Gut-based immunotherapy - implications for NASHGut-based immunotherapy - implications for NASH...
Transcript of Gut-based immunotherapy - implications for NASHGut-based immunotherapy - implications for NASH...
Gut-based immunotherapy - implications for NASHTargeting the gut immune system for alleviation of the systemic
inflammatory response without immune suppression
Yaron Ilan, M.D.
Gastroenterology and Liver Units, Department of Medicine
Hebrew University-Hadassah Medical Center
Jerusalem, Israel
July 2018
Disclosure I have financial relationships with the companies below and the content of my presentation does include a discussion of the investigative use of products being developed by the companies below. The studies described were supported in part by several of these companies.
Consultant:
Teva; Abbott; ENZO; Protalix; Therapix; Betalin Therapeutics; Immunepharma; JTI; Immuron; Chiasma Pharma; Nasvax; Alcobra; One Day Pharma; Cure Tech; Lutea; Kamedis; MedWell; Accelmed; Medial; SciM; Tiziana Pharma;
Medical Director:
Exalenz Bioscience; Natural Shield; Oberon Sciences; Plantylight;
Forward-looking statement Please be advised that the information and projections provided in this presentation may include forward-looking statements with respect to plans, projections or future performance of the compounds and companies presented, the occurrence of which involves certain risks and uncertainties and is not under the control of these companies, including, but not limited to, changes in regulatory environment and success in implementing its research, development, sales, marketing and manufacturing plans, protection and validity of patents and other intellectual property rights, the impact of currency exchange rates and the effect of competition by other companies.
Therapy for NASH: The next decade
a. Target multiple mechanisms
b. Long term safety
c. Target the whole spectrum of the disease: from prevention to cirrhosis
d. A combination therapy
e. Alleviates concomitant disorders (e.g. diabetes, hyperlipidemia)
Ilan, Y Dig Dis Sci. 2018 Apr 20.Ilan, y Ann Gastroenterol. 2018 May-Jun;31(3):296-304.)
Oral immune therapy Examples Advantages
Picasso Stadel Museum, Frankfurt
How does our environment blends into us
Oral immune therapy
Immune system
Metabolic syndrome = low grade chronic inflammation
Based on: Hotamisligil GS. Nature 2006;444:860–7Tilg H, et al. Gastroenterology 2006;131:934–45
Disruption of the interface between inflammatory
and metabolic pathways is central to the
pathogenesis of the metabolic syndrome
Oral immune therapy
Inflammation: Fueling the growing fireDiverse immune pathways at different disease stages
https://seekingalpha.com/article/3546436-revisiting-nash-therapeutic-targets-competitive-landscape
https://imarketsmart.com/why-you-should-add-fuel-to-the-fire/
http://oncologypro.esmo.org/Education-Library/Essentials-for-Clinicians/Lymphomas/Chapter-1-The-Immune-System
Presented to the gut-associated lymphoid tissue /dendritic cells
Antigen / Antibody / adjuvant
Target organs• Liver• Pancreas• Adipose tissue• Bowel• Muscle
Promotion of Tregs in
mesenteric lymph nodes
Image from Fagarasan S & Honjo T. Nat Rev Immunol 2003;3:63–72
Oral immunotherapy: modulation of the systemic immune response via alteration of the gut immune system without immune suppression
Ilan Y, et al. Immunol Cell Biol 2009;87:514–24Ilan Y, Hum Immunol. 10:768-76, 2009
Oral immune therapy
Tregs: Regulatory T cells
Adapted from: Ilan, Y 2016 . Alimentary Pharmacology & TherapeuticsIlan Y, Clinical & Translational Immunology; 2016
Oral immunotherapy: Re-educating the immune system
Gut-associated lymphoid tissue
Liver
Oral immunotherapy compounds
Microbiome
DC
NKT
T cell
MLN
Regulatory cells
Immune signal
• Immune modulation without immunosuppression
• Oral immunotherapy using non-absorbable compounds
are being evaluated in pre-clinical & phase I/II NASH trials
DC: Dendritic cellsMLN: Mesenteric lymph nodesNKT: Natural killer lymphocytes
Induction of oral tolerance towards fatty liver-extracted proteins
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Control
Fed with liver extracts
Reduction of hepatic fat content by MRI
Reduction of hepatic triglycerides content
Improved glucose intolerance
1911 Wells
Jewish sages wrote:
“If one is bitten by a mad dog, he may
eat his liver and be cured.”
ControlFed with liver
extracts
Control
Ilan, Y. Am J of Physiology, 2016
Fig. 1
Journal of Hepatology .2014.11.002
Circulating phospholipid profiling identifies portal contribution to NASH signature in obesity
Prevalence of overweight, insulin resistance and type II diabetes before and after enzyme therapy
Before enzyme therapy
Cross-sectional study (after enzyme therapy, median 11
years)
Prevalence of being overweight (%) 16 56
Prevalence of insulin resistance (%) Not known 6
Prevalence of type II diabetes (%) 0 8.2
Langeveld M, et al. Blood Cells Mol Dis 2008;40:428–32Ilan Y. Immunolgy Cell Biology 2008
Increase in BMI during treatmentwith ERT (n=32)
Bo
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mas
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dex
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Evolutionary advantage of patients with Gaucher’s disease: An immune protective effect of b-glucosylceramide (GC)
GC-treatedControl
Control GC-treated
GC improves glucose intolerance and decreases hepatic fat accumulation in the ob/ob model
Margalit M, et al. J Pharmacol Exp Ther 2006
GC-treated Control
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Lalazar Mole immunology 2008Ilan Y, et al. Immunol Cell Biol 2009;87:514–24
http://acseenotes.wordpress.com/2011/03/07/cytology
GC
Tregs
NKT
T cell
Altered lipid rafts
Altered expression of raft membrane proteins
NFkB
DC
STAT
Flotilin 2
Cross talk
Oral administration of glycosphingolipids alters lipid rafts on cells membranes
GC: b-glycosylceramideLC: b-lactosylceramideIGL: b-glycosylceramide+b-lactosylceramide
Primary endpoint - HbA1c Secondary endpoint - % Fat by MRI
Week 0 Week 40N=2340 weeks
Safety and Effect of Oral Administration of GC (EGS21) in Subjects with Diabetes and NASH: Results of a double blind placebo controlled trial
Lalazar, J Med Food 2017 20(5:)458-464.
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Oral administration of DR6MP: A minimally absorbed delayed-release 6-mercaptopurine
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Phase II double blind placebo controlled trialN=70
Ilan, E. Clin Exp Immunol. 2015 181(2):362-72
No Leukopenia in DR6MP-treated CD
Reduction in IFN-gamma ELISPOT assay
Reduction in CDAI in DR6MP-treated CD
Alteration of systemic Immune system in DR6MP-treated
PLP-EAE in SJL
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CD3 50 gCD3 5 g Control IgG
CD3 500 g
Mea
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core
Days post-immunization
Ochi H, et al. Nat Med 2006;12:627-35
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Induction of oral immunotherapy using oral anti-CD3
Weiner et al. Immunol Rev; Brain. 2016; Immunotherapy. 2016.
Biologically active anti-CD3 recovered from the gut
Ilan Y, et al. Proc Natl Acad Sci U S A; 2010
Induction of oral immunotherapy using oral anti-CD3 for NASH
TGF-b IL-10
IL-2 IFN-g
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IL-2 IFNg
An adjuvant effect on the innate immune system in the gut
TregTGF-bIL10
macrophage
Adipose tissue
Treg
Treg
DCmacrophage
Deactivates innate immune cells
Promotes Treg
Downregulation of inflammation in adipose tissue
T cell
TCR/CD3
NKT
CD1d
Oral anti-CD3 + GCAdaptive immunity Innate immunity
anti-CD3 GC
liver
pancreas
Amelioration of fatty liver &islet hypertrophy in the pancreas
Ilan Y, et al. Proc Natl Acad Sci U S A; 2010 107:9765–70
macrophage
DC=Dendritic cellsTregs=regulatory T cellsNKT=natural killer lymphocytes
Oral anti-CD3 in NASH: promotes regulatory T cells, decreases liver enzymes, and alleviates insulin resistance
Ilan Y J Clin Immunology 2015
Safety:
I. No treatment-related adverse events
II. Normal blood cell counts: No change in CD3+ counts
Efficacy biomarkers:
I. Liver enzymes ↓
II. TG ↓
III. Glucose ↓ Insulin ↓
• Phase II, randomized single blinded clinical trial• 36 subjects with biopsy-proven NASH with type II diabetes• 0.2, 1.0, 5 mg or placebo daily for 30 days
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Oral anti-CD3 increased Tregs
PBS anti-CD3+GC
Decrease CD11b+F4/80 macrophages increase in foxp3 expression in CD4+ T cells
A decrease in cell infiltration into adipose tissue
Decrease TNF
Increase in IL10 & TGFb
Effect of oral administration of anti-CD3 with glycosphingolipids on adipose tissue in a NASH model
Ilan Y, PNAS, 2010
IL10 TNF TGFb
Oral administration of Foralumab
Foralumab: Humanized Oral anti-CD3 in NASH
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Foralumab survives digestion in the stomach
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Foralumab remains localized in gut wall 3Antigen presented to innate immune system in mesenteric lymph nodes
Dendritic cells induce regulatory T cells
TT
Anti-inflammatory cytokines downregulate inflammation in target organs
Increase in Tregs
Does not pass into blood stream
liver
muscle
Ilan, Shailubhai, Sanyal, Clin Exp Immun 2018 (In Press)
IMM124E
Liver damage
Regulatory T cells
Anti LPS Ab
LPS contributes to activation of inflammatory pathways associated with inducing NASH in a background of fatty liver
Adopted from AASLD 2010; J Hepatol 2007
Adjuvants: Glycosphingolipids
Oral administration of anti-LPS antibodies with glycosphingolipids:An adjuvant effect on the innate immune system in the gut
Yaʼacov AB. BMC Gastroenterol. 2015
* P<0.05; ** P<0.009
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Decreased liver enzymes Decreased serum triglycerides
Adar T. Clin Exp Immunol., 2012
Pre clinical: Leptin-deficient model of NASH
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An adjuvant effect on the innate immune system in the gut in NASH &colitis
Mizrahi M. J Inflamm Res. 2012
Day 1 Day 30
Increased GLP1 and adiponectin Increased CD4+CD25+Foxp3+ Tregs
Oral administration of IMM124E in NASH: Results of a phase I/IIA
IMM124E :Results of Phase IIA clinical trial
Mizrahi M. J Inflamm Res. 2012
Improved insulin resistance Decrease in liver enzymes
Alleviation of hyperlipidemia
Oral administration of a BY-2 plant cell-expressing recombinant anti-TNF fusion protein (PRX-106), which consists of soluble form of human TNF receptor fused
to the Fc component of a human antibody IgG1 domain
Ilan Y Immunobiology 222:544-551, 2017Khury T, World J Gastroenterol. 2016
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Oral administration of a recombinant anti-TNF fusion protein is biologically active
in the gut promoting regulatory T cells: Results of a phase I clinical trial
No effect on white blood cells and lymphocytes counts were noted in any of the dosages
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Oral administration of all three dosages was associated with an increase in CD4+CD25+ and CD8+CD25+ subset of suppressor lymphocytes
Almon E, J Immunol . Methods. 446:21-29, 2017
• OPRX-106 was not absorbed systemically.
• Oral administration using OPRX-106 was safe and well tolerated
• OPRX-16 was not associated with immune suppression.
• OPRX-106 was effective as demonstrated by clinical response and improvement in various disease parameters.
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Orally administered recombinant anti-TNF alpha fusion protein for the treatment of ulcerative colitis: Phase 2a clinical trial
Ilan, y Gastroenterology 2018;154:S-153; Abst 739
Mechanism of oral immunotherapy: Promotion of regulatory T cells
Lamina propria
Mesenteric lymph nodes
Regulatory T cell
NKT cell
M cell
DC
Bacterial/viral/ fungal products
Food derived antigens
Systemic immune system
Glycosphingolipids
Anti CD3
IMM124E
DR6MP
PRX106
Macrophage
Ilan Y, Clinical & Translational Immunology; 2016Adopted from: Weiner et al. 2011. Immunol Rev; Brain. 2016; Immunotherapy. 2016
Soy-derived fractions
IL-10 Treg TGF-b Treg
Oral Immunotherapy for NASH: Advantages
Mechanism o An ability of the gut immune system to deliver signals to control the systemic immune response
Target o Not dependent on a specific molecular pathway
o Promotes regulatory T cellsSafety o Non-absorbable
o No immune suppression
o Low dose is sufficient to achieve a clinically meaningful effect
Spectrum of disease o Treatment for early and late stages of diseaseo Induction of remission and maintenance
Associated disorders o Treats type 2 diabetes and hyperlipidemia
Adjuvant o An adjuvant for other metabolic and anti-fibrotic drugs
Ilan, Y 2016. Alimentary Pharmacology & Therapeutics
Ingram Pinn
SummaryOral immunotherapy-based compounds: A new class of drugs for NAFLD
a.Oral immunotherapy using non-absorbable immune modulators redirect the immune system towards an anti-inflammatory pathway.
b.It provides a platform for a long-term safe therapy which targets chronic inflammation in NASH in patients of all disease stages.
Brigham and Women’s Hospital
Harvard Medical School, Boston, MA
Howard Weiner Samia J. Khoury
Ruth Maron Francisco Quintana
Queens College, City University of NY
Robert Bittman
Bonn University, Germany
Gustav Schwarzmann
UC Davis, California
Eric Gershwin
Sharee Zedek, Medical CenterAri Zimran Deborah Elstein
Tel Hashomer, Medical CenterArnon Nagler Meir OhanaBen Gurion UniversitySmadar Cohen
Faculty of MedicineArie Dagan Roni Kalman
Liver Unit
Oren Shibolet
Gadi Lalazar
Eyal Shteyer
Alla Milhem
Ehud Zigmond
Meir Mizrahi
Tomer Adar
Yuval Horwitz
Efrat Orenbuch
Madi El-Haj
Dori Rotnemer
Diabetes Unit
Itamar Raz
Ehud Ziv
Sarah Zangen
Endocrinology
Gil Leibowitz
Gastroenterology
Eran Israeli
Tiberiu Hershcovici
Hebrew University-Hadassah Medical Center, Jerusalem
Menahem Hareati
Nila Hemed
Mina Rowe
Tawfik Huri
Ariel Drori
Yuval Ishay
Dean Nachman
Neurology
Adi Dembinsky
Collaborators
Ron Cialic
Dan Livovsky
Ami Ben Ya’acov
Lidya Zolotarov
Dimitri Kanovich
Elizabeth Axelrod
Sarah Preston
Shivti Trop
Roslana Alper
Yehudit Shabat
Yoav Lichtenstein
Ibrahim Kasis
Athalia Klein
Northwestern University, Chicago
Richard Silveramn