab(MLTA3698A)isahumanizedmAbagainstlymphotoxina(LTa),atransiently expressedcytokineonactivatedBandTcells(Th1,Th17),whichareimplicatedinrheumatoidarthritis(RA) pathogenesis.Thisstudywasconductedtoassessthesafety,tolerability,NOTE:ForclarityandperAMA/S-W Style,pleaserestoretheuseofOxford/serialcommas(ie:Davidlikesvanilla,strawberry,andchocolateicecream) throughout.andbiologicactivityofsingleandmultipledosesofintravenous(IV)orsubcutaneous(SC) pateclizumabinRApatients. Methods:Thesingleascendingdose(SAD)phaseinpatientswithstableRAconsistedofsixcohorts(4:1active: placeboat0.3mg/kgIV,1.0mg/kgIV,1.0mg/kgSC,3.0mg/kgIV,3.0mg/kgSC,and5.0mg/kgIV;n=5/cohort). Inthemultipleascendingdose(MAD)phase,patientswithprespecifiedRAdiseaseactivityreceivedthreedosesof pateclizumaborplacebo(4:1)every2weeks(1.0mg/kgSC,n=10;3.0mg/kgSC,n=20;or5.0mg/kgIV,n=5). Safetyandtolerabilitywereassessedthroughout,andclinicalactivitywasdeterminedafterthreedoses(Week6). Results:Weobservednoseriousadverseevents(AEs)ordose-limitingtoxicities,andthemajorityofAEsweremild tomoderate.Thepharmacokineticprofileswerelinear,andclearancewasindependentofdose.Reductionsin levelsofserumCXCL13wereobserved,supportingthebiologicactivityofpateclizumabontheLTapathway. Patientsreceivingpateclizumabinthe3.0mg/kgMADgroup(3.0mg/kgSC)demonstratedACR20,ACR50,and ACR70responseratesatweek6of75%,56%and25%,respectively,comparedwith57%,29%,and0%inthe placebogroup.ThemedianDiseaseActivityScorein28joints,C-reactiveprotein,reductionwas28%for pateclizumab,versus8.4%forplacebo. Conclusions:Pateclizumabwasgenerallywell-toleratedinRApa