clinically relevant science - reprocell · reducing safety-related drug attrition: the use of in...
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Human Inflammatory Bowel DiseaseFresh Tissue Assays Predictive Drug Discovery Services
Meet clinical needs in IBD research
The incidence of IBD is increasing2 and there is a clinical need for safer, more precise IBD treatments3,4. However, failure to predict the safety and efficacy of drugs during preclinical research means that attrition rates are high5.
REPROCELL offers the most clinically relevant IBD assay on the market, which uses human tissue donated by real IBD patients.
Why use human tissues instead of traditional animal models?
� Avoid species differences � Increase therapeutic relevance6
� Improve understanding of IBD pathology7
� Proof of concept in diseased human tissues� Reduce late-stage failures� Strengthen IND submissions� Explore complex cell interactions in whole tissue
Five reasons to choose REPROCELL’s Human IBD Fresh Tissue Assay1. Access the only commercially available assay using intact, living human tissues.2. Addcommercialvaluebydemonstratingefficacyintissuesfromyourtargetpatientgroup.3. Identifyleadtestagentswithlikelihoodofsuccessinpatients.4. Compareyourtestagentstocurrentstandardofcaredrugs.5. CombinewithREPROCELL’smolecularbiologyservicestorelatephenotypetogenotype.
ClinicallyRelevantScienceIntroducing the Human Inflammatory Bowel Disease (IBD) Fresh Tissue Assay from REPROCELL: the most clinically relevant IBD model on the market. Our living tissue model captures the heterogeneous landscape of IBD1 by combining drug efficacy data with a medical history of each human donor.
www.reprocell.com
AREPROCELLBRAND
Functional validation of healthy and diseased tissues
Control: 0 hrs Control: 24 hrs
Crohn’s Disease: 0 hrs Ulceratice Colitis: 0 hrs
12 well plate
Test agent
Well
Gut mucosal specimen
Culture medium
Breaking Barriers
More scientists would like to use human tissue in their research7. However, poor biobanking infrastructure and techni-cal difficulties present significant barriers. Through our global network of biorepositories, we can access a frequent supply of high-quality intestinal tissues from Crohn’s and Ulcerative Colitis (UC) patients. They are then maintained for 24-hours in our ex vivo culture system, where they can be exposed to a variety of novel and standard-of-care drugs.
As part of our functional validation, biopsies are screened for inflammatory mediators commonly upregulated in IBD. In this example, over 40 inflammatory mediators were measured to investigate the cytokine release profiles in healthy and dis-eased tissue. The disease group showed greatly increased levels of a range of key cytokines and chemokines commonly upregulated in IBD, including IL-17α, IFNγ and IL-12p70.
Histological validation of healthy and diseased tissues
At 0 hours, the control tissue shows good crypt morphology, intact lamina propria and muscularis mucosa. 24 hours later, the crypt morphology and muscularis mucosa are maintained. Although there is slight degradation of epithelial structure, it is generally intact. At 0 hours, Crohn’s disease tissue shows shortened and widespread crypts, increased lamina propria cellularity and granuloma. Ulcerative Colitis tissue demonstrates crypt destruction, widespread mucosal erosion and severely thickened muscularis.
IL12p70n = 3 healthy donorsn = 3 Crohn’s donors
Healthy
4.03.53.02.52.01.51.00.50.0Co
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Investigate interpatient variation in drug response at the preclinical stage
Donor 1Donor 2Donor 3
–10 –9 –8 –7 –6 –50
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DMSO
Log M [Doramapimod]
Precision Medicine
Precision medicine aims to deliver the right drug to the right patient at the right dose. However, most presently available drugs fail to work in a high percentage of pa-tients; including treatments for IBD3.
At REPROCELL, we offer early stage characterization of the patient population. By combining measurements of drug efficacy with clinical histories and access to state-of-the-art molecular phenotyping, we can investigate inter-individual variation in drug response at the preclin-ical stage.
� Only 1 in 4IBD patientsbenefit from
treatment with
Infliximab3
Relate drug response to clinical history
Intestinal biopsies were obtained from 3 UC patients. Following an 18-hour culture period, TNFα release was measured across a wide concentration range of the test agent Doramapimod (see graph).
Differences in response were evident across patient samples, suggesting variation in the UC patient popula-tion, as is known to occur clinically.
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Pred 100 nM
Pred 1 µM
BIRB796 10 nM
BIRB796 100 nM
Control
Compare the meanresponsesofyour test agent to standard-of-carecompounds
n = 10 donorsMean + S.E.M.
“Biopta’s human tissue services have played a critical part in our compound selection and have added considerable value to our lead compound”— President & Head of R&D, Canadian Biotech
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Pred 1 µM
BIRB796 10 nM
BIRB796 100 nM
Control
25 year oldFemaleUlcerative ColitisSteroids for 5 yearsNon-smoker
40 year oldFemaleCrohn’s DiseaseSteroids for 3 yearsSmoker
32 year oldMaleCrohn’s DiseaseSteroids for 3 yearsNon-smoker
MM-BIOPTA-HUMANFTA-D001004-US
REPROCELL Inc (Japan) MetLife Shin-yokohama 381, Bldg. 9F 3-8-11, Shin-yokohama Kohoku-ku, Yokohama Kanagawa 222-0033 Japan
T: +81 45 475 3887 E: [email protected]
REPROCELL USA Inc 9000 Virginia Manor Road Suite 207 Beltsville, MD 20705 USA
T: +1 301 470 3362 E: [email protected]
REPROCELL Europe Ltd Thomson Pavillion, Todd Campus West of Scotland Science Park Acre Road Glasgow, G20 0XAUK
T: +44 (0)141 465 3460 E: [email protected]
www.reprocell.com
REPROCELL India Ltd 3-1-135/1A, CNR Complex Mallapur Hyderabad 500 076 Telangana India
T: +91-40-27178178 E: [email protected]
What is included in our IBD predictive drug discovery services?
� A customized project to meet your research goals.� An expert Study Director assigned to manage each project as your single point of contact from initiation
to report.� Rapid access to human healthy and diseased tissues, through our industry-leading human tissue
network. � GLP projects available.� Ownership of all data generated during the project.
A B
C
REPROCELL’s Research and Development team based at our Centre for Predictive Drug Discovery, Glasgow, UK. A: REPROCELL Study Director preparing a 12 well plate for experimentation. B: Research and Development preparing tissue biopsies. C: A sample of fresh, living tissue from an IBD patient.
1. Ananthakrishnan. Epidemiology and risk factors for IBD. Nature reviews Gastroenterology and Hepatology. 2015, 12:205-17.
2. Porter et al. Can we target endogenous anti-inflammatory responses as a therapeutic strategy for inflammatory bowel disease? Inflammatory Bowel Disease. 2018, 00:1-11
3. Schork. Time for one-person trials. Nature. 2015, 520:609-611.4. Bowes et al. Reducing safety-related drug attrition: the use of in
vitro pharmacological profiling. Nature Reviews Drug Discovery. 2012, 11:909–22.
5. Denson et al. Challenges in IBD Research: Update on progress and prioritization of the CCFA’s Research Agenda. Inflammatory Bowel Disease. 2013, 19:677-682.
6. Jackson et al. The use of human tissue in safety assessment. Journal of Pharmacological and Toxicological Methods (2018).
7. Edwards et al. Human tissue models for a human disease: what are the barriers? Thorax. 2014, 0:1-3.
References