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A Complex Pathway-A Feast of Possibilities
New Immunology and New Immunotherapy of Type 1 Diabetes
Mark D. (The Other) Pescovitz, MD
Professor of Surgery and Microbiology/Immunology
Indiana University School of Medicine
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POTENTIAL CONFLICT BASED ON FINANCIAL/CONSULTING/ RESEARCH
INTERACTIONS• ROCHE
• LILLY
• VICAL
• GENENTECH
• WYETH
• NOVARTIS
• ASTELLAS
• PFIZER
• US GOVERNMENT
Research SupportSpeaker’s Bureau Board Member/Advisory Panel Stock/Shareholder ConsultantTax Payer
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Clinical onset of Clinical onset of diseasedisease
100 %100 %
20%20%
PrimaryPrimary Prevention (genetically at risk) Prevention (genetically at risk)
STOP progression to autoimmunity/beta cell destruction
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Clinical onset of Clinical onset of diseasedisease
100 %100 %
20%20%
Secondary Prevention (antibody positive)Secondary Prevention (antibody positive)
STOP clinical disease
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100 %100 %
20%20%
Tertiary Prevention (early in clinical disease)Tertiary Prevention (early in clinical disease)
Clinical onset of disease
Preserve Beta cellsSTOP complications
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The Immunobiology of Type 1 Diabetes
Activated Activated T cellsT cells
T-cell T-cell proliferationproliferation
Signal 2:Costimulation Signal 3:
IL-2R,IL-15R
RestingRestingDCDC
DC DC Maturation Maturation
Signal 1:MHC/peptides
Recognition by TCR
T-cellT-cellGrowthGrowthFactorsFactors
Normal blood sugar Diabetes
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Immunosuppressive DrugsMechanisms of Action
T-Cell T-Cell ActivationActivation
T-Cell T-Cell ProliferationProliferation
Signal 2:Signal 2:CostimulationCostimulation Signal 3:Signal 3:
IL-2RIL-2RIL-15IL-15
RestingRestingDCDC
DCDCMaturationMaturation
DaclizumabDaclizumabBasiliximabBasiliximab
CCsAsATacrolimuTacrolimuss
Muromonab-CD3Muromonab-CD3
MMFMMF
Signal 1:Signal 1:MHC/peptMHC/peptidesides
Recognition by TCRRecognition by TCR
MHC TCR
MMFMMFSteroidsSteroids
MMFMMFSirolimusSirolimus
T-CellT-CellGrowthGrowthFactorsFactors
B7
CD40
CD28
CD40L
SirolimusSirolimus
Adapted with permission from Professor Dr. Walter Land and M. Schneeberger, University of Munich, Germany.
B
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MONOCLONAL ANTIBODY STRUTURE
MouseMouse Human
HumanizedChimeric
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MONOCLONAL ANTIBODY NOMENCLATURE
Rituximab
Daclizumab
MonoclonalAntibody
Chimeric
Humanized
Muromonab
Murine
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Mechanisms of Action- Anti-CD3
Activated Activated T cellsT cells
T-cell T-cell proliferationproliferation
Signal 2:costimulation Signal 3:
IL-2R,IL-15
RestingRestingDCDC
DCDCMaturationMaturation
Anti-CD3Anti-CD3
Signal 1:MHC/peptides
Recognition by TCR
MHC TCRT-cellT-cell
GrowthGrowthFactorsFactors
B7
CD40
CD28
CD40L
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HUMANIZED, MUTAGENIZEDANTI-CD3 MONOCLONAL ANTIBODY FOR
TREATMENT OF TYPE 1 DIABETES
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Reduced insulin requirements in anti-CD3 treated subjects
Keymeulen, B. et al. N Engl J Med 2005;352:2598-2608
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Example of Mixed Meal Tolerance TestExample of Mixed Meal Tolerance Test
Active Rx
Placebo
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Better c-peptide response to MMTT in anti-CD3 treated subjects
Herold, K. et al. N Engl J Med 2002;346:1692-1698
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Changes in C-Peptide Responses Changes in C-Peptide Responses During MMTT Over TimeDuring MMTT Over Time
0
20
40
60
80
100
120
140
Baseline 6 months 12 months
C-Peptide - Total AUC pmol/ml/240 min
Active RxComparison
Herold et al, NEJM 2002; 346:1692
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Side effects of the anti-CD3 mAb
Symptom/sign Mild* Moderate* Severe*
Headache 33% 0 0
Fever 17% 58% 0
Nausea 8% 0 0
Vomiting 0% 8% 0
Diarrhea 0 0 0
Dyspnea 8% 0 0
Myalgias 17% 0 0
Arthralgias 8% 0 0
Rash 0% 83% 0
Hypotension 0 0 0
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Status of anti-CD3 for Diabetes
Now in phase 2
and soon
phase 3 clinical trials
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Anakinra
Phase II trial: Multiple doses Anti-CD3
Herold
Anti-CD3+ GLP1
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Animal models: Animal models: GLP-1 blocks GLP-1 blocks Beta cell death Beta cell death and increases and increases growthgrowth
L. Baggio and D. DruckerAnnu. Rev. Med, 2006L. Baggio and D. DruckerAnnu. Rev. Med, 2006
Anti-CD3 and GLP-1 to increase Beta cell mass
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EXENITIDE TO INCREASE ISLET MASS
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Phase II trial: Thymoglobulin
Gitelman, UCSF
Randomized, placebo controlled trialRandomized, placebo controlled trial
Adults first; then ages 8-30Adults first; then ages 8-30
4 days of therapy in hospital/GCRC4 days of therapy in hospital/GCRC
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Immunogen Immunogen ProductionProduction
Rabbit SeraRabbit SeraProductionProduction
PurificationPurification of IgGof IgG
Fill/FinishFill/Finish
Thymoglobulin: Anti-thymocyte Globulin (Rabbit) Production Process
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CD1a CD3/TCR
CD4
CD6 CD7 CD8
CD16 CD19
CD20* CD25*
CD6 CD11a/CD18 (LFA-1)
CD44 CD49/CD29 (VLA-4)
CD50 (ICAM-3) CD51/61
CD54 (ICAM-1) CD56*
CD58 (LFA-3) LPAM-1(α4β7)
CD102 (ICAM-2) CD195 (CCR5) CD197 (CCR7)
CD184 (CXCR4)
CD2 CD5
CD11b CD29 CD38 CD40 CD45 CD52 CD95
CD126 CD138
Ankersmit HJ, et al. Am J Transplant. 2003;3:743. Bourdage JS, et al. Transplantation. 1995;59:1194. Michallet M-C, et al. Transplantation. 2003;75:657. Monti P, et al. Int Immunopharmacol. 2003;3:189. Pistillo MP, et al. Transplantation. 2002;73:1295. Préville X, et al. Transplantation. 2001;71:460. Rebellato LM, et al. Transplantation. 1994;57:685. Tsuge
I, et al. Curr Ther Res. 1995;56:671. Zand M, et al. Transplantation. 2005;79:1507. Zand MS, et al. Blood. 2006;107:2895.
CD28* CD30 CD32 CD40
CD80* CD86
CD152 (CTLA-4) HLA class I
HLA DR β2-M
Immune Response Antigens
Adhesion &Cell Trafficking
HeterogeneousPathways
* Results differ among laboratories due to inconsistencies in monoclonal competition assays.
Note: relative concentrations of antibodies targeting the listed antigens is not known.
Thymoglobulin:Anti-thymocyte Globulin (Rabbit)
Target Antigens
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Mechanisms of Action- Anti-IL-2R
Activated Activated T cellsT cells
T-cell T-cell proliferationproliferation
Signal 2:costimulation Signal 3:
IL-2R,IL-15
RestingRestingDCDC
DCDCMaturationMaturation
DaclizumabDaclizumabBasiliximabBasiliximab
Signal 1:MHC/peptides
Recognition by TCR
MHC TCRT-cellT-cell
GrowthGrowthFactorsFactors
B7
CD40
CD28
CD40L
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High Affinity IL-2 Receptor
SL-04
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PDPT: Study Design
Two year open label study
Randomized
Conventional therapy
Conventional therapy + DZB
• DZB infusions
– Q 2 wks X 5
– Q 3 wks X 4
– Q 1 mo X 19
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C-Peptide AUC
0
5
10
15
20
25
30
35
40
0 10 20 30 40 50 60 70 80 90 100Weeks
C-Peptide AUC
ControlDrug on-treatmentDrug off-treatment
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Insulin Requirement
0.0
0.5
1.0
1.5
2.0
0 10 20 30 40 50 60 70 80 90 100Weeks
Insulin Dose (u/kg/day)
ControlDrug on-treatmentDrug off-treatment
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Integrated
C-peptide
(ng/ml x min/wk)
Insulin
Requirement
(u/kg/day/wk)
Hgb A1C
(%/wk)
Control -0.0512 0.0051 -0.0087
Treatment 0.0248 -0.0012 -0.0331
Difference -0.0760 0.0063 0.0244
P-value0.0001 <.0001 0.006
Slope of Change over Time
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Mechanisms of Action-MMF/Anti-IL-2R
Activated Activated T cellsT cells
T-cell T-cell proliferationproliferation
Signal 2:costimulation Signal 3:
IL-2R,IL-15
RestingRestingDCDC
DCDCMaturationMaturation
DaclizumabDaclizumabBasiliximabBasiliximab
MMFMMF
Signal 1:MHC/peptides
Recognition by TCR
MHC TCRT-cellT-cell
GrowthGrowthFactorsFactors
B7
CD40
CD28
CD40L
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Phase II trial: MMF and DZB
P. Gottlieb, Denver
Ages 8-45 Diagnosed within past 3 monthsAges 8-45 Diagnosed within past 3 monthsRandomized trialRandomized trialN=126N=126Outcome: Insulin secretion at 2 yearsOutcome: Insulin secretion at 2 years
Oral MMF x 2 yearsOral MMF x 2 years
IV DZB x 2 dosesIV DZB x 2 doses
Oral MMF x 2 yearsOral MMF x 2 years
IV placeboIV placebo
Oral Placebo x 2 yearsOral Placebo x 2 years
IV placeboIV placebo
RECRUITMENT DONE- RESULTS HERE MONDAYRECRUITMENT DONE- RESULTS HERE MONDAY
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Mechanisms of Action- CD28 Blockade
Activated Activated T cellsT cells
T-cell T-cell proliferationproliferation
Signal 2:costimulation Signal 3:
IL-2R,IL-15
RestingRestingDCDC
DCDCMaturationMaturation
Signal 1:MHC/peptides
Recognition by TCR
MHC TCR
BELATACEPTBELATACEPT
T-cellT-cellGrowthGrowthFactorsFactors
B7
CD40
CD28
CD40L
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Full T-cell activation requires 2 signals
APC
Signal 1
T Cell
Signal 2
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CD28 is critical for T-cell activation
APC
T Cell
CD80 (B7-1) CD86 (B7-2)
CD28
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The absence of signal 2 results in T-cell anergy or apoptosis
APC
Signal 1
T Cell
Signal 2
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Mechanisms of Action- B cells
T-Cell T-Cell ActivationActivation
T-Cell T-Cell ProliferationProliferation
Signal 2:Signal 2:CostimulationCostimulation Signal 3:Signal 3:
IL-2RIL-2RIL-15IL-15
RestingRestingDCDC
DCDCMaturationMaturation
Signal 1:Signal 1:MHC/peptMHC/peptidesides
Recognition by TCRRecognition by TCR
MHC TCRT-CellT-Cell
GrowthGrowthFactorsFactors
B7
CD40
CD28
CD40L
Adapted with permission from Professor Dr. Walter Land and M. Schneeberger, University of Munich, Germany.
B
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B-CELLS IN DIABETES
• ANTIBODIES DETECTED IN TYPE 1 DIABETICS
• B-CELLS ARE PRESENT IN HISTOLOGIC SECTIONS (SIGNORE)
• B-CELL DEPLETION BY GENE KNOCKOUT OR ANTI-MU REDUCES DIABETES IN NOD (NOORDCHASM, YANG OTHERS)
• B-CELLS NEEDED FOR ANTIGEN PRESENTATION IN NOD MICE (FALCONE, SERREZE)
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Autoantibody Production by B Cells
• A variety of autoantibodies (antibodies directed against self antigens) are found in patients with diabetes
• Autoantibodies may act as self-perpetuating stimuli for B cells5,6
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B-Cell Antigen Presentation
Step 1:
• High-affinity binding of antigen
– B cell binds antigen on B-cell receptor (BCR)1,2
References: 1. O’Neill SK et al. J Immunol. 2005;174:3781-3788. 2. Lund FE et al. Curr Dir Autoimmun. 2005;8:25-54.
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B-Cell Antigen Presentation
Step 2:
• Internal processing of antigen
– Antigen processed by B cell1,2
– Antigen fragment presented on MHC-II molecule1,2
– Costimulatory molecule expressed on B cell1,2
Reference: 1. Dale DC et al. WebMD Scientific American Medicine. Chapter 6. WebMD ProfessionalPublishing; 2002. 2. Roitt I et al. Immunology. 6th ed. Chapter 8. Mosby; 2001.
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B-Cell Antigen Presentation
Step 3:
• Presentation of antigen to T cell1-4
– B cell presents antigen to T-cell receptor (TCR) and also provides costimulatory signal to T cell1-3
– Activated T cell produces proinflammatory cytokines that activate macrophages1-3
References: 1. Silverman GJ et al. Arthritis Res Ther. 2003;5(suppl 4):S1-S6. 2. Dale DC et al. WebMD Scientific American Medicine. Chapter 6. WebMD Professional Publishing; 2002. 3. Klippel JH et al. Primer on the Rheumatic Diseases. 12th ed. Chapter 9. Arthritis Foundation; 2001. 4. Roitt I et al. Immunology. 6th ed. Chapter 8. Mosby; 2001.
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Cytokine Production by B Cells May Be Stimulated by Multiple Pathways
• Antigen binding to the BCR stimulates cytokine production1,2
References: 1. Lund FE et al. Curr Dir Autoimmun. 2005;8:25-54. 2. Duddy ME et al. J Immunol. 2004;172:3422-3427.
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B Cells Express Specific Cell-Surface Molecules
References: 1. Roitt I et al. Immunology. 6th ed. Chapter 8. Mosby; 2001. 2. Sell S et al. Immunology, Immunopathology, and Immunity. 6th ed. Chapter 4. ASM Press; 2001. 3. Duddy ME et al. J Immunol. 2004;172:3422-3427.
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RITUXIMAB: AN ANTI-CD20 MONOCLONAL ANTIBODY
• Genetically engineered chimeric murine/human monoclonal antibody– Variable light- and heavy-
chain regions from murine anti-CD20 antibody IDEC-2B8
– Human IgG constant regions
• First monoclonal antibody to be approved by the FDA for treatment of cancer
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Rituximab: Mechanism of Action
Anderson et al. Biochem Soc Trans. 1997;25:705–708. Golay et al. Blood. 2000;95:3900–3908. Reff et al. Blood. 1994;83:435–445. Clynes et al. Nat Med. 2000;6:443–446. Shan et al. Cancer Immunol Immunother. 2000;48:673–683.
Rituximab selectively Rituximab selectively depletes B cells bearing depletes B cells bearing the CD20 surface the CD20 surface marker via:marker via:
• Antibody-dependent Antibody-dependent cellular cytotoxicity cellular cytotoxicity (ADCC)(ADCC)
• Complement-Complement-dependent cytotoxicity dependent cytotoxicity (CDC)(CDC)
• Induction of apotosisInduction of apotosis
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Absolute CD19 (B cells) after Rituximab
0
50
100
150
200
250
300
350
400
0 7 21 42 73 181
Grp 1 (50mg)Grp 2 (150)Grp 3 (375)Control Avg.Con+SDCon -SD
Days after Rituximab Dose
Cel
ls/m
m3
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Prevention/Treatment of Diabetes HuCD20-NOD
Hu et al. J Clin Invest 117:3857-67, 2007
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Role of CD4+CD25+Foxp3+ Tregs in Immune Responses
Adapted from Najafian N, et al. Clin Dermatol. 2001;19:586.
CD4+
T cell
Apoptosis
Anergy
Memory
Effector
Termination
Regulation
Donor APC
Signal 1Signal 2
Activation
Indirect Pathway
Direct Pathway
B cell help
DTH
CTL help
CD4+CD25+Foxp3+
Self APC
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Prevention of Diabetes in HuCD20-NOD
Xiu et al. The Journal of Immunology, 2008, 180: 2863–2875.
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Treatment of Diabetes in HuCD20-NOD
Xiu et al. The Journal of Immunology, 2008, 180: 2863–2875
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HYPOTHESIS FOR RITUXIMAB ACTION IN DIABETES
• B-CELLS ARE NECESSARY ANTIGEN PRESENTING CELL FOR MAINTENANCE OF ANTI-ISLET T-CELL MEDIATED DESTRUCTION
• RITUXIMAB DEPLETES ANTIGEN SPECIFIC CD27 MEMORY B-CELLS
• IMMUNE REACTION IS SUPPRESSED
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RITUXIMAB IN TYPE 1 DIABETESSTUDY OUTLINE
• TYPE 1 DIABETICS AS PER TRIALNET DEFINTION
• AGE: 8 TO 40 YEARS
• N=87 2:1 RATIO BLINDED RITUXIMAB VS PLACEBO
• DOSE: 375mg/m2 Q WEEK x4
• ENDPOINT 2 HOUR MMTT C-PEPTIDE AUC AT 1 YEAR
• RITUXIMAB PK/PD
• IMMUNIZATION RESPONSE: phiX174, Hep A, TETANUS
• RECOVERY OF B-CELL SUBSETS
• MECHANISTIC STUDIES
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RITUXIMAB DIABETES IMMUNIZATION SCHEDULE
0 6 12 52 583
WEEKS
DE NOVO DEPLETED TOLERANCE?
RECALL/PRESERVATION
DE NOVO POST RECOVERY
MMTTMMTT
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NEXT GENERATION ANTI-B CELL AGENTS
BR3-FC
ANTI-BR3
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TertiaryTertiary (then secondary?) Prevention (then secondary?) Prevention
Anti-CD3+GLP
Anti-CD3 multiple dose
MMF/DZB
CTLA4-Ig
Rituximab
Thymoglobulin
MetabolicIL-2+Rapamycin
GAD65alum
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TrialNet Sites – North America
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TrialNet International Sites
• AustraliaAustralia
• United KingdomUnited Kingdom
• FinlandFinland
• Italy & GermanyItaly & Germany
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SUMMARY
• TYPE 1 DIABETES IS AN AUTOIMMUNE DISEASE
• MULITPLE CELL TYPES HAVE BEEN HYPOTHESIZED TO PLAY A ROLE IN THE PATHOPHYSIOLOGY
• IF THESE PILOT TRIALS SHOW A MODALITY IS SAFE AND EFFECTIVE, LARGER TRIALS INCLUDING PREDIABETICS, WOULD BE PLANNED