Upload
truongphuc
View
216
Download
2
Embed Size (px)
Citation preview
IMO-8400, a novel TLR7, TLR8 and TLR9 antagonist, inhibits disease development in mouse models ofinhibits disease development in mouse models of
psoriasis
Weiwen Jiang, Fu-Gang Zhu, Dong Yu, Ekambar R. Kandimalla, Nicola La e e J a g, u Ga g u, o g u, a ba a d a a, co a aMonica, and Sudhir Agrawal
Idera Pharmaceuticals, Inc, 167 Sidney Street, Cambridge, MA 02139 USA02139, USA
Poster Board Number: P1537Session: Novel and Cellular Approaches to Autoimmunity
IMMUNOLOGY 2012,
Date and Time: May 6, 2012 from 2:30 PM to 3:30 PMLocation: Exhibit Hall (Hynes Convention Center)
May 4-8, 2012Boston, Massachusetts
IntroductionIntroduction
T ll lik R t (TLR ) 7 8 d 9 i dToll-like Receptosr (TLRs) 7, 8 and 9 can recognize endogenous immune complexes containing self-RNA and -DNA, respectively. In many autoimmune diseases, TLR7- and 9-mediated inflammation induced by immune complexes leads to maintenance and progression of disease. p p g
Activation of TLR7, TLR8 and TLR9 in pDC and mDC through the interaction of these receptors with the antimicrobial peptide LL37 complexed with self RNA or DNA contributes to psoriasis development1 2 Thereforewith self-RNA or DNA contributes to psoriasis development1,2. Therefore, inhibition of TLRs 7, 8 and 9 through the use of a TLR antagonist could provide therapeutic effect in this autoimmune disease.
We have identified a first-in-class DNA-based antagonist of TLR7, 8, and 9, referred to as IMO-8400. IMO-8400 inhibitsTLR7- and 9-mediated immune responses in mice and TLR7-, 8- and 9-mediated immune responses in human cell based assays and in non human primatesin human cell-based assays and in non-human primates.
In the present study, we have evaluated IMO-8400 as a therapeutic agent in IL-23- and LL-37-induced psoriasis models in mice.
© 2011, Idera Pharmaceuticals www.iderapharma.com 2
1Lande R, et al., Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449: 564-569, 20072Ganguly D, et al., Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J. Exp. Med. 206: 1983-1994, 2009
Role of TLRs 7, 8 and 9 in Psoriasis : Induction of IL-23 and IL-17 PathwaysRole of TLRs 7, 8 and 9 in Psoriasis : Induction of IL-23 and IL-17 Pathways
Protein-RNA/DNAl
TLR7/9
pDC
IFN-α
complexp
IMO-8400TLRs 7, 8 and 9
antagonist
TLR8
CD11c+ DC IL-20
activation
KC
B-DefensinS100A7IL 8
TLR8
IL-23
Th17
IL-22
IL-17 KC IL-8
IL-12
Th1
IFN-γTNF-α KC
activation MIGIP-10
© 2011, Idera Pharmaceuticals www.iderapharma.com 3
Th1 KC
Outline of Study Protocol of IL-23-Induced Psoriasis
TerminationDay 0 1 2 3 4 5 6
IL-23, 1 μg, i.d. once a day IMO-8400, s.c. once a day
Female C57BL/6 mice, 6 weeks old
Evaluation
Skin histology
Gene expression in skinExperimental groups (n = 8/group)
IMO-8400, 300 μg/dose (15 mg/kg)
PBS
Gene expression in skin
PBS
Naïve
© 2011, Idera Pharmaceuticals www.iderapharma.com 4
Treatment with IMO-8400 Suppresses Skin Lesions Induced by IL-23
PBS t t d IMO 8400 t t dPBS-treated IMO-8400-treated
© 2011, Idera Pharmaceuticals www.iderapharma.com
IL-23 induced various degrees of erythema and induration. IMO-8400 inhibited inflammation induced by IL-23
5
Treatment with IMO-8400 Inhibits Skin Inflammation Induced by IL-23
Treatment with IMO-8400 Inhibits Skin Inflammation Induced by IL-23
PBS-treatedNaive IMO-8400-treated
**
© 2011, Idera Pharmaceuticals www.iderapharma.com 6
HE stain, Magnification x 200Inflammatory cell infiltrationEpidermal hyperplasia Abscess*
Treatment with IMO-8400 Impacts Gene Expression in IL-23-Injected Skin
12180 2100
S100A DEFB4 IL-10
8
12
120
180
1400
2100
*
4
Fold
Cha
nge
60
Fold
cha
nge
700
Fold
Cha
nge
*
0S O
0S O
0*
Naive PBS IMO-8400Naive PBS IMO-8400 Naive PBS IMO-8400
* P < 0.05 vs PBS group
© 2011, Idera Pharmaceuticals www.iderapharma.com
g p
Expression of S100 and β-defensin (DEFB4) genes is up-regulated in lesions of psoriasis patients; IMO-8400 significantly suppressed expression of both genes. Gene expression was determined by quantitative real-time PCR
7
Treatment with IMO-8400 Reduces IL-17 and Increases IL-10 Levels in IL-23-Injected Skin
40 *IL-10IL-17
25
30
ein
*
15
20
ein
20
pg/m
g pr
ot
10
15
pg/m
g pr
ot0
10
0
5
Naive PBS IMO-8400 Naive PBS IMO-8400
© 2011, Idera Pharmaceuticals www.iderapharma.com
* P < 0.05 vs PBS group. Cytokine levels were determined by ELISA
8
Splenocytes From IMO-8400-Treated Mice Show Reduced Response to TLR9 Agonist
StimulationStimulation
IL-12IL-6 IL 12IL 6
*
*
**
* **
© 2011, Idera Pharmaceuticals www.iderapharma.com
*P < 0.05 vs PBS. Cytokine levels were determined by ELISA.
9
Outline of Study Protocol of LL-37-Induced Psoriasis
Day 0 4 7 13 16 17 18
LL-37, 50 μg, i.d. at root of ear once every two days
Termination
EvaluationFemale C57BL/6 mice, 8 weeks old
IMO-8400, s.c. once every two days
Experimental groups (n = 7/group)IMO-8400, 50 μg/dose (2.5 mg/kg)IMO-8400, 100 μg/dose (5 mg/kg)IMO-8400 300 μg/dose (15 mg/kg)
EvaluationEar thicknessSkin histology
IMO 8400, 300 μg/dose (15 mg/kg)PBS Naïve
© 2011, Idera Pharmaceuticals www.iderapharma.com 10
Treatment with IMO-8400 Suppresses Ear Thickness Increase Induced by LL-37
Treatment with IMO-8400 Suppresses Ear Thickness Increase Induced by LL-37
550550
PBS
450
hick
ness
, μm
***
*
*
* *100 μg
50 μg
300 μgIMO-8400
350Ear t
h μg
Treatment start day
2500 2 4 6 8 10 12 14 16 18 19
Days
day
© 2011, Idera Pharmaceuticals www.iderapharma.com 11
* P < 0.05 vs. PBS group
Treatment with IMO-8400 Reduces Skin Inflammation Induced by LL-37
Treatment with IMO-8400 Reduces Skin Inflammation Induced by LL-37
IMO-8400, 300 μg
Naive PBS
Epidermal hyperplasia
Inflammatory cell infiltration
p yp p
© 2011, Idera Pharmaceuticals www.iderapharma.com
HE stain, Magnification x 100
12
SummarySummary
IMO-8400 is a first-in-class antagonist of TLR7, 8 and 9
In IL 23 induced psoriasis model IMO 8400 suppressedIn IL-23-induced psoriasis model, IMO-8400 suppressedPsoriatic lesions, epidermal hyperplasia and inflammatory cell infiltrationDEFB4 and S100A gene expression and IL-17 protein levelsTLR9-mediated immune responses in splenocytesp p y
IMO-8400 treatment increased IL-10 gene expression and protein levels in skin
I LL 37 i d d i i d l IMO 8400 d dIn LL-37-induced psoriasis model, IMO-8400 reducedEar thickness, epidermal hyperplasia and inflammatory cell infiltration
IMO-8400 is in development for treatment of autoimmune diseasesIMO 8400 is in development for treatment of autoimmune diseases
© 2011, Idera Pharmaceuticals www.iderapharma.com 13