A Strategy for Adenovirus Vector Targeting with a Secreted Single Chain Antibody 英文参考文献.docVIP

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A Strategy for Adenovirus Vector Targeting with a Secreted Single Chain Antibody 英文参考文献.doc

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A Strategy for Adenovirus Vector Targeting with a Secreted Single Chain Antibody 英文参考文献

AStrategyforAdenovirusVectorTargetingwitha SecretedSingleChainAntibody JoelN.Glasgow1,2*,GalinaMikheeva3,VictorKrasnykh3,DavidT.Curiel2 1DivisionofCardiovascularDisease,DepartmentsofMedicine,ObstetricsandGynecology,Pathology,Surgery,andtheGeneTherapyCenter,UniversityofAlabamaat Birmingham, Birmingham, Alabama, United States of America, 2Division of Human Gene Therapy, Departments of Medicine, Obstetrics and Gynecology, Pathology, Surgery,andtheGeneTherapyCenter,UniversityofAlabamaatBirmingham,Birmingham,Alabama,UnitedStatesofAmerica,3DepartmentofExperimentalDiagnostic Imaging,UniversityofTexasM.D.AndersonCancerCenter,Houston,Texas,UnitedStatesofAmerica Abstract Background: Successful gene therapy will require targeted delivery vectors capable of self-directed localization. In this regard,theuseofantibodiesorsinglechainantibodyfragments(scFv)inconjunctionwithadenovirus(Ad)vectorsremains anattractivemeanstoachievecell-specifictargeting.However,alongstandingbarriertothedevelopmentofAdvectors withgeneticallyincorporatedscFvshasbeenthebiosyntheticincompatibilitybetweenAdcapsidproteinsandantibody- derivedspecies.Specifically,scFvrequireposttranslationalmodificationsnotavailabletoAdcapsidproteinsduetotheir cytoplasmicroutingduringproteinsynthesisandvirionassembly. Methodology/PrincipalFindings:WehavethereforesoughttodevelopscFv-targetedAdvectorsusingasecretedscFvthat undergoestherequisiteposttranslationalmodificationsandistraffickedforsecretion.FormationofthescFv-targetedAd vectorisachievedviahighlyspecificassociationoftheAdvirionandatargetingscFvemployingsyntheticleucinezipper- like dimerization domains (zippers) that have been optimized for structural compatibility with the Ad capsid and for associationwiththesecretedscFv.Ourresultsshowthatzipper-containingAdfibermoleculestrimerizeandincorporate intomaturevirionsandthatzipperscanbegeneticallyfusedtoscFvwithoutablatingtargetrecognition.Mostimportantly, weshowthatzipper-taggedvirionsandscFvprovidetarget-specificgenetrans