Program for Autoimmune Disease Intervention (PADI)

1. 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

2. Program for Autoimmune Disease Intervention • Unmet medical need • Scientific opportunities • Economic growth opportunities

3. Autoimmune Diseases 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 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

4. 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.

5. 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;

6. 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;

7. 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

8. Immune lymphocyte Antigen presenting cell ”Enabling Technology”: co-opt molecular mechanisms responsible for immune specificity

9. Immune lymphocyte Antigen presenting cell Precise molecular handshakes provide the cell-to-cell contacts responsible for immune specificity

10. Immune lymphocyte Antigen presenting cell Precise molecular handshakes provide the cell-to-cell contacts responsible for immune specificity

11. Immune lymphocyte Antigen presenting cell Mimic the body’s molecular strategy

12. HLA Tetramer =

14. Early treatment is the goal; Early identification of autoimmunity is the key Immune activation Progressive loss of islet cells Genetic Predisposition Surviving islet cells Normal insulin release Overt diabetes Glucose normal Time 

15. TMr-GAD+ CD4+

16. The therapeutic window for intervention using immunomodulation Immune activation Progressive loss of islet cells Genetic Predisposition Surviving islet cells Normal insulin release Overt diabetes Glucose normal Time 

17. Immune activation Genetic Predisposition Immune regulation Surviving islet cells Normal insulin release Glucose normal Time  The therapeutic window for intervention using immunomodulation

18. 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 The Pipeline of Immunotherapy Trials in New Onset Type 1 Diabetes

19. 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;

20. 0.1% 0.0% 0.0% 11.2% 0.1% 0.0% 0.2% 5.2% 17.4% 19.4% 17.9% 82.5% 82.0% 69.3% 23.2% 71.4% 0.0% 0.1% 21.1% 78.8% TGEM: Tetramer Guided Epitope Mapping 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 56 57 58 59 Patient blood sample for analysis 60 FACS staining with pooled tetramer of VP16-stimulated PBMC Tetramers loaded with single peptide FACS staining with peptide-specific tetramer Overlapping peptides Pooled peptides Pooled tetramers

21. 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.

22. Health Impact “Deliverables”:A toolkit for a new approach to autoimmunity

23. 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

24. 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;

25. Immune lymphocyte Antigen presenting cell Mimic the body’s molecular strategy

26. Program for Autoimmune Disease Intervention • Autoantigen targeting – the PADI interdisciplinary approach to novel autoimmune therapy

27. 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;

28. Greater Seattle Tacoma Olympia Vancouver Wenatchee Spokane Bellingham Everett Yakima Tri-Cities Program for Autoimmune Disease Intervention State-wide network of collaborating providers Access to trials, Education of patients and families

29. Program for Autoimmune Disease Intervention • Key LSDF elements • Institutional Commitment • Partnerships with other organizations • Financial cost-sharing • Deliverables • Milestones • Commercialization plan

30. 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

31. 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

32. 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