The NMDA Receptor Antibody Paradox: A Possible Approach ...

Anti-NMDAR encephalitis is a devastating autoimmune condition characterized by the onset of psychiatric manifestations including psychosis, ... ThisarticleispartoftheResearchTopic UpdateonTranslationalNeuroimmunology-ResearchofISNI2018 Viewall 21 Articles Articles FabienneBrilot TheUniversityofSydney,Australia MariaPiaGiannoccaro UniversityofBologna,Italy KeikoTanaka NiigataUniversity,Japan JennyLinnoila MassachusettsGeneralHospital,HarvardMedicalSchool,UnitedStates Theeditorandreviewers'affiliationsarethelatestprovidedontheirLoopresearchprofilesandmaynotreflecttheirsituationatthetimeofreview. Abstract Introduction TheNMDAReceptor AuthorContributions Funding ConflictofInterest References SuggestaResearchTopic> DownloadArticle DownloadPDF ReadCube EPUB XML(NLM) Supplementary Material Exportcitation EndNote ReferenceManager SimpleTEXTfile BibTex totalviews ViewArticleImpact SuggestaResearchTopic> SHAREON OpenSupplementalData MINIREVIEWarticle Front.Neurol.,03July2020 |https://doi.org/10.3389/fneur.2020.00635 TheNMDAReceptorAntibodyParadox:APossibleApproachtoDevelopingImmunotherapiesTargetingtheNMDAReceptor DeborahYoung1,2* 1MolecularNeurotherapeuticsLaboratory,DepartmentofPharmacologyandClinicalPharmacology,TheUniversityofAuckland,Auckland,NewZealand 2CentreforBrainResearch,TheUniversityofAuckland,Auckland,NewZealand N-methyl-D-aspartatereceptors(NMDAR)playakeyroleinbraindevelopmentandfunction,includingcontributingtothepathogenesisofmanyneurologicaldisorders.ImmunizationagainsttheGluN1subunitoftheNMDARandtheproductionofGluN1antibodiesisassociatedwithneuroprotectiveandseizure-protectiveeffectsinrodentmodelsofstrokeandepilepsy,respectively.WhilstthesedatasuggestthepotentialforthedevelopmentofGluN1antibodytherapy,paradoxicallyGluN1autoantibodiesinhumansareassociatedwiththepathogenesisoftheautoimmunediseaseanti-NMDAreceptorencephalitis.ThisreviewdiscussespossiblereasonsforthedifferentialeffectsofGluN1antibodiesonNMDARphysiologythatcouldcontributetothesephenotypes. Introduction Antibody-basedimmunotherapiesformakeycomponentofthepharmacologicalarsenalfortreatmentofcancer(1),andinflammatorydiseases(2),withprofoundclinicalsuccessachievedfortheseconditions.Monoclonalantibodytherapieshaveseveraldesirableattributesovertraditionalsmallmoleculedrugsincludinglonghalf-livesandhighspecificityforthetargetmoleculardiseasedriverleadingtoreducedoff-targettoxicityandaloweradverseeffectprofile.ThepipelineofimmunotherapiesforcentralnervoussystemdisordersisnotasextensiveandhaslargelybeendominatedbyactiveorpassiveimmunizationapproachesforAlzheimer'sdiseaseandParkinson'sdiseasethataimtomodifydiseaseprogressionbytargetingproteinsimplicatedindiseasepathogenesis(3).Differentstrategieshavebeenemployedincludingusingantibodiestoneutralizetheactionsofputativeneurotoxicproteinspeciesortopromoteclearanceoftheoffendingdiseaseprotein.Clinicaltrialshaveshownsomepromise(4),butmuchworkisstillrequiredtoimprovethetherapeuticefficacyoftheseapproaches. Thepotentialofantibodiestomodulatethefunctionofothermoleculartargetsinthecentralnervoussystem(CNS)fortherapeuticbenefithasnotbeenextensivelyinvestigated.Inthisreview,Iwillprovideanoverviewofourstudiesandthoseofothersexploringthepossibilityofanimmunoprotectiveapproachforneurologicaldiseasesincludingstrokeandepilepsyinvolvingantibody-mediatedtargetingoftheN-methyl-D-aspartate(NMDAR)subclassofglutamatereceptor. TheNMDAReceptor TheNMDARplaysapivotalroleinbraindevelopment,neuronalsurvival,andsynapticplasticityassociatedwithlearningandmemory.Thereceptorisahetero-tetramercomposedoftwoobligatoryGluN1subunitsofwhichthereareeightdistinctsplicevariants,andtwovariablesubunitsfromtheGluN2(GluN2A-2D)orGluN3(GluN3A-3B)subunitfamilies.ThecombinationofGluN1withdifferentGluN2/3familymembersprovidesforthecreationofdiverseNMDARsubtypesvaryingintheirregionaldistributionandfunctionalproperties.ThemajorityofnativeNMDARaretriheteromeric,withGluN1/GluN2A/GluN2Breceptorsbeingthemostcommonsubtypeinforebrainexcitatoryneurons(5). Thesubunitsaretransmembrane-spanningandarrangedtoformanionchannelporethatisgatedinaligand-andvoltage-dependentmanner.TheextracellularregionsofthereceptorresemblingtwoclamshellstructureswithbindingsitesforglutamateontheGluN2subunitandsitesforglycinebindingontheGluN1subunit.Theinteractionbetweenthedistalaminoterminaldomain(ATD)ofthereceptorandotherproteinsregulatesubtype-specificreceptorassemblyandreceptortraffickingandsitesforallostericmodulationofNMDARfunctionarealsofoundintheATD.ThecytoplasmicC-terminusdomainengagesininteractionswithscaffoldproteinsandintracellularmessengersystemsinthepostsynapticdensity. TheimportanceofNMDARinthemaintenanceofphysiologicalbrainfunctionisunderpinnedbyobservationsthatNMDAR-mediatedhypofunctioncausedbyeitherreceptorloss,oraltereddistributionatsynapses,isimplicatedinneurodevelopmental(autismspectrumdisorders)(6)andneuropsychiatricdisorders(schizophrenia)(7).Moreover,excessiveglutamatereleasethatleadstoNMDARoveractivationcontributestoneurodegenerationinacuteorchronicneurodegenerativediseasesincludingAlzheimer'sdisease(8,9).ThecentralityoftheNMDARinthepathophysiologyofabroadrangeofconditionsmakesthesereceptorsanattractivedrugtargetbuthumantrialsofNMDARantagonistsofdifferentcompoundclassesandatdifferentsitesofreceptoractionhavebeendisappointingandareassociatedwithanarrowtherapeuticindexandanunacceptableadverseeffectprofile(10).GreaterinsightintoNMDARfunction,andthediscoverythatsynapticandextrasynapticNMDARmaybedifferentiallylinkedtocellsurvivalvs.celldeathpathways,respectivelyhascontributedtoongoingeffortstodevelopsubunit-selectiveNMDARantagonists.WeakerGluN2B-selectiveblockersthatmaypreferentiallytargetextrasynapticNMDARhaveamuch-improvedside-effectprofileinhumansthanearlygenerationbroadspectrumantagonists(11).OtherapproachestoamplifytheNMDAR-mediatedcellsurvivalsignalingwarrantinvestigation. TheNMDAReceptorasanImmunotherapeuticTarget WepreviouslydescribedanimmunotherapeuticapproachforstrokeandepilepsyinvolvingtargetedvaccinationagainsttheGluN1subunitoftheNMDAR(12).Ratsgeneticallyimmunizedtoexpressafull-lengthGluN1subunitproteindevelopedhigh-titerserumGluN1autoantibodiesandweremoreprotectedinratmodelsoftemporallobeepilepsyandstroke.Systemicinjectionoftheneurotoxinkainatehasbeenusedextensivelytoinduceseizureactivityandapatternofselectiveneuronalcelllossinthehippocampusthatrecapitulatestheneuropathologicalfeaturesobservedinhumantemporallobeepilepsy(13).Wefoundthatfollowingachallengewithkainate,fewerGluN1-vaccinatedrats(22vs.68%control-vaccinatedrats)developedseizuresandofthetwoanimalsthatexperienced45minofprolongedstatusepilepticus,onlyoneshowedevidenceofneuronalcelldeathinthehippocampus.Moreover,inamiddlecerebralarteryocclusionmodelofischaemicstroke,infarctlesionsizesfortheGluN1-vaccinatedanimalsweresignificantlysmallercomparedtothecontrol-vaccinatedanimalsfollowinginfusionofendothelin-1(12).Wedidnotdetectanyevidenceofcell-mediatedimmuneresponsessuggestingtheprotectivephenotypeislikelytobeGluN1antibody-mediated.Moreover,GluN1IgGwasdetectedatlowlevelsinthecerebrospinalfluid(CSF)ofGluN1-vaccinatedratsunderbasalconditionspriortoanyinsultandGluN1antibodiesareboundtoantigensuggestinglow-levelpassageacrossanintactbloodbrainbarrier(BBB)(12).Ithasbeenestimatedthat0.1%ofsystemicIgGareabletotrafficthroughtheBBBintothebrainparenchyma(14).Inindividualanimals,wefoundthatGluN1antibodiesreactedpreferentiallywithafewspecificextracellularepitopesratherthanabroadrangeofepitopes.Toidentifyregionsofimportance,weimmunizedratswithrecombinantGluN1peptidesthatcontributetovariousfunctionaldomainsoftheNMDAR(15).DifferentialeffectsonseizureexpressionandinjurybetweenthedifferentGluN1peptidetreatmentswereobserved.Theseresultsalsoconfirmedtheprotectivephenotypeisnotauniquefeatureoftheimmunizationapproachused.Almostnohippocampalcelldeathwasobservedinratsimmunizedwithapeptideconsistingofaminoacids654–800ofGluN1(GluN1[654–800])despiteextensivekainate-inducedseizuressufficientindurationandintensitytoinduceneuronalcelldeath.Incontrast,ratsimmunizedwithaGluN1peptidecoveringaminoacids21–375(GluN121–375)wasassociatedwithreducedseizureseverityasassessedbya5-pointseizureratingscalefollowingkainatechallengebuthippocampalcelldeathwasclearlyevidentintheserats.Expressionofheatshockprotein70(HSP70)andbrain-derivedneurotrophicfactor(BDNF)proteinwereelevatedby~1.5-foldinthebrainsoftheGluN1[654–800]-vaccinatedanimalsthatwereprotectedagainstneuronalcelldeathcomparedtothecontrolanimals(naïveandHomer1aimmunized)suggestingthatGluN1antibody-mediatedeffectsatNMDARleadstodownstreamupregulationofsignalingpathwayslinkedtocellsurvival.TheseresultsindicatethatGluN1antibodiestospecificfunctionaldomainsoftheNMDARareabletoinduceastateoftolerancetoinsultakintopreconditioningwherebyshort-termexposuretoNMDARantagonists(16,17)orNMDARactivation(18)caninduceastateofresistancetosubsequentinsult. OurstudiessuggestthataGluN1immunotherapycouldhavebroadutilityforarangeofneurodegenerativedisordersbutfurthermechanisticcharacterizationisrequiredtoassessthefeasibilityandsafetyofsuchanapproach.Thisisofcriticalimportanceaswithinthelastdecade,NMDARautoantibodiestargetingtheGluN1subunithavebeenlinkedtothepathogenesisoftheautoimmunediseaseNMDARencephalitis. AutoimmuneDiseasesAssociatedWithNMDARAntibodies Anti-NMDARencephalitisisadevastatingautoimmuneconditioncharacterizedbytheonsetofpsychiatricmanifestationsincludingpsychosis,rapidmemorylossandseizuresandthepresenceofhigh-titerCSFautoantibodiesoftheIgGclassagainsttheGluN1subunit(19–21).Theconditionismoreprevalentinwomen,andassociatedwiththeectopicexpressionofNMDARproteinsinovarianteratomaalthoughtherearealsoaffectedindividualswhodonothavedetectabletumors(21,22).TheclinicalfeaturesinpatientsandanimalmodelsresemblethosecausedbygeneticorpharmacologicalattenuationofNMDARfunction.Indeed,evidencefromstudiesexaminingtheeffectofpatientantibodiesincellandanimalmodelshaveledtothehypothesisthattheclinicalsyndromeisasaresultofNMDARhypofunctionatanetworklevel.PatientGluN1autoantibodiescross-linkNMDARexpressedonculturedneuronsthattriggerstheirlossatthesynapsebyinternalizationatextrasynapticsites.Similarly,cerebroventricularinfusionofpatientNMDARantibodiesintorodentbraindecreasesNMDARexpressionlevelsleadingtoimpairedsynapticplasticitythatisassociatedwithmemorydeficits,anhedonia,depression-likebehavior,andalowseizurethreshold(23–26).DepletedNMDARexpressionisconsistentwithobservationsinpost-mortembrainfromhumanswithanti-NMDARencephalitis(23,24,27).TheeffectsofpatientantibodiesarespecifictoNMDARasnoeffectonexpressionofAMPAreceptorsorothersynapticproteinsarefound(27,28). WhilsttheroleofGluN1autoantibodiesindiseasepathogenesishasbeenthekeyfocus,morerecentlyamousemodelofNMDARencephalitisinvolvingactiveimmunizationwithintactnative-likeNMDARGluN1/GluN2Btetramersembeddedinaliposomescaffoldhasbeendescribedthatrecapitulatesabroaderrangeoffeaturesreminiscentofthatfoundinthehumandisease(29).Immunizedmicedevelopedovertneurologicalsignsincludemarkedhyperactivityandstereotypicmotorfeaturesincludingtightcircling,seizures,andahunchedposture,orlethargyasearlyas4weeks,withnearlyallanimalsshowingabnormalbehaviorsby6weeks.Thiswasassociatedwithinfiltrationofperipheralimmunecellsandneuroinflammationby6weeksassupportedbyincreasedimmunoreactivitytomarkersofplasmacells,CD4-positiveTcells,andCD20-positiveBcells,activatedmicroglia,andastrocytesgliosis.Neuronallosswasrare.SerumautoantibodiesthattargetepitopesonGluN1waspredominantbutreactivitytoGluN2subunitsaswellasapeptidethatlackedtheamino-terminaldomainofGluN1wasalsoobservedbyWesternblotinthemicetestedsuggestingapolyclonalresponsebythetimefulminantsymptomswerepresentat6weeksafterimmunization.ChronicexposureofculturedhippocampalneuronstoserumautoantibodiesreducedNMDARproteinexpressionandassociatedNMDAR-mediatedcurrentswithoutaneffectonsynapsenumbers(29).StudiesofNMDARencephalitisinhumanshasfocusedontheroleoftheautoantibodies,butthisstudysuggeststhatmatureTcellsarealsoinvolvedincausingamorecomplexdiseasepathogenesisleadingtobroaderrepertoireofsymptomsbypromotingneuroinflammationandpotentiatingBcell-andplasmacell–mediatedantibodyresponses.TheuseofconformationallystableNMDARholoproteinsmaybeacriticalcomponentininitiatingamorecomplexpatternofimmunogenicity. TheNMDARAutoantibodyParadox Thepathogeniceffectsinducedbypatientantibodiescontrastsharplytotheprotectivebenefitachievedinourstudiesinrodentmodels.SingleaminoacidsubstitutionsatkeyresidueswithintheextracellularregionsoftheGluN1subunitcansignificantlyaffectchannelpermeability(30),soitisentirelyplausiblethatsite-specifictargetingbyGluN1antibodiestodifferentextracellularregionsontheNMDARcouldhavedifferentialeffectsonreceptorfunctionordistribution.OurobservationsshowingdistinctdifferencesbetweeneffectsonseizureexpressionandneuroprotectiveeffectsfollowingimmunizationwithdifferentGluN1peptidefragmentprovidesupportforthishypothesis(15).Usingalibraryofpeptidesthatspantheentire938aminoacidsofthenativeGluN1subunitasascreeningplatform,wefoundthatGluN1IgGantibodiesfromindividualratsgeneticallyvaccinatedwithGluN1cDNAreactmostcommonlywithpeptidesthatcorrespondtodomainsthatformpartoftheextracellularvestibuleoftheNMDAreceptorchannel,includingregionsimportantforglycinebinding(12).Similarly,wefoundneuroprotectionwasassociatedwithGluN1antibodiestargetingtheGluN1[654–800]regionthatcontributestotheS2loopoftheglycinebindingdomain(15).Wedevelopedarecombinantproteinconsistingoftheextracellularpre-TM1regionthatincludestheamino-terminaldomain(ATD)linkedtotheextracellularloopbetweenTM3-4domainsofGluN1andimmunizedgroupsofratswiththisrecombinantprotein(recGluN1).WefoundthatthehumoralresponsefollowingimmunizationwiththisproteingeneratedGluN1antibodiesthatpreferentiallyreactedwithpeptidesthatcorrespondtodomainsimportantforglycinebindingwhenwescreenedanIgGfractionpurifiedfrompooledratserumagainstourGluN1peptidelibrary.StructuralmodelingpredictsthatthebindingofGluN1antibodytothistargetregionwouldpromoteclosureoftheNMDARionchannel(31). Incontrast,NMDARpatientautoantibodiesrecognizeconformationalepitopesattheGluN-ATD(28).ScreeningofpatientautoantibodiesagainstaseriesofGluN1proteindeletionmutantsshowedaminoacidresiduesN368/G369attheGluN1-ATDwerecrucialforthecreationofreactivityofpatientantibodies.Moreover,patientantibodiesdidnotimmunostainaGluN1proteinlackingtheATD,suggestingthattheseantibodiesdonottargetregionsimportantinglycinebinding(28).TheGluN1-ATDisamajorlocusforinteractionsbetweentheNMDARandvarioussynapticproteinsthatregulatethetrafficking,surfacedistribution,andfunctionofNMDAR(32,33).AnybiologicagentordrugcompoundcapableofmodifyingtheseinteractionscouldhavesignificanteffectsonNMDARsignaling.Mechanistically,NMDARencephalitispatientantibodiesblocktheabilityofEphrinBreceptorstoregulatesynapticNMDARnumbers(33),leadingtotheirdepletionandastateofNMDARhypofunction(20,27,34). Conversely,neuroprotectioninmousemodelsofstrokeandexperimentalautoimmuneencephalitiscanbeproducedusingGluN1antibodiesthattargettheinteractionsiteoftheserineproteasetissueplasminogenactivator(tPA)attheATD(35–37).GluN1antibodiesdirectedagainstanepitopeataminoacids163–192aswellasGlunomab,amonoclonalantibodythatinteractswiththelysineresidueatposition178,blocksthetPA-mediatedpotentiationofNMDAR-mediatedsignalingandexcitotoxicityinneuronsbyreducingthesurfacedynamicsandclusteringofextrasynapticNMDAR(36–39).ThetherapeuticbeneficitengenderedbytheseGluN1antibodiesarenotrestrictedtoactionsatneuronalNMDAR,withGlunomabshowntopromotethemaintenanceofbloodbrainbarrierintegrityviaactionsonNMDARexpressedonendothelialcells(36,37).Ofnote,inourownworkwefoundGluN1antibodiesthatinteractwiththeglycinesiteonNMDARexpressedonplateletscaninhibitplateletfunctionandthrombusformationthatcouldalsocontributetolimitingstroke-inducedneuronaldamage(31)suggestinganytherapeuticbenefitcouldoccurthroughadditiveeffectsatmultiplecellsites.FurtherinvestigationisrequiredtounderstandthefullspectrumofeffectsontherapeuticGluN1antibodiesincludingtheimpactonNMDAR-dependentprocessessuchaslearningandmemory.GluN1-ATDantibodieshavebeenreportedtoimpairhippocampal-dependentspatialmemoryinrodents(35,39,40)althoughalaterstudysuggestedthattheGluN1-ATDantibodiesarenotassociatedwithcognitiveorbehavioraldeficits(36). Altogether,thesedatasuggestthatNMDAreceptorlocation,andfunction,canbedifferentiallymodulatedbyGluN1antibodiesinatarget-dependentmannerwithGluN1immunotherapeuticbenefitmadefeasiblethroughstrategictargetingtodefinedsites.Whatarethechallengesforapplyingsuchanapproach,forexample,asapreventativetreatmentagainststroke-induceddamageinhumans? ChallengesforaGluN1Immunotherapy—theRoleofGluN1AutoantibodiesinHealthandDisease Inpreclinicalstudies,GluN1antibodiesgeneratedfollowingimmunizationofnaïveanimalsarepresumedtobeabletofreelyinteractwiththeirtargetsitefollowingpassageintothebrain.HowthetherapieswouldperforminhumanswithpreexistingserumantibodiesdirectedagainsttheNMDARthatcoulddirectlycompeteforthesameepitopetargets(ifpresentinsufficientquantities),isunknown.SerumGluN1autoantibodiesarefoundinhealthyolderadultsandthereisincreasedseroprevalence(>20%)inindividualsaffectedbyawide-rangeofdiseasesincludingstroke,neuropsychiatricillnesses,anddementia(41–45),witharecentstudysuggestingGluN1autoantibodiesmaybepartofthenormalautoimmunerepertoire(46).Thesignificanceoftheseantibodiesincontributingtofunctionaloutcomesintheseconditionsisanareaofcurrentinvestigation.UnlikeNMDARencephalitisthatisprimarilyassociatedwiththeoccurrenceofIgGGluN1antibodies,GluN1IgA,andIgMantibodiesaremainlyfoundinnon-specificallyinhealthyolderadultsandindiseaseconditions(44,47).TherearecontradictoryreportsthatGluN1antibodiespromoteNMDARinternalizationirrespectiveofimmunoglobulinclassandepitope,whereasothergroupsfindtheseeffectsareonlyproducedbyNMDARencephalitis-associatedGluN1IgGantibodies(44,46,48),suggestingfurtherinvestigationintoanypossiblepathogeniceffectsisrequired. GluN1autoantibodiesinstrokehavebeenassociatedwithlarger(45)aswellasreducedlesionsizesafteracuteischemicstroke(47).ThediscrepancybetweenthesefindingscoulddependantibodytiteraswellasthehealthoftheBBB.UsingapolipoproteinE4(APOE4)carrierstatusasamarkerforaleakyBBB,thepresenceofpreexistingserumGluN1autoantibodiesatthetimeofacuteischemicstrokewasassociatedwithreducedinfarctsizesinindividualswithanintactBBB(APOE4+/+),howeverlesionsizesappearedtobethelargestinAPOE4carrierswithacompromisedBBB(47).WespeculatethesefindingsareinlinewiththeneuroprotectionobservedinrodentstrokemodelswithanintactBBBatthetimeofinsult(12,36).WhetherourglycinebindingsitetargetingGluN1antibodiespromotemaintenanceofBBBintegritylikeGluN1-ATDantibodiesisunknown(37).RecentdatahasindicatedGluN1antibodyseropositivitywasnotassociatedwithanylong-termfunctionalbenefitat1yearfollowingstroke(49)butfurtherstudiesarerequiredtoexaminewhethertherapeuticbenefitsmightbefoundinspecificpatientsubgroupssuchasAPOE4non-carriers. Therearemanyoutstandingquestions.WhetheraGluN1immunotherapycouldcounteractoroverrideanypossiblepathogeniceffectsproducedbyGluN1autoantibodiesorhelpboosttheneuroprotectivecapabilityofendogenousantibodiesatmultiplelevelsincludingmodulatingNMDARsignalingatneurons,maintainingBBBhealth,andfunctionremainstobedetermined. DeliveryChallengesforCNSImmunotherapeutics AnotherkeychallengeiswhethersufficientamountsofantibodyasoneofthekeydrawbacksofimmunotherapiesforCNSdisordersisthelowefficiencyofdeliveryintothebrain.TheBBBstrictlyregulatestheentryofmoleculesincludingtherapeutics,immunecells,andimmunemediatorsfromthesystemiccirculationintoandoutofthebrain.OsmoticorchemicaldisruptionofBBBintegritycanfacilitatedeliveryoftherapeuticsintothebrainbutthelackofspecificityforthetherapeuticbiologicagentisproblematic.AlternativemethodologieshaveexploitedthepropertiesofendogenousBBBreceptor-mediatedtransportersresponsibleforthepassageofendogenouslargemoleculessuchasinsulin,transferrin,insulin-likegrowthfactor,andleptinintothebrain.ThesecirculatingproteinsbindtotheircognatereceptorsontheluminalsurfaceoftheendothelialcellsliningtheBBB.Uponbinding,thereceptor–ligandcomplexisinternalizedintotheendothelialcellbyreceptor-mediatedendocytosiswheretheligandmoleculeistransportedacrosstheabluminalmembraneoftheendothelialcellintothebrain.MolecularTrojanhorsesthatareengineeredtocarrypeptidesorproteinsligandsthattargetreceptormediatedtransportsystems(e.g.,receptor-bindingsequencesofinsulin)ormonoclonalantibodiesthatspecificallytargettransferrinandinsulinreceptorshavebeenshowntobeeffectiveinfacilitatingdeliveryofvarioustherapeuticproteinsintothebrain(50,51).Progressinantibodyengineeringhasledtothegenerationofdifferentantibodyconfigurationsincludingtheartificialbispecificantibodythatcombinetwoantigen-recognizingcomponentsintoasingleconstruct.BispecificantibodiescouldalsoactasscaffoldstodelivertherapeuticantibodiesintothebrainbyincorporatingonearmwithspecificityagainstaBBBreceptor-mediatedtransportreceptorthatfacilitatespassageacrosstheBBBandthetherapeuticarmthatproducesthepharmacologicaleffect(52).Useofthesetechnologiescoupledwithsite-specifictargetingoftheGluN1couldbeexploredinfuturestudiesifrequired. AuthorContributions DYwrotethepaperandconceivedthiswork. Funding ThisworkwasfundedbygrantsfromBrainResearchNZandtheAucklandMedicalResearchFoundation(1113009)toDY. ConflictofInterest Theauthordeclaresthattheresearchwasconductedintheabsenceofanycommercialorfinancialrelationshipsthatcouldbeconstruedasapotentialconflictofinterest. 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Citation:YoungD(2020)TheNMDAReceptorAntibodyParadox:APossibleApproachtoDevelopingImmunotherapiesTargetingtheNMDAReceptor.Front.Neurol.11:635.doi:10.3389/fneur.2020.00635 Received:30November2019;Accepted:28May2020;Published:03July2020. Editedby:FabienneBrilot,UniversityofSydney,Australia Reviewedby:KeikoTanaka,NiigataUniversity,JapanJennyLinnoila,MassachusettsGeneralHospital,UnitedStatesMariaPiaGiannoccaro,UniversityofBologna,Italy Copyright©2020Young.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(CCBY).Theuse,distributionorreproductioninotherforumsispermitted,providedtheoriginalauthor(s)andthecopyrightowner(s)arecreditedandthattheoriginalpublicationinthisjournaliscited,inaccordancewithacceptedacademicpractice.Nouse,distributionorreproductionispermittedwhichdoesnotcomplywiththeseterms. *Correspondence:DeborahYoung,[email protected] COMMENTARY ORIGINALARTICLE Peoplealsolookedat SuggestaResearchTopic>