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Antibody-Mediated Targeting of the Orai1 Calcium Channel Inhibits T Cell Function.doc

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Antibody-Mediated Targeting of the Orai1 Calcium Channel Inhibits T Cell Function

Antibody-MediatedTargetingoftheOrai1Calcium ChannelInhibitsTCellFunction JenniferH.Cox1,ScottHussell1,HenrikS?ndergaard2,KirstineRoepstorff3,John-VuBui1 ,Jen RunningDeer4,JunZhang5,Zhan-GuoLi6,KasperLamberth7,PeterHeldingKvist3,S?renPadkj?r8, ClausHaase2,StefanZahn9,ValerieH.Odegard1* 1Department of Cellular Immunology, Novo Nordisk Research Center, Seattle, Washington, United States of America, 2Department of Immunopharmacology, Novo NordiskA/S,Mal?v,Denmark,3DepartmentofHistology,NovoNordiskA/S,Mal?v,Denmark,4DepartmentofMolecularImmunology,NovoNordiskResearchCenter, Seattle, Washington, United States of America, 5Department of Cell Biology, Beijing Novo Nordisk Pharmaceuticals Science Technology Co., Beijing, China, 6DepartmentofRheumatologyImmunology,BeijingUniversityPeople’sHospital,Beijing,China,7DepartmentofScreeningandCellTechnology,NovoNordiskA/S, Mal?v,Denmark,8DepartmentofProteinStructureandBiophysics,NovoNordiskA/S,Mal?v,Denmark,9DepartmentofAntibodyTechnology,NovoNordiskA/S,Mal?v, Denmark Abstract Despitetheattractivenessofionchannelsastherapeutictargets,therearenoexamplesofmonoclonalantibodiesdirected againstionchannelsinclinicaldevelopment.Antibody-mediatedinhibitionofionchannelscouldofferadirected,specific therapeuticapproach.Toinvestigatethepotentialofinhibitingionchannelfunctionwithanantibody,wefocusedonOrai1, theporesubunitofthecalciumchannelresponsibleforstore-operatedcalciumentry(SOCE)inTcells.EffectorTcellsare keydriversofautoimmunediseasepathogenesisandcalciumsignalingisessentialforTcellactivation,proliferation,and cytokineproduction.Weshowherethegenerationofaspecificanti-humanOrai1monoclonalantibody(mAb)againstan extracellularloopoftheplasmamembrane-spanningprotein.Theanti-Orai1mAbbindsnativeOrai1onlymphocytesand leadstocellularinternalizationofthechannel.Asaresult,Tcellproliferation,andcytokineproductionisinhibitedinvitro.In vivo,anti-Orai1mAbisefficaciousinahumanTcell-mediatedgraft-versushostdisease(GvHD)mousemodel.Thisstudy demonstrates