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1、MAJORARTICLEDevelopmentandCharacterizationofaSevereAcuteRespiratorySyndromeAssociatedCoronavirusNeutralizingHumanMonoclonalAntibodyThatProvidesEffectiveImmunoprophylaxisinMiceThomasC.Greenough,1GregoryJ.Babcock,2AnjeanetteRoberts,3HectorJ.Hernandez,2WilliamD.Thomas,Jr.,2JenniferA.Cocci
2、a,2RobertF.Graziano,4MohanSrinivasan,4IsraelLowy,4RobertW.Finberg,1KantaSubbarao,3LeatriceVogel,3MohanSomasundaran,1KatherineLuzuriaga,1JohnL.Sullivan,1andDonnaM.Ambrosino21DepartmentsofPediatricsandMedicine,PrograminMolecularMedicine,UniversityofMassachusettsMedicalSchool,Worcester,an
3、d2MassachusettsBiologicLaboratories,UniversityofMassachusettsMedicalSchool,JamaicaPlain;3LaboratoryofInfectiousDiseases,NationalInstituteofAllergyandInfectiousDiseases,NationalInstitutesofHealth,Bethesda,Maryland;4Medarex,Inc.,Bloomsbury,NewJerseyBackground.Severeacuterespiratorysyndro
4、me(SARS)remainsasignificantpublichealthconcernaftertheepidemicin2003.Humanmonoclonalantibodies(MAbs)thatneutralizeSARS-associatedcoronavirus(SARS-CoV)couldprovideprotectionforexposedindividuals.Methods.Transgenicmicewithhumanimmunoglobulingeneswereimmunizedwiththerecombinantmajorsurface
5、(S)glycoproteinectodomainofSARS-CoV.Epitopesof2neutralizingMAbsderivedfromthesemiceweremappedandevaluatedinamurinemodelofSARS-CoVinfection.Results.BothMAbsboundtoSglycoproteinexpressedontransfectedcellsbutdifferedintheirabilitytoblockbindingofSglycoproteintoVeroE6cells.Immunoprecipitat
6、ionanalysisrevealed2antibody-bindingepitopes:oneMAb(201)boundwithinthereceptor-bindingdomainataa490510,andtheotherMAb(68)boundexternallytothedomainataa130150.Micethatreceived40mg/kgofeitherMAbpriortochallengewithSARS-CoVwerecompletelyprotectedfromvirusreplicationinthelungs,anddosesaslo
7、was1.6mg/kgofferedsignificantprotection.Conclusions.TwoneutralizingepitopesweredefinedforMAbstoSARS-CoVSglycoprotein.AntibodiestobothepitopesprotectedmiceagainstSARS-CoVchallenge.ClinicaltrialsareplannedtotestMAb201,afullyhumanMAbspecificfortheepitopewithinthereceptor-bindingregion.Seve
