Transcript Program for Autoimmune Disease Intervention (PADI)

Innovative Programs to Advance Health Research
(LSDF 07-02)
Program for
Autoimmune Disease Intervention (PADI)
Immune Monitoring & Targeted Therapeutics
Interdisciplinary translational research
applied to autoimmune diseases
to improve health outcomes
Program for
Autoimmune
Disease
Intervention
• Unmet medical need
• Scientific opportunities
• Economic growth opportunities
Autoimmune Diseases
Autoimmune Diabetes
Multiple sclerosis
Lupus
Alopecia areata
Ankylosing spondylitis
Addisons disease
Hemolytic anemia
Autoimmune Hepatitis
Thrombocytopenic purpura
Behcets disease
Pemphigus
Crohns disease
Dermatomyositis
Graves disease
Hashimotos Thyroiditis
Myasthenia gravis
Pernicious anemia
Polyarteritis
Polychondritis
Polymyositis
Psoriasis
Rheumatoid arthritis
Scleroderma
Sjogren’s syndroms
Stiff man syndrome
Giant cell Arteritis
Ulcerative colitis
Vasculitis
Uveitis
Vitiligo
Program for
Autoimmune
Disease
Intervention
• Unmet medical need
Autoimmune diseases affect 50 million
in the US, and are one of the top 10
leading causes of death in children and
women age 65 and younger.
Program for
Autoimmune
Disease
Intervention
• Unmet medical need
Morbidity and mortality are directly
related to late diagnosis, lack of
effective treatments, and problems in
access to care;
Program for
Autoimmune
Disease
Intervention
• Scientific Opportunity
Morbidity and mortality are directly
related to late diagnosis, lack of
effective treatments, and problems in
access to care;
Program for
Autoimmune
Disease
Intervention
• Scientific Opportunity:
We now, for the first time, can
identify, isolate, and study the cells
(specific lymphocytes) which trigger
and cause autoimmune diseases
”Enabling Technology”: co-opt
molecular mechanisms responsible for
immune specificity
Immune lymphocyte
Antigen presenting cell
Precise molecular handshakes provide
the cell-to-cell contacts responsible for
immune specificity
Immune lymphocyte
Antigen presenting cell
Precise molecular handshakes provide
the cell-to-cell contacts responsible for
immune specificity
Immune lymphocyte
Antigen presenting cell
Mimic the body’s molecular strategy
Immune lymphocyte
Antigen presenting cell
=
HLA Tetramer
A molecular probe for autoimmunity
Tetramer analysis of blood sample from patient
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Diabetes tetramer
Early treatment is the goal;
Early identification of autoimmunity is the key
Surviving islet cells
Immune
activation
Genetic
Predisposition
Normal insulin
release
Progressive
loss of islet
cells
Glucose
normal
Time 
Overt
diabetes
CD4+
TMr-GAD+
The therapeutic window for intervention
using immunomodulation
Surviving islet cells
Immune
activation
Genetic
Predisposition
Normal insulin
release
Progressive
loss of islet
cells
Glucose
normal
Time 
Overt
diabetes
The therapeutic window for intervention
using immunomodulation
Surviving islet cells
Immune
activation
Genetic
Predisposition
Immune
regulation
Normal insulin
release
Glucose
normal
Time 
The Pipeline of Immunotherapy Trials in
New Onset Type 1 Diabetes
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MMF and DZB
HSP 65 p277
Multi-dose DZB
Exanitide and DZB
Multidose anti-CD3
Anti-CD20
CTLA4-Ig
• Rapamycin and IL-2
• Phase III Anti-CD3
• Anti-CD3 and Exanitide
• GAD 65 in Alum
• Proinsulin DNA Vaccine
• ATG
• Anti-CD3 and insulin
Program for
Autoimmune
Disease
Intervention
type 1 diabetes and multiple sclerosis and lupus?
Related by:
genetic susceptibility,
molecular mechanisms,
potential therapeutics directed at fundamental
immune pathways;
TGEM: Tetramer Guided Epitope Mapping
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FACS staining
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Program for
Autoimmune
Disease
Intervention
Our vision for this Program is to evaluate
new and emerging markers of lymphocyte
lineage and function, in combination with
new and emerging markers of genetic
propensity for autoimmune phenotypes, in
patients at all stages of autoimmune
disease—from predisposition through
disease diagnosis and response to
immunotherapy.
Health Impact “Deliverables”:
A toolkit for a new approach to autoimmunity
Genetic
profile
Immunologic
profile
HLA
Treg freq
CTLA4
Treg function
PTPN22
Teff
phenotype
PTPN2
IL7R
CD25
B cell
phenotype
At-risk/pre-clinical
Flares/disease progression
cytokines
Disease remission
Program for
Autoimmune
Disease
Intervention
• We anticipate that a successful result from this
Program will be the widespread use of such
profiling tools for early diagnosis, selection of
therapy, monitoring of therapy, and design of the
next generation clinical trials for T1D, MS, and
lupus.
…better outcomes
…reduced costs
Program for
Autoimmune
Disease
Intervention
• Scientific Opportunity
Morbidity and mortality are directly
related to late diagnosis, lack of
effective treatments, and problems in
access to care;
Mimic the body’s molecular strategy
Immune lymphocyte
Antigen presenting cell
Program for
Autoimmune
Disease
Intervention
• Autoantigen targeting – the PADI interdisciplinary
approach to novel autoimmune therapy
Program for
Autoimmune
Disease
Intervention
• Immediate benefits
Morbidity and mortality are directly
related to late diagnosis, lack of
effective treatments, and problems in
access to care;
Program for
Autoimmune
Disease
Intervention
State-wide network of collaborating providers
Access to trials,
Education of patients and families
Greater Seattle
Tacoma
Olympia
Vancouver
Wenatchee
Spokane
Bellingham
Everett
Yakima
Tri-Cities
Program for
Autoimmune
Disease
Intervention
• Key LSDF elements
– Institutional Commitment
– Partnerships with other organizations
– Financial cost-sharing
– Deliverables
– Milestones
– Commercialization plan
Program for
Autoimmune
Disease
Intervention
• Economic track record
Jeffrey Ledbetter
Martha HaydenLedbetter
Edward Clark
•Inventors of abatacept (CTLA4Ig)
•Chimeric CD20 Mabs
•Founders of Trubion Pharmaceuticals
Program for
Autoimmune
Disease
Intervention
Jane Buckner
Carla Greenbaum
Heather Shilling
Keith Elkon (UW)
Mark Wener (UW)
Mariko Kita
Jerry Nepom
Translational Medicine
Clinical Trials
Genotyping Core
Lupus targeting
Lupus clinic
Multiple Sclerosis
Immunomonitoring
www.benaroyaresearch.org
•Translational Immunology
Registry-repository-autoimmunity-allergy-asthma-matrix biology
•Clinical Trials
NIDDK TrialNet, NIAID ITN, JDRF, SWOG, IIT (VM)
•215 employees
•20 senior scientists
•$26 million/year research volume
•65% from competitive research grants
•the rest from pharma/biotech, donations, endowment
•Formerly the Virginia Mason Research Center, est 1956