HUB Organoids: a Patient in the Lab A Paradigm-shifting Technology - - PowerPoint PPT Presentation

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 Lab A Paradigm-shifting Technology

Drug Discovery & Development, Companion Diagnostics and (pre) Clinical Patient Stratification

Summary

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Drug Development – Inefficient, Unpredictable, Expensive

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Bridge the Gap Between Lab & Clinic Patient in the Lab Highly Innovative Drugs Very limited predictive biomarker development

Biomarkers & Predictive Tests Small Molecules Antibodies IO Drugs

Pre-Clinical Development Clinical Phase I-III Post Registration

Why HUB Organoids: Credible Models for Drug Development

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Mim imic Pa Patie ient Resp sponse se. Al All Pa Patie ients. Repre resent nt Tumo Tumor r Het eter erogen enei eity. Comb mbina natio ion n The Thera rapy. Bi Biom

• marker.

Mo Most t Pati tient R t Relevant t Mo Model. Pr Preclinical Identif ification

• n of
• f

Cli linic ical R Respon

• nse

Pati tient Str t Strati tificati tion Comp mpanio nion n Diagnos

• stic.

Personalized Medicine – Current Practice

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Patient Diagno sis & Treatm ent Novel Biomarkers Patient Stratific ation

Molecular & Genomic Data Clinical Data

Sta tati tisti tics- bas based d Pred rediction

• n of
• f

Pati tient’ nt’s Respon

• nse

Organoids – Key to Next Generation Predictive Diagnostics

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Molecular & Genomic Data Clinical Data

Org rganoi

• id

Dat ata Func uncti tiona nal T Test t

• f E

Each P h Pati tient nt Patient Diagno sis & Treatm ent Novel Biomarkers Patient Stratific ation

HUB Organoids – From Drug Discovery to Patient Application

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From Traditional to Patient Centric

Pre-Clinical Development Clinical Phase I-III Post Registration

Patient in the Lab

Post Registrations Population Clinical Trial Pre-clinical Patient Stratification Organoid Characterization Preclinical Disc Dev Biomarker Ident

HUB Organoids – Central Role in Different Applications

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HUB Organoids

Deeper understanding of tumour biology and drug response

Pha harma maceuti utical Develop

• pment

More/better targeted drugs Clin linic ical T l Tria ials ls (Pre)Clinical patient stratification Clin linic ical l Appl pplicat ation Predictive diagnostics

Personalized Medicine

HUB – Global Reference Center for Organoid Technology

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Indu dustry C y Collabo aborat ation

(Partnering/Licensing) E.g. J&J, GSK, Eli Lilly, Boehringer Ingelheim, Vertex, Roche, AstraZeneca, Pfizer, Merck, CrownBio and many biotech companies.

• Inv

nvento entor of Organoid Technology

• Extended IP portfolio covering all aspects
• f Organoid Technology
• Global coverage
• >50 granted Pate

tents nts globally (EU as one)

• First Organoid Pred

edicti tive Dia

iagn gnostic ics

used for reimbursement (NL, CF)

• Implementation of predictive diagnostic

centers in EU, US and China

• In process of EMA and FDA approval
• 7 Organoid-based Clin

linic ical T l Tria ials ls

• ngoing
• >10 new drugs developed on Organoids in

clinical trial (>3years developmental time)

• HUB Bi

B Bioban bank containing most cancers

• Diverse range of disease models

(CF, IBD, COPD, AAT, malaria, virology,….) HUB D Dat atabas abase Containing:

• Organoid characterization data
• Patient clinical data
• Genomics and proteomics data

HUB Organoids: Most Patient Relevant Models

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Genetically & phenotypically stable. Mimic clinical patient response. Capturing patient & tumor heterogeneity. Patient in the Lab

In-vitro Models Generated From Any Patient and Most Organs

Sato to et a t al., ., Natu ture 2 2009; Gastoe

• enterol
• log
• gy 20

2011 11

HUB Organoids

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HUB Organoid Application

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Living Biobanks Heterogeneity of (cancer) patient population in the lab Drug Discovery and Validation Predict activity and toxicity of new compounds (combinations) Preclinical Clinical Trials Organoid-based efficacy and toxicity data for patient stratification Database Data-driven drug development and treatment Predictive Diagnostics Improve patient treatment and cost effectiveness Organoid-based predictive diagnostics Grown in vitro from patient biopsies Unlimited expansion, stable genotype and phenotype High-throughput in vitro drug screening Organoid-based clinical trial

HUB Organoid Drug Development Platform Technology

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Bioban

• bank C

Can ancer Mode

• dels

HUB B Exper erti tise & e & Metho ethods Dru rug Dev evel elopment ent

• Lung
• Colon
• Ovarian
• Pancreas
• Liver
• Stomach
• Small intestine
• Head & Neck
• Breast, and more…
• IHC, IF
• Transfection
• Gene editing
• 384-w screens
• Imaging
• Automation
• Genetic modification
• High throughput

Screening

• Expand and diversify

bio-banks

• Platform for high

throughput screening

• Run ex-vivo clinical trials

for combinations

• Pre-clinical clinical trials
• Target population

identification

• Biomarker ident.

Bey eyond nd Kno Known Ta Targ rgets

• New assays
• Pathway Identification
• Co-culture with immune

cells

• Discover new,

actionable targets

• Translation of drug

sensitivity to genomics

• Predictive Diagnostics

HUB Ca Capabilit ilitie ies I s Inf nfra rast struc ructure ure Cha Chang nging ing P Para radig igm I In n Onc ncolog

• logy

HUB Organoids – Unique Platform to Develop Drugs for Patients

• n Patients

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Huma uman O n Organ Huma uman D n Disease Animal ( (Spec ecies es)

Breast Colon Kidney Lung Liver Pancreas Small intestine Stomach Head & Neck Ovary … Cystic Fibrosis Genetic Diseases (A1AT, etc) IBD COPD Cancer Infectious Diseases (Virology (e.g. SARS- COVID), Malaria, HBV etc.) … Dog Mouse Mini pig Rat Monkey

Repla lacin ing g Anim imals ls. Red educ ucing ng Time e & C Costs ts. Pati tient R ent Rel elev evant nt Mode

• del.

PDX DX Pri rimary ry Tissue Ce Cell ll-Line Orga ganoi

• ids

Sc Scalability Costs Reprod

• ducibility

Thr hroughp hput ut Clinical Rel elev evan ance Captu apture R e Rar are e Mutati tations

Clinical Validation of Organoids

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Cancer Organoids – Independent Clinical Validation

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Con

• ntrol

rol Org rganoi

• id

Pati tient nt Org rganoi

• id

Orga rganoid gro growth Tumor gro r growth

Pre-treatment

Organ anoid de d deat ath

Post-treatment

Pati tien ent t CT Sca Scan

A living biobank of breast cancer organoids capture disease heterogeneity

• Sachs et al., Cell 2018; 172: 373-386.

Patient-derived organoids model treatment response of metastatic gastrointestinal cancers

• Vlachogiannis et al., Science 2018; 359: 920-926.

Organoid Profiling identifies common responders to chemotherapy in pancreatic cancer

• Tuveson et al., Cancer Discov 2018; 8(9): 1112–29.

Pancreatic cancer organoids recapitulate disease and allow personalized drug screening

• Driehuis et al., PNAS 2019; 26, 116 (52) 26580-26590.

Patient-derived organoids predict chemoradiation responses of locally advanced rectal cancer

• Hua et al., Cell Stem Cell 2020; 26, 17-26.

Predictive Diagnostics in Practice - Cancer

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Organoids Mimic Clinical Responses

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Sa Sachs hs et a al.

• l. C

Cell 2 ll 2017, 172, 3 373-386 86

Organoid Response in the Lab and Patient Response in the Clinic Match

Metastatic Breast Cancer Patie ient R Response Pati tient ent 1 1 Tu Tumor R r Response Pati tient ent 2 2 Progr gressiv ive D Dis isease Clinical Response Organoid R d Respon

• nse

Pati tient ent 1 1 Organoid d Responde der Pati tient ent 2 2 Or Organ anoid N Non

• n-

Responde der

Organoid Generation and Characterization

Tissue Organoid Breast Cancer Characterization

Histology Whole Genome DNA Seq. RNA-Seq. Drug Testing Personalize Diagnostics

Predictive Diagnostics in Practice – Cystic Fibrosis

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Predictive Diagnostics Cystic Fibrosis, First Organoid Clinical Success

• A CF assay on Cystic Fibrosis patient

Organoids

• Patients treated based on results of
• rganoid tests

Implemented in the Netherlands Organoids as reimbursement tool for insurance companies

Healthy CFTR activation: Swelling of Organoids Mutated CFTR activation: No-Swelling of Organoids

Mutated CFTR activation after Drug Treatment: Swelling of Organoids

Next Gen. Treatment – Focus Shift From Drug to Patient

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• This paradigm shift from a drug-centric view towards personalized diagnostic will improve

treatment efficiency, cost effectiveness, drug development process, etc.

• Revolution that started with NGS can be realized with Organoid Technology

Fo Focus o s on Dru rugs gs Focus us o

• n

n Patie ient nt

Human Organoid Models Examples: IBD, Toxicology and Immuno-Oncology

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Intestinal Organoids: Disease Models VEO-IBD

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Tissue Patient (2 days old) Organoid Patient TTC7 Mutation, Rock Inhibitor Reverses Phenotype

Bigo gorgn rgne et. al. l., J

• J. Clinic

linical I l Inv nvestig igatio ion, n, 2 2014

Animal-Derived Organoid Models

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Wistar WU Minipig Beagle

• Organoids derived from

different species recapitulate discrepancies in toxicity.

• Species:
• Rat (Wistar WU)
• Dog (Beagle)
• Mouse
• Mini pig
• Monkey
• More in pipeline…

Differences in GI Tract Toxicity Between Species

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0.001 0.01 0.1 1 10 100 50 100 150 Gefitinib (μM) relative viability % Gefitinib 72 hrs Rat_Gefitinib Human_Gefitinib Dog_Gefitinib

Gefitinib

Dog Human Rat

Relative Viability %

Small Molecules Against NSCLC (OTX05)

Relative Viability %

• Organoids derived from different species recapitulate

discrepancies in toxicity.

Loss of Barrier Function: Basolateral vs Apical Toxicity of Gefitinib

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Gefitinib Basolateral DMSO

Intestinal Organoids Consist of All Cell Types

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Stem tem C Cel ell

WNT NT Not

• tch

ch EG EGF

Enter ntero- end endoc. Paneth neth cel ell Enter ntero- cytes tes WN WNT Notc tch EGF GF Gobl Goblet cel ell WN WNT Notc tch EGF GF WN WNT Notc tch EGF GF WN WNT Notc tch EGF GF AP AB GLP1 LYS Ki67 H&E

Ki67

Hepatocyte Maturation in Differentiated Liver Organoids

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7 Days Diff 11 Day Diff 15 Day Diff CYP3A4; KR7; DNA

P450 Cytochrome Activity Assay

7 d a y s d iff. 1 1 d a y s d iff 1 5 d a y s d iff. 1 ×1 0 6 2 ×1 0 6 3 ×1 0 6 4 ×1 0 6 L u m in e s c e n c e /m l/1 x 1 0 ^ 6 c e ll C Y P 3 A 4 7 d a y s d iff. 1 1 d a y s d iff 1 5 d a y s d iff. 2 ×1 0 5 4 ×1 0 5 6 ×1 0 5 8 ×1 0 5 1 ×1 0 6 L u m in e s c e n c e /m l/1 x 1 0 ^ 6 c e ll C Y P 2 C 9

Human Liver Organoids Predict Known Clinical Liver Toxicity

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1 1 0 1 0 0 1 0 0 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 µ M re la tiv e v ia b ility %

Immune system dependent toxicity Clinical trial failure due to human liver toxicity

Liver Organoid Models vs. Other Models

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Industry Validation

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Generation Antibody Library >500 Screening Antibody Panels >50 5 Candidate Leads Lead

IN D

# Different Organoids Used for Screening 1 3 25-50 Biobank >50K Compound Library 500 Primary Hits 5-10 Candidate Leads Lead

IN D

Human Organoid Models Co-Culture Immune System

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Engineered T Cells Induce Tumor Specific Cell Death

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Patient 1 Patient 2

Nor

• rmal

al Or Organ anoi

• ids

Tumor

• r Or

Organ anoi

• ids

ds Mock T-cells IFN-γ Measurements Show a Wide Range

• f T-Cell Response

Engineered T-cells Mock T-cells Engineered T-cells

HUB Organoid – T Cell Co-Culture

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Aut utolo logous us T TIL Deriv ived C CD8 And nd T-Cell R ll Reactiv ivit ity to Organo noid ids Dijks jkstra, , Vo Voest, Cle levers, C Cell 2 ll 2018

Modelling for Immuno-Oncology

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T-Cells Organoids Death

About HUB Organoid Technology

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HUB Business Propositions

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• New model

development

• Biobank generation
• Predictive diagnostics
• Co-development
• Combining innovative

technologies

• Drug development

(target discovery to clinic)

• Preclinical clinical trials
• Organoid clinical trial
• Biomarker

identification

• Patient stratification
• IP & know-how
• Tech-transfer
• Access to HUB

biobanks

Licensing CRO

(fee-for- services)

R&D Collab. Partnerin g

Scientific Base and Industry Adaptation of HUB Organoid Technology

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Jan 2020 Scienti entific B Base ( e (Hub ubrec echt ht Ins nsti titute) tute)

• Prof Dr Clevers: inventor of the Organoids; pioneer in adult stem cells discovery,

leader in stem cell biology & Organoids research

• >700 Scientific publication
• >90 Science, Nature & Cell publications
• >100 Clevers Organoid specific publications
• The Breakthrough Prize in Life Sciences
• Louis-Jeantet Prize for Medicine, Geneva, Switzerland
• Member of the National Academy of Sciences of the USA
• Member of the Academie des Sciences de I'Institut de France

Ind ndus ustr try B Base e (HUB)

• Collaboration/partnering with pharma and biotech
• >50 granted patents (broad coverage in China)
• >7 organoid-based clinical trials
• >7 new drugs developed on Organoids in clinical trial
• First Organoid predictive test used for reimbursement (NL, CF)

Hubrec echt ht Or Organoi

• id Tec

echno hnology (HUB UB) was as foun unded ed by by the the Hubrec echt ht Insti titute, tute, th the Uni niver ersity ty Medi dical al Center enter Utr trec echt, ht, and nd the the Royal Nether therlands Academy my of

• f Art

rts and nd Scienc ences es (KNAW) W). HUB UB’s ’s techno hnology cons nsti titute utes a pa parad adigm-shi hifti ting ng pl plat atfor

• rm

fo for dru rug di discov

• very

and nd devel elopment, ent, (pre)clin linic ical pati tient nt str trati tificati tion, n, pred edicti tive diagn gnostic ics, pe person

• nal

alized med edicine, ne, clin linic ical tria ials ls, reg egene enerati tive med edicine, ne, and nd com

• mpan

panion dia iagn gnostic ics. As As the the globa bal lea eader er in in the the field ld of

• f Or

Organ anoi

• id Tec

echn hnology, HUB UB offe ffers licen enses es to to its ts proprietar ary tec techn hnology, pr provide des ser ervices es and nd acce ccess ss to to its ts livin living or

• rgan

anoi

• id bi

bioban

• banks.

ABOUT HUB

Contact Us: Business Development bd@huborganoids.nl www.huborganoids.nl