imo-8400, a novel tlr7, tlr8 and tlr9 antagonist, inhibits ... · pdf fileinhibits disease...

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


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


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

**


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


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


* 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

*

*

**

* **


*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


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


* 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


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


imo-8400, a novel tlr7, tlr8 and tlr9 antagonist, inhibits ... · pdf fileinhibits disease...

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