IL1RAP as a therapeutic target...IL-1 blockade - recent intriguing clinical data Placebo High dose...
Transcript of IL1RAP as a therapeutic target...IL-1 blockade - recent intriguing clinical data Placebo High dose...
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IL1RAP as a therapeutic target
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Göran Forsberg, CEO
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Cantargia
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• Specialized in antibody therapy/immunology, with initial focus on oncology • Lead antibody CAN04 (nidanilimab) in clinical development• Listed on Nasdaq Stockholm, approximately 5000 shareholders• Based in Lund, Sweden at Medicon Village Science park• Virtual company, with strong academic and corporate collaborations
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IL-1 blockade - recent intriguing clinical data
Placebo
High dose
CANTOS trial (>10000 pat)• Canakinumab (anti-IL-1β )• Reduced lung cancer incidence
by 67 % and death by 77 %.
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Canakinumab NSCLC phase 3 trials
Adjuvant NSCLCAfter surgery, no mets, placebo control1500 patients, recruitment ongoingCompletion 2021/22
First line (CANOPY-1)Untreated locally advanced/metastaticCombination Pembro/Platinum doublet627 patients, start Dec 2018Completion 2021/22
Second line metastatic (CANOPY-2)Previously treated loc adv/metastaticCombination Docetaxel240 patients, start Dec 2018Completion 2021
Source clinicaltrials.gov
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CANTOS additional findings (from Canakinumab)
CANCER decreased risk of death with treatment (high dose)
Lung cancer 77 % P=0.0002
Non-lung cancer 37 % P=0.06
Decreased incidence of inflammatory disease (all doses)
Arthritis 32% p<0.0001
Ostheoartritis 28% P=0.0005
Gout 53% p<0.0001
Cardiovascular 12% P=0.02
Biomarker levels (reduction)
CRP 26-41% P<0.0001
IL-6 25-43% P<0.001
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IL-1 is a “broad-spectrum” cytokine implicated in a number of inflammatory diseases
• IL-1 is released by tissues or the innate immune system to induce inflammation, IL-1 has highly pro-inflammatory properties and affect a large number of cells
• IL-1 is involved in several autoimmune diseases and is the dominant cytokine in autoinflammatory diseases
• Blocking drugs are on the market (anakinra, rilonacept, canakinumab) Doherty et al., J Leukoc Biol 90(1):37-47 2011
Approved IL-1 inhibiting drugs, IL1RaccP = IL1RAP
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Next step in IL-1 blockade?
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• IL-1 blockade can be used to treat disease• Approved for autoimmune/inflammatory disease• Promising clinical data for cancer treatment/prevention
• Is IL-1β the optimal target?• Advantages of receptor targeting?• Antibodies against IL1RAP.
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IL1RAP – IL-1 Receptor Accessory Protein
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Low expression of IL1RAP on normal cells
• Low reactivity on monocytes and lymphocytes• No significant tissue reactivity seen on normal tissue (frozen tissues FDA/EMA panel)• Low-to-moderate expression on monocytes
• The highest expression is found on cancer cells
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IL1RAP
• Three different systems signal through IL1RAP• These systems contribute to various inflammatory diseases• Can be blocked by antibodies against IL1RAP
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The IL-33 and IL-36 signaling pathways - novel targets for several diseases
• IL-33 and IL-36 are barrier-associated cytokines highly expressed in skin and mucosal tissues.
• IL-33 is involved in allergic inflammation and Th2-responses
• IL-36 is heavily upregulated in inflamed skin and mediates e.g. certain psoriatic conditions
• No approved product on the market but several projects in preclinical or clinical phase
• Allergy
• Asthma
• Atopic Dermatitis
• Rhinosinusitis
• Pustular psoriasis
• Palmo-Plantar Pustulosis
• Ulcerative Colitis
• Crohn’s Disease
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Unique binding properties of IL-1 and IL-33
Günther et al, Immunity 2017, 47, 510-523
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Cantargia pipeline
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CAN04 and CAN03 both inhibit IL-1b and IL-33 signaling but with different properties
0 .0 1 0 .1 1 1 0 1 0 0
0
2 5
5 0
7 5
1 0 0
IL 1 b in h ib it io n
C A N 0 4 (n M )
Inh
ibit
ion
(%
)
0 .0 1 0 .1 1 1 0 1 0 0
0
2 0
4 0
6 0
8 0
1 0 0
IL 3 3 in h ib it io n
C A N 0 4 (n M )
Inh
ibit
ion
(%
)
0 .0 1 0 .1 1 1 0 1 0 0
0
2 5
5 0
7 5
1 0 0
IL 1 b in h ib it io n
C A N 0 3 (n M )
Inh
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0 .0 1 0 .1 1 1 0 1 0 0
0
2 0
4 0
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1 0 0
IL 3 3 in h ib it io n
C A N 0 3 (n M )In
hib
itio
n (
%)
CAN04 CAN03Potent IL1b and IL33 inhibitor, but only blocks IL33 signaling partially
Less potent, but the binding mode allows full inhibition of IL1band IL33 signaling
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Wang et al., 2010, Nature Immunology, 11, 905-912.
IL-1RIIIL-1RAP
IL-1β
D3
D2
D1
CAN04
CAN03
CAN04 and CAN03 bind different domains of IL1RAP
Antibody ka (1/M•s) kd (1/s) KD (M)
CAN03 2.26E+05 7.25E-05 3.21E-10
CAN04 4.27E+05 4.72E-05 1.10E-10
Measurement of binding affinities to IL1RAP by SPR
Epitope mapping in collaboration withEric Sundberg, University Maryland
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IL1RAP as a target in cancer
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The original finding:IL1RAP - a novel target on cancer cells
Leukemic cells from patients Genomics & Bioinformatics IL1RAP identified as upregulated on CML leukemia stem cells
Isolation of CML leukemia stem Cells based on IL1RAP expression
0
10
20
30
40
0 0,01 0,1 1 10
Antibody concentration (µg/mL)
Sp
ecif
ic c
ell
dea
th (
%)
control IgG
KMT-1
Production of a polyclonalanti-IL1RAP antibody (KMT1)
Selective killing of leukemia stem cells using antibodies
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IL1RAP expressed in several tumor forms
Size of each indication corresponds to annual deaths in USA 17
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Tumor inflammation – key to cancer progression
Genomic instability
and mutation (2000)
Sustaining proliferative signaling
Evading growth suppressors
Resisting cell death
Enabling replicative immortality
Inducing angiogenesis
Activating invasion and metastasis
Hanahan D & Weinberg RA, The Hallmarks of Cancer, Cell 2000; Hanahan D & Weinberg RA, Hallmarks of Cancer: The Next Generation, Cell 2011
Cancer
hallmarks
Enablers
Tumor-promoting
inflammation (2011)
Avoiding immune destruction
Deregulating cellular energetics The inflammatory cytokine IL-1
– Well established role in cancer progression:
Tumor cells
• Signaling/proliferation of cancer cells
• Chemoresistance
Tumor microenvironment
• Metastasis
• Crosstalk between tumor cells and stroma
• Inflammation and local suppression of the immune system
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CAN04 phase I clinical data at ESMO (Oct 2018)
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• CAN04 has generally been welltolerated
• 6 mg/kg is safe.• Biomarker results (IL-6 and CRP)
support target engagementalready after two doses ofCAN04.
• In a heavily pre-treated patientpopulation, 5 of 13 patients(38%) had SD. One patient withNSCLC had SD for 6 months.
• Recently 10 mg/kg was shownto be safe (Dec 2018)
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CAN04 – CANFOUR clinical trial
• Phase I/IIa trial - NSCLC and pancreatic cancer• Norway, Denmark, Netherlands and
Belgium
• 22 patients treated, good safety
• NSCLC, pancreatic cancer, colon cancer, triple negative breast cancer
• Phase IIa: focused on NSCLC and pancreatic cancer (appr 20 centres)
• Monotherapy
• Combination with standard therapy
• NSCLC Cisplatin/Gemcitabine
• Pancreatic cancer Gemcitabine/nab-paclitaxel
20Details on www.clinicaltrials.gov
Q4 2018 Early 2020
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Receptor blockade vs IL-1β blockade
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Canakinumab• Antibody directed against one
of the two IL-1 ligands, IL-1β
CAN04 • Binds the common signaling
receptor and counteracts both ligands
• Induce killing via the immune system (ADCC)
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CAN04 - immuno-oncology mechanism withantitumor effect
• Antitumor effects in NSCLC PDX models
• CAN04 stimulates immune cells to infiltrate tumor
• (CAN04 not cross reactive with mIL1RAP)
Control CAN04
Cancer cells
Stroma cells
Inflammatory
immune cells
Blood vessels
Stroma withinfiltratingimmune cells
Iso
typ
e c
trl
CA
N04
0
5
1 0
1 5
2 0
N K 1 .1+ in tu m o r
% N
K1
.1+
tu
mo
r t
iss
ue p = 0 ,0 0 7 2
22
0 5 1 0 1 5
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
2 5 0 0
C A N 0 4 1 0 m g /k g (n = 1 0 )
D a y s
Tu
mo
r v
olu
me
(m
m3
)
V e h ic le
**
C A N 0 4
Is o ty p e c o n tro l
*
* *
*
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Activity in AML
Isotype mAb81.20.00
0.05
0.10
0.15
0.20
0.25
% le
uk
em
ic c
ells
in
BM p<0.0001
Treating AML (PDX) in vivo
AML5 AML60
1
2
3
Fo
ld p
rolif
era
tio
n
Isotype mAb3F8
p=0.006 p=0.033
Blocking proliferation ex vivo
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Inflammation and metastasis
• Cancer cells (seeds) needs a good soil to form a metastasis
• The IL-1 system (inflammation) can provide such environment (soil)
A tumor can create its own ”seed and soil” 24
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CAN04 attacks several cell types in the tumor
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IL-1 and resistance to therapy
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NSCLC CAN04/Cisplatin combination
Ctr
l (n
=8)
3F
8 (
n=10)
Cis
pla
t in
(n
=5)
Cis
pla
t in
+ 3
F8 (
n=8)
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
2 5 0 0
C is p la t in 5 m g /k g
Tu
mo
r v
olu
me
(m
m3
)
* *
Combination CAN04/Cisplatin superior to individual agents• Reduction in severe toxicity• Increased efficacy
Control CAN04 Cisplatin Combination
Animals withdrawn
20 % (Tumor) 0 % 50 % (Toxicity) 20 % (Toxicity)
Tumorreduction
N/A 14% 18% 52 %
Comment Highest tumorburden
Best safety Highest toxicity Superiorefficacy and reducedtoxicity
Co
ntr
ol
CA
N0
4C
isp
lati
nC
om
bin
ati
on
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Cantargia pipeline
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IL1RAP
• Three different systems signal through IL1RAP• These systems contribute to various inflammatory diseases• Can be blocked by antibodies against IL1RAP
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Cantargia partnership with Panorama Res Inc (Sunnyvale, CA)
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IL1RAP summary
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• IL1RAP is a novel target for antibody therapy• IL-1, IL-33 and IL-36 use IL1RAP for signaling• IL-1 and IL-33 function through distinct binding• Generating antibodies blocking various function of these cytokines• CAN04 is entering phase IIa clinical trials in NSCLC and pancreatic cancer