psoriasis: therapeu.c advances based on increased … · 2018-01-28 · il-23/th17 pathway in...
TRANSCRIPT
Psoriasis:Therapeu.cAdvancesBasedonIncreasedUnderstandingof
DiseasePathways
JamesG.Krueger,MDPhDProfessorandLaboratoryHeadTheRockefellerUniversity
Conflicts• Researchsupport,consul.ng,orlecturefeesbymostpharmaandbiotechcompanieswithapsoriasisproductorinves.ga.onalagentduringthepast20years
• Nopatents,ownership,orfinancialgainfromanypsoriasisproductordrug
Immune-MediatedInflammatoryDiseasesaffectatleast1:10PeopleWorldwide• Skin:PsoriasisVulgaris,AtopicDerma..s,AlopeciaAreata,
Vi.ligoandnumerousothers• Diges.veSystem:Crohn’sDisease,Ulcera.veColi.s,and
Type1Diabetes• Skeletal:RheumatoidArthri.s,Psoria.cArthri.s• CNS:Mul.pleSclerosis• Respiratory:Asthma• Mul.-organ:SystemicLupus,SystemicSclerosis
PsoriasisVulgaris
• Themostsuccessfulcaseofmoleculartherapeu.ctarge.nginahumanimmune-mediateddisease
• Withasingledrugcannowcontrolpsoriasisextremelywellin~80-90%ofpa.ents
• Nowhavedrugsthatdirectlytargetelementsofgene.c/genomicdiseaserisk
Genera.onsofPathogenicModels• 1st-SimpleT-cellmodel(agnos.cofT-cellpolarity)• 2nd-PolarT-cellmodel(IL-12/Th1T-cells)• 3rd-InnateImmunityModel--ItsTNFandnotT-cells• 4th-ComplexT-cellModel(Th1,Th17&Th22T-cells)• 5th-IL-23/T17T-cellmodel--Type17T-cells(Th17,Tc17,innatelymphocytessynthesizeIL-17undercontrolofIL-23)
Psoriasisvulgaris
Anautoimmuneskindiseaseassociatedwithincreasedsystemicinflamma.onthatimpactsoverallhealthandlifespan
Phenotypesofpsoriasis• Thecellular(histologic)diseasedefini.on• Themoleculardefini.onbasedongeneexpression
Howarethesefeaturescreatedbyimmune-derivedcytokinesandhowdoestarge.ngthosecytokineswith
immuneantagonistschangethephenotypes?
Unaffected Skin of Patient Psoriasis Lesion
Histopathologyofnormalappearingbackgroundskinandapsoriasisplaque(bothatsamemagnifica.on).
CD3+T-cellsinPsoriasisUninvolvedSkin PsoriasisPlaque
Immunocompetentcellsinpsoriasis.Insituimmunophenotypingbymonoclonalan<bodies.BosJDetal.ArchDermatolRes.1983;275(3):181-9.Predominanceof"memory"Tcells(CD4+,CDw29+)over"naive"Tcells(CD4+,CD45R+)inbothnormalanddiseasedhumanskin.BosJDetalArchDermatolRes.1989;281(1):24-30.
NON-LESIONALLESIONAL
S100A7
Psoriasin(S100A7)isaproteinfirstisolatedfromscalesofpsoria.clesions.
NON-LESIONALLESIONAL
HBD-2
LCN-2
HBD2(β-defensin)andlipocalin2(LCN2)arean.-microbialproteins
NON-LESIONAL PSORIASIS PLAQUE
H&E
CD11c
Myeloid(CD11c+)Dendri.cCellsinPsoriasis
CD3 cell counts
NL LS
0
50
100
150
200
250
300
350
CD11c cell counts
NL LS
0
100
200
300
400
500
600
Langerin cell counts
NL LS
0
25
50
75
100
125
8-foldaverageincrease 7-foldaverageincrease
p<0.0001 p<0.0001nosignificantchange
Conceptofaninflammatorydendri.ccell.CD11c+DCsinpsoriasislesionshaddifferentmarkersanddifferentfunc.onsfromnormalskin
Theevolvingpsoriasistranscriptome—diseaseroadmapsbasedonstudyofskinbiopsies
2001n=24
2003n=24
2008n=26
2010n=90
159genes
800genes
2800genes
4175genes
Oestreicheretal Zhouetal Yaoetal Suarez-Farinasetal
FundamentalHypothesis:Psoriasisvulgarisisanimmune-mediateddiseasecausedbyT-lymphocytes(T-cells)andassociatedcytokines.
PolarT-cellsubsets
IL-12 (TSLP, IL-33) IL-23
IFN-γ IL-4, IL-13 IL-17
Th1Tc1
Th2 Th17Tc17
(IL-23)
IL-22
Th22Tc22
AutoimmunityiscausedbyinappropriateactivationofoneormorepolarT-cellsubsets
PolarT-cellsubsets
IL-12 (TSLP, IL-33) IL-23
IFN-γ IL-4, IL-13 IL-17
Th1Tc1
Th2 Th17Tc17
(IL-23)
IL-22
Th22Tc22
AnearlyhypothesisproposedTh1T-cellscausedpsoriasis
Type1Devia<oninPsoriasis
Type1(γ-Interferon)
Type2(Interleukin-4)
Psoriasis
˜2-3foldexpansionofType1T-cellsJ.Invest.Dermatology113:752-759(1999)
Symbol Description FCH FDRCXCL10 chemokine (C-X-C motif) ligand 10 8285.866 0CXCL9 chemokine (C-X-C motif) ligand 9 7501.063 0CXCL11 chemokine (C-X-C motif) ligand 11 7427.648 0UBD ubiquitin D 5627.575 0CXCL11 chemokine (C-X-C motif) ligand 11 5515.316 0ICAM1 intercellular adhesion molecule 1 (CD54), human rhinovirus receptor1523.346 0C1S complement component 1, s subcomponent 1501.382 0HLA-DRA major histocompatibility complex, class II, DR alpha 1454.124 0HLA-DRB1 major histocompatibility complex, class II, DR beta 1 1237.32 0HLA-DPA1 major histocompatibility complex, class II, DP alpha 1 1191.56 0HLA-DRA major histocompatibility complex, class II, DR alpha 1079.847 0C1R complement component 1, r subcomponent 974.816 0HLA-DRB5 major histocompatibility complex, class II, DR beta 5 948.089 0RARRES3 retinoic acid receptor responder (tazarotene induced) 3 935.545 0CCL2 chemokine (C-C motif) ligand 2 895.502 0RSAD2 radical S-adenosyl methionine domain containing 2 807.346 0CTSS cathepsin S 800.808 0ISG20 interferon stimulated exonuclease gene 20kDa 716.4 0HLA-DMA major histocompatibility complex, class II, DM alpha 663.205 0PSMB9 proteasome (prosome, macropain) subunit, beta type, 9 (large multifunctional peptidase 2)645.756 0APOL3 apolipoprotein L, 3 616.127 0GBP2 guanylate binding protein 2, interferon-inducible 607.721 0CD74 CD74 molecule, major histocompatibility complex, class II invariant chain604.205 0HLA-DRB1 major histocompatibility complex, class II, DR beta 1 568.493 0ICAM1 intercellular adhesion molecule 1 (CD54), human rhinovirus receptor449.759 0ISG20 interferon stimulated exonuclease gene 20kDa 441.654 0BST2 bone marrow stromal cell antigen 2 415.635 0IRF1 interferon regulatory factor 1 380.93 0CTSS cathepsin S 379.723 0SERPING1 serpin peptidase inhibitor, clade G (C1 inhibitor), member 1, (angioedema, hereditary)375.298 0AIM2 absent in melanoma 2 372.634 0INDO indoleamine-pyrrole 2,3 dioxygenase 357.325 0APOL1 apolipoprotein L, 1 337.112 0HLA-DPA1 major histocompatibility complex, class II, DP alpha 1 334.534 0GLDC glycine dehydrogenase (decarboxylating) 256.429 0IL32 interleukin 32 256.145 0RARRES1 retinoic acid receptor responder (tazarotene induced) 1 236.388 0SECTM1 secreted and transmembrane 1 228.298 0ETV7 ets variant gene 7 (TEL2 oncogene) 196.912 0APOL6 apolipoprotein L, 6 187.719 0IL15 interleukin 15 179.367 0GBP1 guanylate binding protein 1, interferon-inducible, 67kDa 172.54 0IFI35 interferon-induced protein 35 160.635 0HLA-DRB4 major histocompatibility complex, class II, DR beta 4 160.437 0IFIT3 interferon-induced protein with tetratricopeptide repeats 3 146.128 0XAF1 XIAP associated factor-1 139.351 0CCL8 chemokine (C-C motif) ligand 8 133.609 0CFB complement factor B 132.853 0CEACAM1 carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein)128.47 0CFH complement factor H 125.194 0HCP5 HLA complex P5 117.354 0
Top50genes:IFNγ treatedKCs
Cytokine-drivenpathogenesis
ϒ-IFN
CXCL9CXCL10CXCL11IL-8ICAM-1MHC-IIImmuneamplifica.on
humankera.nocytes
(invitro)
Cytokine-drivenpathogenesis
ϒ-IFN
CXCL9CXCL10CXCL11IL-8ICAM-1MHC-IIImmuneamplifica.on
humankera.nocytes
(invitro)
PolarT-cellsubsets
IL-12 (TSLP, IL-33) IL-23
IFN-γ IL-4, IL-13 IL-17
Th1Tc1
Th2 Th17Tc17
(IL-23)
IL-22
Th22Tc22
In2005theTh17T-cellwasidentifiedasassociatedwithCNSautoimmunity
ExperimentsinmiceclearlyshowthatIL-23drivesac.va.on&expansionofTh17T-cells,
notTh1T-cells.γ-interferon
(Th1)IL-17(Th17)
p40
1.0
10.0
100.0
1,000.0
10,000.0
Rela
tive G
en
e E
xp
ress
ion
p19
1.0
10.0
100.0
1,000.0
10,000.0
Rela
tive G
en
e E
xp
ress
ion
Consistentup-regula.onofp40andp19mRNAs(IL-23subunits)inpsoriasisplaques,asdetectedbyreal-.meRT-PCR(normalizedtoHARP)
uninvolved uninvolvedlesion lesion
p<0.000001
LeeetalJEM(2005)Dendri.cCellsestablishedasmajorproducersofIL-23inpsoriasislesions
Gene.cBiomarkersofIncreasedRisk
O’ReilleyNatRevRheum(2011)
Th1
Th17
Blood
PsoriasisLesion
Th17T-cellsincreasedinpsoriasislesions
Loweset.al.J.Invest.Dermatol(2008)
Geneexpressionduringcyclosporinetreatment
T-cellproducedcytokinesactonkera.nocytestoinducespecificgeneproducts
IL-17AIL-17F
S100A7(psoriasin)CXCL1,2,3,8CCL20β-defensinandotheran.-microbialpep.des
humankera.nocytes
(invitro)
IL-23/Th17 pathway in psoriasis
neutT17DC
KC
Tcell DC
IL-23 IL-17
CCL20
CCR6+cells
CXCchemokinesCXCL1,2,3,5IL-8
An.-microbialpep.desβ-defensinsLipocalinLL-37S100A7,S100A8
Th17Tc17Tgamma-delta17ILC17
Butdoesnotexplainepidermalhyperplasia
PolarT-cellsubsets
IL-12 (TSLP, IL-33) IL-23
IFN-γ IL-4, IL-13 IL-17
Th1Tc1
Th2 Th17Tc17
(IL-23)
IL-22
Th22Tc22
TheTh22T-cellsubsetisalsoactivatedinpsoriasisandIL-22isakeratinocytemitogen
IL-22promotesacanthosisandimpairsterminaldifferen.a.on
NogralesKEetal,Bri<shJournalofDermatology,2008
Fullthicknessskinrars(epidermis+fibroblasts/dermis)
§ ConfirmseffectofIL-22onacanthosisofepidermis(SaetalJImmunology2007)§ *Parakeratosis
*
Three immune axes are activated in psoriasis
An.microbialpep.desIL-1βIL-6TNF-αS100CXCL8CXCL9CXCL10CXCL11CCL20
Th/Tc1
Th/Tc17
Th/Tc22
IL-23(p40/p19)
IL-12(p40/p35) TNF-α
IFN-γ
IL-17A/FIL-21
IL-22
kera.nocyte
kera.nocyte
NKTcell
plasmacytoidDendri.ccell
macrophage
ac<va<on
IL-1βIL-6
TNF-αTNF-αIFN-γ
TIP-DCIFN-α
TNF-α
LESIONFORMATION
Figureadaptedfrom:NestleFO,etal.NEnglJMed.2009;361:496-509
HoweverIL-23/Type-17axisdrivesthediseasephenotype
IL-17SignalingLigand/ReceptorCombina3ons
Gaffen.NatRevImmunol2009;9(8):556-67.
IL-17A IL-17A/F IL-17F
IL-17C
IL-17D
IL-17E/IL-25 IL-17B ??
??
FN1 FN2
SEFIR
TILL
CBAD IL-17RA IL-17RC
IL-17RA IL-17RB/ IL-25R
IL-17RA IL-17RD/
SEF
IL-17RB/ IL-25R
IL-17RE
IL-17RD/ SEF
X X X X
IxekizumabSecukinumab
Brodalumab
Anti-IL-17 Receptor Antibody AMG 827 Leads to Rapid Clinical Response in Subjects with Moderate to Severe Psoriasis: Results from a Phase I, Randomized, Placebo-Controlled Trial Kim A Papp, Cathy Reid, Peter Foley, Rod Sinclair, David H Salinger, Gary Williams, Hua Dong, James G Krueger, Chris B Russell and David A Martin JournalofInves3ga3veDermatology(2012)132,2466–2469;doi:10.1038/jid.2012.163;publishedonline24May2012
DatafirstpresentedatSocietyforInves.ga.veDermatologyin2010
Double-blind, placebo controlled study with a single dose of AMG827
Placebo(n=4)350mgSC(n=8)700mgIV(n=8)
Keyinclusioncriteria:ModeratetosevereplaquePsO≥6mos,PASIscore≥10, BSA≥10,eligibletoreceive phototherapyorsystemictherapy
Keyexclusioncriteria:Anyprioruseofbiologics;recentuseofsystemicsteroidsorcalcineurininhibitors
RussellCB,RandH,BiglerJ,KerkofK,TimourM,Bau.staE,KruegerJG,SalingerDH,WelcherAA,Mar.nDA.JImmunol.2014Apr15;192(8):3828-36.
IL-23/Th17 pathway in psoriasis
neutT17DC
KC
Tcell DC
IL-23 IL-17
CCL20
CCR6+cells
CXCchemokinesCXCL1,2,3,5IL-8
An.-microbialpep.desβ-defensinsLipocalinLL-37S100A7,S100A8
Th17Tc17Tgamma-delta17ILC17
RoleofIL-17Aprobedwithixekizumab
Expression of IL-17 Target Genes (RT-PCR)
log2(expression/hARP)=mRNAexpression(RT-PCR)normalizedtothehousekeepinggenehumanacidicribosomalproteingene(hARP)
Lipocalin2 Interleukin8
β-defensin2 CXCL1
Genes Modulated by ixekizumab (FCH>6)– very rapid effects and much faster response than etanercept
LS=LesionalSkinBiopsiesatBaseline
NL=Non-LesionalSkinBiopsiesatBaseline
Proportion of Patients with PASI 75
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20
Placebo SC (n=8) LY 150 mg SC (n=8)
Dose Dose Dose Weeks
Prop
or.o
nofPa.
ents
HighEfficacyofIL-17antagonistsinPhase3Studies
• Secukinumab(an.-IL-17A)superiortoustekinumabinCLEARstudy,87%PASI75inJUNCTUREstudy2
• Ixekizumab(an.-IL-17A)superiortoetanerceptinUNCOVERstudy,90%PASI75inbestperformingdosinggroup1
• Brodalumab(an.-IL-17Receptor,Asubunit)superiortoustekinumabinAMAGINE-3study,386%PASI75inAMAGINE-2Study,bestperformingdosegroup4
1.‘Lilly'sIxekizumabSuperiortoEtanerceptandPlaceboinPhase3PsoriasisStudies’pressreleaseavailableat:h{ps://investor.lilly.com/releasedetail.cfm?releaseid=867193.Dateaccessed:May2015.2.PaulCetal.JEurAcadDermatolVenereol.2014[Epubaheadofprint].3.’AmgenandAstraZenecaannounceposi.veresultsfromsecondpivotalPhaseIIIstudyofBrodalumabinpa.entswithmoderate-to-severeplaquepsoriasis’pressrelease.Availableat:h{p://www.astrazeneca.com/Media/Press-releases/Ar.cle/11112014--amgen-and-astrazeneca-announce-posi.ve-results.‘AmgenandAstraZenecaannounceposi.veresultsfromthirdandfinalpivotalPhaseIIIstudyofBrodalumabinpa.entswithmoderate-to-severeplaquepsoriasis’pressrelease.Availableat:h{p://www.astrazeneca.com/Media/Press-releases/Ar.cle/20141125-amgen-and-astrazeneca-posi.ve-results-brodalumab.Dateaccessed:May2015.
AmgenhasterminatedbrodalumabpartnershipwithAstraZeneca.Brodalumabandixekizumabarenotcurrentlylicensedfortherapeu.cuse
Does IL-23 drive the Th17 pathway?
An.microbialpep.desIL-1βIL-6TNF-αS100CXCL8CXCL9CXCL10CXCL11CCL20
Th1
Th17
Th/Tc22
IL-23(p40/p19)
IL-12(p40/p35) TNF-α
IFN-γ
IL-17A/FIL-21
IL-22
kera.nocyte
kera.nocyte
NKTcell
plasmacytoidDendri.ccell
macrophage
ac<va<on
IL-1βIL-6
TNF-αTNF-αIFN-γ
TIP-DCIFN-α
TNF-α
LESIONFORMATION
Figureadaptedfrom:NestleFO,etal.NEnglJMed.2009;361:496-509
STAT1STAT3CEBP/NFkB
Adalimumab
Guselkumab
Blauvetetal.J.Am.Acad.Dermatol.76:405(2017)Voyage1Study
DiseaseProfileNeutralizedbyCNTO1959(Guselkumab)• Diseaseprofile(lesionalvs.non-lesionalskin)–1224transcripts• Highdose*broughttheexpressionlevelbacktonormalatWeek12
*Highdose=combined100&300mgtreatmentgroups
TreatmentvisitPASI50skinCNTO1959HighDay2yesNLCNTO1959HighDay2yesLSCNTO1959HighDay7yesLSCNTO1959HighDay84yesLS
-2.00 2.00
BaselineNon-Lesional
Week12Lesional
Week1Lesional
BaselineLesional
Sorenetal.J.AllergyClin.Immunol.133:1032(2014)
ustekinumab
risankizumab
Pappetal.NEJM376:1551(2017)
Kruegeretal.,J.AllergyClin.Immunol.136:116(2015).
HawkesJE,ChanTC,KruegerJG.JACI(2017).
TakeHomeMessage• PsoriasisisdrivenbyapolarT-cell(Th17/Tc17)axis,regulatedbyIL-23
• Kera.nocytesamplifytheresponse• Alltherapiesthatimprovepsoriasisdirectlyorindirectlylowerexpressionorsignalingofthisimmune-responseaxis