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1、REVIEWSOpportunitiesfortherapeuticantibodiesdirectedatG-protein-coupledreceptorsCatherineJ. Hutchings1,MarkusKoglin1,WilliamC. Olson2andFionaH. Marshall1Abstract
2、G-protein-coupledreceptors(GPCRs)areactivatedbyadiverserangeofligands,fromlargeproteinsandproteas
3、estosmallpeptides,metabolites,neurotransmittersandions.Theyareexpressedonallcellsinthebodyandhavekeyrolesinphysiologyandhomeostasis.Assuch,GPCRsareoneofthemostimportanttargetclassesfortherapeuticdrugdiscovery.ThedevelopmentofdrugstargetingGPCRshastherapeuticv
4、alueacrossawiderangeofdiseases,includingcancer,immuneandinflammatorydisordersaswellasneurologicalandmetabolicdiseases.TheprogressmadebytargetingGPCRswithantibody-basedtherapeutics,aswellastechnicalhurdlestoovercome,arepresentedanddiscussedinthisReview.Antibod
5、ytherapeuticstargetingC-Cchemokinereceptortype4(CCR4),CCR5andcalcitoningene-relatedpeptide(CGRP)areusedasillustrativeclinicalcasestudies.G-protein-coupledreceptors(GPCRs)constituteoneoveranother.Suchligandsaretermed‘biased’andmayofthelargestsuperfamiliesofpro
6、teinsencodedbytheshowdifferentin vivopropertiesandside-effectprofileshumangenomewithmorethan800familymembers,comparedwithother,non-biasedligands12,13.Agonisticincluding~370non-olfactoryreceptors1.Aberrantsignal-antibodiesthatbindtoGPCRsmayalsoexhibitasimilarl
7、ingormutationsinGPCRs,Gproteinsordownstreambiaswithrespecttodownstreamsignallingpathways14signallingpathwayshavebeenimplicatedinmanydis-andmayalsodifferfromsmall-moleculeligandsineases2–4,andpharmacologicalmodulationofGPCRshastheircapacitytoinducereceptordese
8、nsitizationduringbeensuccessfullyusedinthesymptomatictreatmentofachronicdrugexposure.widerangeofdiseasesinthecardiovascular,endocrine,ThecanonicalGPCRconsistsofanextracellularneuralandimmunesystems.Notsurprisingly,~40%ofamino-terminaldomain15,whichrangesinsiz
9、efromapproveddrugs(includingprescriptiondrugs)mediatearound10to600aminoacids,linkedto7α-helicaltheireffectsthroughGPCRs5,6.GPCRscansignaltoawidetransmembranedomains(TMDs)andanintracellu-r
