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Immune Monitoring & Targeted Therapeutics
Innovative Programs to Advance Health Research (LSDF 07-02)
Program for Autoimmune Disease Intervention (PADI)
Interdisciplinary translational research applied to autoimmune diseases
to improve health outcomes
• Unmet medical need
• Scientific opportunities
• Economic growth opportunities
Program for Autoimmune Disease Intervention
Autoimmune DiabetesMultiple sclerosisLupusAlopecia areataAnkylosing spondylitisAddisons diseaseHemolytic anemiaAutoimmune HepatitisThrombocytopenic purpuraBehcets diseasePemphigusCrohns diseaseDermatomyositisGraves diseaseHashimotos Thyroiditis
Myasthenia gravisPernicious anemiaPolyarteritisPolychondritisPolymyositisPsoriasisRheumatoid arthritisSclerodermaSjogren’s syndromsStiff man syndromeGiant cell ArteritisUlcerative colitisVasculitisUveitisVitiligo
Autoimmune Diseases
• Unmet medical need
Program for Autoimmune Disease Intervention
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.
• Unmet medical need
Program for Autoimmune Disease Intervention
Morbidity and mortality are directly related to late diagnosis, lack of
effective treatments, and problems in access to care;
• Scientific Opportunity
Program for Autoimmune Disease Intervention
Morbidity and mortality are directly related to late diagnosis, lack of
effective treatments, and problems in access to care;
• Scientific Opportunity:
We now, for the first time, can identify, isolate, and study the cells (specific lymphocytes) which trigger and cause autoimmune diseases
Program for Autoimmune Disease Intervention
”Enabling Technology”: co-opt molecular mechanisms
responsible for immune specificity
Immune lymphocyteAntigen presenting cell
Precise molecular handshakes provide the cell-to-cell contacts
responsible for immune specificity
Immune lymphocyteAntigen presenting cell
Precise molecular handshakes provide the cell-to-cell contacts
responsible for immune specificity
Immune lymphocyteAntigen presenting cell
4100 101 102 103 104
0.10%
100 101 102 103 104
0.11%
100 101 102 103 104
7.28%
A molecular probe for autoimmunity
Tetramer analysis of blood sample from patient
Control Control Diabetes tetramer
Early treatment is the goal;Early identification of autoimmunity is the key
Genetic Predisposition
Surv
ivin
g isl
et
cells
Immune activation
Normal insulinrelease
Progressive
loss of islet cells
Glucosenormal
Overtdiabetes
Time
The therapeutic window for intervention using immunomodulation
Genetic Predisposition
Surv
ivin
g isl
et
cells
Immune activation
Normal insulinrelease
Progressive
loss of islet cells
Glucosenormal
Overtdiabetes
Time
The therapeutic window for intervention using immunomodulation
Genetic Predisposition
Surv
ivin
g isl
et
cells
Immune activation
Normal insulinrelease
Glucosenormal
Time
Immune regulation
The Pipeline of Immunotherapy Trials in New Onset Type 1 Diabetes
• 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
type 1 diabetes and multiple sclerosis and lupus?
Related by: genetic susceptibility, molecular mechanisms, potential therapeutics directed at fundamental
immune pathways;
Program for Autoimmune Disease Intervention
123456
87
10
1211
13
9
1415
56
60
5857
59
TGEM: Tetramer Guided Epitope Mapping
1 00 1 01 1 02 1 03 1 04
Em
pt
y
10
01
01
10
21
03
10
4
E m p t y
0 . 2 %
2 3 . 2 %
5 . 2 %
7 1 . 4 %
0.2%
23.2%
5.2%
71.4%
1 00 1 01 1 02 1 03 1 04
Em
pt
y
10
01
01
10
21
03
10
4
E m p t y
0 . 0 %
2 1 . 1 %
0 . 1 %
7 8 . 8 %
0.0%
21.1%
0.1%
78.8%
1 00 1 01 1 02 1 03 1 0410
01
01
10
21
03
10
4
0 . 1 %
1 9 . 4 %
1 1 . 2 %
6 9 . 3 %
0.1%
19.4%
11.2%
69.3%
1 00 1 01 1 02 1 03 1 0410
01
01
10
21
03
10
4
0 . 0 %
1 7 . 9 %
0 . 0 %
8 2 . 0 %
0.0%
17.9%
0.0%
82.0%
1 00 1 01 1 02 1 03 1 0410
01
01
10
21
03
10
4
0 . 0 %
1 7 . 4 %
0 . 1 %
8 2 . 5 %
0.0%
17.4%
0.1%
82.5%
Overlapping peptides
Pooled peptides
Pooled tetramers
FACS staining with pooled
tetramer of VP16-stimulated PBMC
Tetramers loaded with
single peptide
FACS staining with peptide-specific
tetramer
Patient blood sample for analysis
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
At-risk/pre-clinical
Flares/disease progression
Disease remission
HLA
CTLA4
PTPN22
PTPN2
IL7R
CD25
Treg freq
Treg function
Teffphenotype
B cell phenotype
cytokines
Genetic profile
Immunologic profile
At-risk/pre-clinical
Flares/disease progression
Disease remission
HLA
CTLA4
PTPN22
PTPN2
IL7R
CD25
Treg freq
Treg function
Teffphenotype
B cell phenotype
cytokines
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
• Scientific Opportunity
Program for Autoimmune Disease Intervention
Morbidity and mortality are directly related to late diagnosis, lack of
effective treatments, and problems in access to care;
• Autoantigen targeting – the PADI interdisciplinary approach to novel autoimmune therapy
Program for Autoimmune Disease Intervention
• Immediate benefits
Program for Autoimmune Disease Intervention
Morbidity and mortality are directly related to late diagnosis, lack of
effective treatments, and problems in access to care;
Greater SeattleTacomaOlympiaVancouverWenatcheeSpokaneBellinghamEverettYakimaTri-Cities
Program for Autoimmune Disease Intervention
State-wide network of collaborating providersAccess to trials,Education of patients and families
• 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 Hayden-Ledbetter
Edward Clark
•Inventors of abatacept (CTLA4Ig)
•Chimeric CD20 Mabs
•Founders of Trubion Pharmaceuticals
Program for Autoimmune Disease Intervention
Jane Buckner Translational Medicine
Carla Greenbaum Clinical Trials
Heather Shilling Genotyping Core
Keith Elkon (UW) Lupus targeting
Mark Wener (UW) Lupus clinic
Mariko Kita Multiple Sclerosis
Jerry Nepom Immunomonitoring
Program for Autoimmune Disease Intervention
•Translational ImmunologyRegistry-repository-autoimmunity-allergy-asthma-matrix biology
•Clinical TrialsNIDDK 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
www.benaroyaresearch.org