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A Selective Inhibitor of Endosomal Toll-Like A Selective Inhibitor of Endosomal Toll Like Receptors, IMO-8400, Suppresses Activation of
Multiple Cytokines, Th17 Response and I fl A ti tiInflammasome Activation
Presented at American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) Annual MeetingHealth Professionals (ACR/ARHP) Annual Meeting
November 9-14, 2012, Washington, D.C Abstract 1068
© 2012, Idera Pharmaceuticals www.iderapharma.com© 2011, Idera Pharmaceuticals www.iderapharma.com© 2012, Idera Pharmaceuticals www.iderapharma.com 1
IntroductionIntroduction• Idera’s therapeutic approach for the treatment of autoimmune diseases is to inhibit inductionIdera s therapeutic approach for the treatment of autoimmune diseases is to inhibit induction
of disease associated cytokines and signaling cascades by modulating activation of Toll-like Receptors (TLRs) 7, 8 and 9
• We have selected Psoriasis as disease model to evaluate the efficacy of our approach• Psoriasis is a chronic inflammatory skin disease primarily associated with a Th1 and Th17
response. The activation of inflammasomes and subsequent release of IL-1β has also been shown to contribute to disease development
• Current therapies for psoriasis include oral and injectable drugs such as Retinoids,Current therapies for psoriasis include oral and injectable drugs such as Retinoids, Methotrexate, Cyclosporine, Hydorxyurea and Biologics such as Amevive (anti-CD2 protein), Enbrel (anti-TNFα inhibitor), Remicade (anti-TNFα antibody), Stelara (anti-IL-12/23 antibody), Humira (anti-TNFα antibody) and Simponi (anti-TNFα antibody)
• We have developed novel TLR antagonists that block TLR7 8 and 9 signaling These• We have developed novel TLR antagonists that block TLR7, 8 and 9 signaling. These antagonists improve disease outcome in autoimmune disease models by blocking interaction of immune complexes carrying self nucleic acids with TLRs, thereby preventing induction of disease associated cytokines and signaling cascades
O f• IMO-3100, an antagonist of TLR7 and 9 is currently in Phase 2 clinical trial in patients with moderate to severe psoriasis
• IMO-8400, an antagonist of TLR7, 8 and 9, is in clinical development for the treatment of lupus
© 2012, Idera Pharmaceuticals www.iderapharma.com
p• In this study, we evaluated the ability of IMO-8400 to control disease development in mouse
models of psoriasis
2
IMO-8400 Inhibits Induction of Cytokines in NHP Mediated by TLR7, 8 or 9
0
25
e-do
se
0
25e-
dose
0
25
e-do
se
0
25
e-do
se
TLR7 TLR8 TLR9 TLR4
TNF-αIL-6IL-12IL-1β-50
-25
ange
from
pre
-50
-25
ange
from
pre
-50
-25
hang
e fr
om p
re
-50
-25
ange
from
pre
IFN-αIP-10
-100
-75
48 hr post-IMO-8400
% C
h
-100
-75
48 hr post-IMO-8400d i i t ti
% C
h
-100
-75
48 hr post-IMO-8400
% C
h
-100
-75
48 hr post-IMO-8400d i i t ti
% C
h
administration administration administration administration
Cynomolgus macaques (N=4) were injected sc with IMO-8400 at a dose of 1.5 mg/kgBlood was collected prior to IMO 8400 administration (pre dose) and 48hr post dosing
© 2012, Idera Pharmaceuticals www.iderapharma.com 3
Blood was collected prior to IMO-8400 administration (pre-dose) and 48hr post dosingPBMCs were isolated and cultured with agonist of TLR4, 7, 8 or 9Cytokine measurements in supernatants were carried out by multiplex or ELISA assay
TLR7, 8 and 9 in PsoriasisTLR7, 8 and 9 in Psoriasis
Injury or infection Psoriasis
TLR7TLR8 TLR9
IL 21 IL 22IL 12 IL 17Neutrophil
Keratinocyte Peptides
DNA/RNA
Th1 or Th17
IL-21, IL-22IL-23, IL-6
IL-12, IL-17, IFN-α, X
Peptides
Immunecomplexes
cells
TLR7, 8 and 9
complexes
Antagonist
© 2012, Idera Pharmaceuticals www.iderapharma.com
Dendritic Cell
Experimental models of PsoriasisExperimental models of Psoriasis
Day 0 2 3 4 6 9 12 14 15 18
C57BL/6 miceear IL-23, 0.5 μg, i.d. once every 2 day
TerminateIMO-8400, s.c. Parameters:HistologyEar thickness
Experimental groups (N = 7)IMO-8400, 2.5 mg/kg Ear thicknessIMO-8400, 5 mg/kg
IMO-8400,15 mg/kg
Control Oligo, 15 mg/kg
PBS
Day 0 1 2 3 4 5 6
C57BL/6 micedorsal skin
TerminateIL-23, 1 μg, i.d. IMO-8400, s.c. Parameters:HistologyExperimental groups (N = 8)
© 2012, Idera Pharmaceuticals www.iderapharma.com 5
gySkin mRNA Skin proteinSerum cytokine
IMO-8400, 15 mg/kg (300 µg)
PBS
IMO-8400 Suppresses IL-23-Induced Ear Thickness IncreaseIMO-8400 Suppresses IL-23-Induced Ear Thickness Increase
PBS IMO-8400Naive Control
HE stain, Magnification x 100Epidermal hyperplasia Inflammatory cell infiltration
m
450
IMO-8400: 15mg/kg
thic
knes
s,μm
390
420
**
Ear
PBS 2.5 mg/kg 5 mg/kg 15 mg/kg Control 360
IMO 840015 mg/kg
© 2012, Idera Pharmaceuticals www.iderapharma.com 6
IMO-8400
*, P < 0.05 vs PBS group by two-tailed Student’s t test
IMO-8400 Inhibits Dorsal Skin Lesions Induced by IL-23IMO-8400 Inhibits Dorsal Skin Lesions Induced by IL-23
Naive PBS IMO-8400Naive PBS IMO 8400
**
HE stain, Magnification x 200Inflammatory cell infiltrationEpidermal hyperplasia * Abscess
© 2012, Idera Pharmaceuticals www.iderapharma.com 7
IMO-8400 Inhibits Cytokine ProductionIMO-8400 Inhibits Cytokine Production
130330 IL-12IL-6
L-12
, pg/
ml
90
110
IL-6
, pg/
ml
110
220 * *
I
Naive PBS IMO-840070
90
Naive PBS IMO-84000
110
Naive PBS IMO 8400Naive PBS IMO 8400
© 2012, Idera Pharmaceuticals www.iderapharma.com 8
*, P < 0.05 vs PBS group by two-tailed Student’s t test; Serum levels of cytokines were measured by ELISA
IMO-8400 Inhibits Expression of Multiple CytokinesIMO-8400 Inhibits Expression of Multiple Cytokines
IL 6 IFN γ
RQ 60
90Q
80
120 IL-6 IFN-γ
IFN
- γ, R
30
IL-6
, RQ
40
*
Naive PBS IMO-84000
Naive PBS IMO-84000
*
150 36IL-17A IL-17F
A, R
Q 100
F, R
Q
18
27* *
IL-1
7A
50 IL-1
7F
9
18
© 2012, Idera Pharmaceuticals www.iderapharma.com 9
*, P < 0.05 vs PBS group by two-tailed Student’s t testNaive PBS IMO-8400
0Naive PBS IMO-8400
0
IL 21
IMO-8400 Inhibits Expression of Multiple CytokinesIMO-8400 Inhibits Expression of Multiple Cytokines
IL 22
Q
3000
4000
Q
44
66 IL-21 IL-22
IL-2
2, R
Q
1000
2000
IL-2
1, R
Q
22 **
Naive PBS IMO-84000
1 9
Naive PBS IMO-84000
IL-23 p19
9, R
Q
1.6
1.9
IL-2
3 p1
9
1.0
1.3
*
© 2012, Idera Pharmaceuticals www.iderapharma.com
Naive PBS IMO-84000.7
10*, P < 0.05 vs PBS group by two-tailed Student’s t test; mRNA levels of cytokines in skin were measured by qPCR
IMO-8400 Does Not Affect Th2 CytokinesIMO-8400 Does Not Affect Th2 Cytokines
15
20
6
8IL-4 IL-10
IL-4
, RQ
5
10
IL-1
0, R
Q
2
4
Naive PBS IMO-84000
5
Naive PBS IMO-84000
2
© 2012, Idera Pharmaceuticals www.iderapharma.com 11
mRNA levels of cytokines in skin were measured by qPCR
270 9
IMO-8400 Inhibits Expression of Anti-Microbial Peptides IMO-8400 Inhibits Expression of Anti-Microbial Peptides
DEFB4 S100A7a4,
RQ 180
7a, R
Q 6
DEF
B
90 S100
A7
3
*
*
Naive PBS IMO-84000
1.4
Naive PBS IMO-84000
S100A4 4 LL-37
0A4,
RQ 1.2
* -37,
RQ
2
3
S100
0 8
1.0 LL-
0
1
© 2012, Idera Pharmaceuticals www.iderapharma.com
Naive PBS IMO-84000.8
12
* , P < 0.05 vs PBS group by two-tailed Student’s t test; mRNA levels of anti-microbial peptides in skin were measured by qPCR
Naive PBS IMO-84000
Inflammasome Pathway in PsoriasisInflammasome Pathway in Psoriasis
1st signal 2nd signal
Endosome9R7
ATPATP
RNADNA
TLR
8
TLR
9
TLR
MyD88MyD88 MyD88
NLRP3
CARD ASCPro-Caspase-1
Nucleus
NF-κB
pro IL-1β IL-1β
Caspase-1
psoriasisPro-inflammatory
cytokines
© 2012, Idera Pharmaceuticals www.iderapharma.com 13
9 4
IMO-8400 Inhibits Inflammasome ActivationIMO-8400 Inhibits Inflammasome ActivationNLRP3 AIM2
3, R
Q 6
RQ
3
**
NLR
P3
3
AIM
2,
1
2*
21039
Naive PBS IMO-84000
Naive PBS IMO-84000
IL-1β IL-1β protein
mg
prot
ein
140
β, R
Q 26
IL-1
β, p
g/
70IL-1
β
13*
*
© 2012, Idera Pharmaceuticals www.iderapharma.com
Naive PBS IMO-84000
Naive PBS IMO-84000
14
* , P < 0.05 vs PBS group by two-tailed Student’s t test; mRNA expression levels of inflammasome in skin were measured by qPCR;IL-1β levels in skin were measured by ELISA.
ConclusionConclusion
• IMO-8400, an antagonist of TLR7, 8 and 9 exerts a therapeutic effect in mouse models of psoriasis induced by IL-23• A li t di th l• Ameliorates disease pathology• Inhibits expression of Th1 cytokines such as IL-12, IL-6 and IFN-γ• Inhibits expression of genes associated with the IL-23/Th17 axis• Does not affect expression of Th2 cytokines IL-4 and IL-10• Inhibits expression of psoriasis-associated anti-microbial peptides such as
DEFB4, S100A4 and S100A7a• Inhibits inflammasome activation
• IMO-3100, a TLR7 and 9 antagonist in Phase II clinical trial for the gtreatment of moderate to severe psoriasis is equally effective as IMO-8400 in IL-23- induced psoriasis model
© 2012, Idera Pharmaceuticals www.iderapharma.com 15
SummarySummary
• Antagonist blocks TLR activation thereby affecting the signaling cascade that controls the expression of multiple cytokines
• Inhibition of TLR activation ultimately results in the simultaneous blockadeInhibition of TLR activation ultimately results in the simultaneous blockade of many cellular events
• Blockade of TLR activation is not expected to perturb triggering of downstream signals mediated by other cellular eventsdownstream signals mediated by other cellular events
• Mechanism of action of the antagonist is significantly different from that of immunosuppressants or monoclonal antibodies utilized for the treatment of psoriasis and other autoimmune diseasesof psoriasis and other autoimmune diseases
© 2012, Idera Pharmaceuticals www.iderapharma.com 16