Rise and Fall of an Anti-MUC1 Specific Antibody 英文参考文献.docVIP

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Rise and Fall of an Anti-MUC1 Specific Antibody 英文参考文献.doc

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Rise and Fall of an Anti-MUC1 Specific Antibody 英文参考文献

RiseandFallofanAnti-MUC1SpecificAntibody HolgerThie1.¤a,LarsToleikis1.¤b,JiandongLi1¤c,ReinhardvonWasielewski2¤d,GuntherBastert3¤e ThomasSchirrmann1,IsabelTouraisEsteves4,ChristianK.Behrens4,Be′ne′dictFournes4 ,Nathalie Fournier4,ChristophedeRomeuf4,MichaelHust1,StefanDu¨bel1* , 1TechnischeUniversita¨tBraunschweig,Institutfu¨rBiochemieundBiotechnologie,Braunschweig,Germany,2HannoverMedicalSchool,InstituteofPathology,Hannover, Germany,3Universita¨tsfrauenklinik Heidelberg,Heidelberg,Germany,4LFBBiotechnologies-ResearchDepartment,Lille,France Abstract Background:Sofar,humanantibodieswithgoodaffinityandspecificityforMUC1,atransmembraneproteinoverexpressed onbreastcancersandovariancarcinomas,andthusapromisingtargetfortherapy,wereverydifficulttogenerate. Results:AhumanscFvantibodywasisolatedfromanimmunelibraryderivedfrombreastcancerpatientsimmunisedwith MUC1. The anti-MUC1 scFv reacted with tumour cells in more than 80% of 228 tissue sections of mamma carcinoma samples,whileshowingverylowreactivitywithalargepanelofnon-tumourtissues.Bymutagenesisandphagedisplay, affinityofscFvswasincreasedupto500foldto5,7610210M.Half-lifeinserumwasimprovedfrombelow1daytomore than4weeksandwascorrelatedwiththedimerisationtendencyoftheindividualscFvs.ThescFvboundtoT47DandMCF-7 mammaliancancercelllineswerereclonedintothescFv-FcandIgGformatresultingindecreaseofaffinityofonebinder. TheIgGvariantswiththehighestaffinityweretestedinmousexenograftmodelsusingMCF-7andOVCARtumourcells. However,theexperimentsshowednosignificantdecreaseintumourgrowthorincreaseinthesurvivalrates.Tostudythe reasons for the failure of the xenograft experiments, ADCC was analysed in vitro using MCF-7 and OVCAR3 target cells, revealingalowADCC,possiblyduetointernalisation,asdetectedforMCF-7cells. Conclusions: Antibody phage display starting with immune libraries and followed by affinity maturation is a powerful strategytogeneratehighaffinityhumanantibodiestodifficulttargets,inthiscaseshownbythecreationofahighlyspecific ant