hub organoids: a patient in the lab · 2019. 11. 20. · •dog (beagle) •mouse •mini pig ......
TRANSCRIPT
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H U B R E C H T O R G A N O I D T E C H N O L O G Y
HUB Organoids: a patient in the labA Paradigm-shifting Technology
Drug Discovery & Development, Companion Diagnostics and
(pre) Clinical Patient Stratification
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Drug Development – Inefficient, Unpredictable, Expensive
2
Bridge the Gap Between
Lab & Clinic
Patient in the Lab
Drug Development Focus:
Highly Innovative Drugs
Developed on
>50y Old Models
Small Molecules
Antibodies
IO DrugsPre-Clinical
Development
Clinical Phase I-III
Post Registration
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Adult Stem Cells
3 Hans Clevers
Hubrecht Institute
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LGR5 Stem Cell Derived Organoids
4
1 2 3 4 5 6 7 8 9
10 11 12 13 14
day
day
Organoids Recapitulate
Organ Function
Organoids Represent
Tumor Heterogeneity
In vitro Models Generated From Any Patient and Most Organs
Sato et al., Nature 2009; Gastoenterology 2011
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Why Organoids: Credible Models for Drug Development
5
Mimic PatientResponse.
All Patients.
Represent Tumor
Heterogeneity.Combination Therapy.
Biomarker.
Patient Relevant Model.
(Pre)-clinical Identification of
Clinical ResponsePatient Stratification
Companion Diagnostic.
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Organoid Technology: Personalized Medicine
6
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HUB Organoid Biobanks:
Pre-clinical Patient Population
7
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Co
ntr
ol
Org
an
oid
Pati
en
t
Org
an
oid
Organoid growth
Tumor growth
Pre-treatment
Organoid death
Post-treatment
Pati
en
t
CT
Scan
A living biobank of breast cancer organoids capture disease heterogeneity
Sachs et al., 2018, Cell 172, 1–14
Patient-derived organoids model treatment response of metastaticgastrointestinal cancers
Vlachogiannis et al. Science 2018;359:920-926
Organoid Profiling identifies common responders to chemotherapy in pancreatic cancer
Tuveson et al. Cancer Discov; 8(9); 1112–29
Organoid Predict Clinical Response
Organoids Are A Patient in the Lab
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HUB Organoid Platform
9
Human Organ Human Disease Animal (Species)
Breast
Colon
Kidney
Lung
Liver
Pancreas
Small intestine
Stomach
Head & Neck
Ovary
…
Cystic Fibrosis
Genetic diseases (AAT, etc)
IBD
COPD
Cancer
Infectious Diseases (Virology,
Malaria, etc.)
…
Dog
Mouse
Mini pig
Rat
Monkey
Replacing
Animals.Reducing
Time & Costs.
Patient Relevant
Model.
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Organoid Drug Development
10
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First Organoid Based Drug in Clinical Trial
11
Biclonics®
Fe
atu
re M
ea
su
rem
en
ts
High content screening on tumor
and normal organoidsBiclonics® targeting CRC
Organoids – ex vivo patient-
derived tumor tissue
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HUB, Merus develop New CRC Treatment Using Organoids
12
Identify effective compound on
patient derived relevant>500 Bispecific antibodies
3 Organoid Lines
52 Hits screened24 CRC organoids lines
1 BispecificOptimization
CT
Pre-clinical identification of target
population
Mechanism and Lead development
Clinical Trial start Q1 2018
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Identification of Specific Target Pair: LGR5/EGFR
13
Frac
tio
n a
po
pto
tic
nu
clei
MCLA-158
Cetuximab
LGR
4
LGR
5
ZNR
F3
RN
F43
LGR
4
LGR
5
ZNR
F3
RN
F43
LGR
4
LGR
5
ZNR
F3
RN
F43
LGR
5
TT Mock Control RNF43
1st Arm
Ce
tuxi
mab
PI3
Ki
Biclonics®
Dose
10 μg/ml
2 μg/ml
Normal
Tumor
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Lead Antibody Differentiates Between Normal & Tumor Organoid
14
+
Strong Inhibition Weak Inhibition
KRASmut MCLA-158Lgr5 mAb +
EGFR mAbCetuximab
G12D
G12D
G12V
WT
G12C
WT
WT
WT
WT
WT
WT
Tum
or
Org
an
oid
s
Norm
al
Org
anoid
s
Organoid Growth
Organoids (Ex vivo): From Tumor and Normal Colon
Tissue from CRC Patients
MCLA-158
CetuximabVehicle
PDX (In vivo): Mice Transplanted with Tumor Organoids
and Treated with Cetuximab and MCLA-158
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1-3
10-20
10-50
>100
Primary Screen
Diseased/Normal Control
Patients
Mechanism and Lead
Selection
Lead and Patient
Stratification
<50K Compound Library
100-200 Primary Hits
5-10 Candidate Leads
1 Lead
# Organoid Biobank
Used for Screening
Patient Derived Organoid Based Drug Development
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Human Organoid Models
Intestinal Organoids
Characterization & Assays (IBD &Tox)
16
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17
Wistar WU
Minipig
Beagle
Animal Derived Organoid Models
•Organoids derived from different species recapitulate discrepancies in toxicity.
•Species: • Rat (Wistar WU)
• Dog (Beagle)
• Mouse
• Mini pig
• Monkey
• More in pipeline…
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18
Rat
Dog
Human
OTX, Bromodomain InhibitorGefetinib HDM2 Antagonist
Organoids Predict Efficacy and Safety
μMμMμM
0.001 0.01 0.1 1 10 1000
50
100
150
Gefitinib (μM)
rela
tive
via
bili
ty %
Gefitinib 72 hrs
Rat_Gefitinib
Human_Gefitinib
Dog_Gefitinib
0.01 0.1 1 10 100
0
50
100
150
200
JNJ-233 (µM)
rela
tive
viab
ility
%
JNJ-233 EM
HDM2 antagonist
DuodenumToxicity screen 168h
Dog duodenum_JNJ-233-AAA (EM)
Rat duodenum_JNJ-233-AAA (EM)
Human duodenum_JNJ-233-AAA (EM)
Z-score: Rat duodenum: 0.551101Human duodenum: -0.087418Dog duodenum: 0.643017
quadruplicate
0.01 0.1 1 10 100 10000
50
100
150
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Metabolism in human GI tract organoids
10 60 120
0
500
1000
1500
t (min)
Meta
bolit
e (
ng/m
l)
BIBR0951_CES2_organoids
10 60 120
0
500
1000
1500
t (min)
Meta
bolit
e (
ng/m
l)
Estradiol-3-glucoronide_UGT1A1_organoids
10 60 120
0
20
40
60
80
t (min)
Meta
bolit
e (
ng/m
l)
7-Hydroxycoumarin-sulfate_SULT_organoids
10 60 120
0
50
100
150
t (min)
Meta
bolit
e (
ng/m
l)
5-NAcetylASA_NAT1_organoids
pIEC: Pooled Human Enterocytes
Metmax™: Pooled Human Enterocytes
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Intestinal Organoids to Test Barrier Function and Transporters
20Pourfazad et al., in preparation.
Side view
Top view
Monolayer in Expansion
WENR
Enterocyte Differentiation
(iWNT)
Trans Epitelial Electerical Resistance (TEER)
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Monolayer Transport: Basal to Apical
21
PSC833
Rhodamine 123Cell permeable
P-g
p
RFU in Top Compartment
Basal to Apical Transport• Rhodamine 123: transport via P-gp (MDR1, ABCB1,
apical )• PSC833: P-gp inhibitor
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Monolayer Transport: Apical to Basal
22
Apical to Basal Permeability, Basal to Apical Transport• Rhodamine 123: transport via P-gp (MDR1, ABCB1,
apical )• PSC833: P-gp inhibitor
RFU in Bottom Compartment
PSC833
Rhodamine 123Cell permeable
P-g
p
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Human Organoid Models
Liver Organoids
23
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Human Hepatocyte Organoids for Toxicology
24 DAPI / AFP / MRP2 / F-actin
Anna Rios, Hans Clevers
Prinses Maxima Center, Netherlands
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Genetic Diseases Platform
25
Acute Liver Failure
Alpha-1 antitrypsinA1AT mutation
Cirrohsis
COPDAlpha-1 antitrypsin
Huch et al. Cell 2015
Wilson’s DiseaseATP7B mutation
Cupper overload
Vomiting
Brain, eye, kidney damage
Crigler NajjarUGT1A1 gene
UDP glucuronosyltransf.
Metabolism of bilirubin
Brain damage
Alagille SyndromeJAG1 or NOTCH2
bile ducts development
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Hepatocyte maturation in differentiated liver organoids7
da
y d
iff
7 da y s d
if f.
1 1 da y s d
if f
1 5 da y s d
if f.
0
11 0 6
21 0 6
31 0 6
41 0 6
Lu
min
es
ce
nc
e/m
l/1
x1
0^
6 c
ell
C Y P 3 A 4
7 da y s d
if f.
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21 0 5
41 0 5
61 0 5
81 0 5
11 0 6
Lu
min
es
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nc
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l/1
x1
0^
6 c
ell
C Y P 2 C 9CYP2C9 activity
CYP3A4 activityP450-GloTM
CYP3A4
KR7
DNA
CYP3A4
KR7
DNA
CYP3A4
KR7
DNA
11
da
y d
iff
15
da
y d
iff
0
50
100
150
200
250
300
350
0 5 10 15 20 25
OH
-Mid
ng/m
l
Time (hrs)
Hepatocyte
OrganoidsMidazolam metabolism
-4
1×104
1×105
1×106
1×107
CYP3A4P450-Glo™ Assays
lum
inesence/1
0^6
cells
/ml
Organoids diff. day 15
Hepatocytes
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27
1 1 0 1 0 0 1 0 0 00
2 0
4 0
6 0
8 0
1 0 0
1 2 0
1 4 0
M
re
lati
ve
via
bil
ity
%
1 4 d a y -re fre s h e d
Immune system
dependent
toxicity
Human Liver Organoids Predict Known Clinical Liver Toxicity
Clinical trial failure
due to
Human liver toxicity
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Human Organoid Models
Co-Culture Immune System
28
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Modeling Immuno-Oncology
29
T cellsOrganoidsDeath
Anna Rios, Hans Clevers
Prinses Maxima Center, Netherlands
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Engineered T-Cells Induce Tumor Specific Cell Death
30
Patient 1
Patient 2
Normal OrganoidsTumor Organoids
Mock T-cells
IFN-γ Measurements
Show a Wide Range of
T-Cell Response
Engineered
T-cellsMock T-cells Engineered
T-cells
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Organoid – T-Cell Co-Culture
31
Dijkstra, Voest, Clevers, Cell 2018
Au
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us
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De
rive
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An
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-
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ea
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Develop Drugs for Patients on Patients
Patient in the Lab
Pre-clinical Patient
Stratification
Post Registrations
Population
Organoid Characterization
Preclinical Disc Dev
Clinical Trial
32
Pre-Clinical Development
Clinical Phase I-III
Post Registration
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Contact Us
33
Hubrecht Organoid Technology is anot-for-profit organization founded in2013 by the Hubrecht Institute, KNAWand the University Medical CenterUtrecht (NL).
Based on the work of Prof. Dr. Hans
Clevers, who discovered the HUBorganoid technology, HUB has adedicated team acting as a global
expertise & reference center
Contact:
Dr. Bahar [email protected]+31 611957039
ABOUT HUB