Immune Monitoring & Targeted Therapeutics Innovative Programs to Advance Health Research (LSDF 07-02) Program for Autoimmune Disease Intervention (PADI)

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

Mimic the body’s molecular strategy

Immune lymphocyteAntigen presenting cell

HLA Tetramer

=

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

TM

r-G

AD

+

CD4+

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

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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;

Mimic the body’s molecular strategy

Immune lymphocyteAntigen presenting cell

• 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