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A Complex Pathway-A Feast of Possibilities New Immunology and New Immunotherapy of Type 1 Diabetes

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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A Complex Pathway-A Feast of Possibilities New Immunology and New Immunotherapy of Type 1 Diabetes

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  1. A Complex Pathway-A Feast of PossibilitiesNew 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

  2. POTENTIAL CONFLICT BASED ON FINANCIAL/CONSULTING/ RESEARCH INTERACTIONS • ROCHE • LILLY • VICAL • GENENTECH • WYETH • NOVARTIS • ASTELLAS • PFIZER • US GOVERNMENT Research Support Speaker’s Bureau Board Member/Advisory Panel Stock/Shareholder Consultant Tax Payer

  3. Primary Prevention (genetically at risk) 100 % STOP progression to autoimmunity/beta cell destruction Clinical onset of disease Beta cell function 20% Time

  4. Secondary Prevention (antibody positive) 100 % STOP clinical disease Clinical onset of disease Beta cell function 20% Time

  5. Tertiary Prevention (early in clinical disease) 100 % Preserve Beta cells STOP complications Clinical onset of disease Beta cell function 20% Time

  6. The Immunobiology of Type 1 Diabetes Normal blood sugar Diabetes Resting DC T-cell proliferation DC Maturation Activated T cells Signal 2: Costimulation Signal 3: IL-2R, IL-15R T-cellGrowthFactors Signal 1: MHC/peptides Recognition by TCR

  7. MMF B7 CD28 CD40 CD40L Daclizumab Basiliximab Immunosuppressive DrugsMechanisms of Action Resting DC MMFSteroids B T-Cell Proliferation DC Maturation T-Cell Activation MMF Sirolimus Signal 2: Costimulation Signal 3: IL-2R IL-15 T-CellGrowthFactors TCR MHC Sirolimus Signal 1: MHC/peptides Recognition by TCR CsA TacrolimusMuromonab-CD3 Adapted with permission from Professor Dr. Walter Land and M. Schneeberger, University of Munich, Germany.

  8. MONOCLONAL ANTIBODY STRUTURE Human Mouse Chimeric Humanized

  9. MONOCLONAL ANTIBODYNOMENCLATURE Murine Chimeric Rituximab Monoclonal Antibody Muromonab Daclizumab Humanized

  10. B7 CD28 CD40 CD40L Anti-CD3 Mechanisms of Action- Anti-CD3 Resting DC T-cell proliferation DC Maturation Activated T cells Signal 2: costimulation Signal 3: IL-2R, IL-15 T-cellGrowthFactors TCR MHC Signal 1: MHC/peptides Recognition by TCR

  11. HUMANIZED, MUTAGENIZEDANTI-CD3 MONOCLONAL ANTIBODY FOR TREATMENT OF TYPE 1 DIABETES

  12. Reduced insulin requirements in anti-CD3 treated subjects Keymeulen, B. et al. N Engl J Med 2005;352:2598-2608

  13. Example of Mixed Meal Tolerance Test Active Rx Placebo

  14. Better c-peptide response to MMTT in anti-CD3 treated subjects Herold, K. et al. N Engl J Med 2002;346:1692-1698

  15. Changes in C-Peptide Responses During MMTT Over Time Herold et al, NEJM 2002; 346:1692

  16. Side effects of the anti-CD3 mAb

  17. Status of anti-CD3 for Diabetes Now in phase 2 and soon phase 3 clinical trials

  18. Anakinra Phase II trial: Multiple doses Anti-CD3 Herold Anti-CD3+ GLP1

  19. Anti-CD3 and GLP-1 to increase Beta cell mass Animal models: GLP-1 blocks Beta cell death and increases growth L. Baggio and D. DruckerAnnu. Rev. Med, 2006

  20. EXENITIDE TO INCREASE ISLET MASS

  21. Phase II trial: Thymoglobulin Gitelman, UCSF Randomized, placebo controlled trial Adults first; then ages 8-30 4 days of therapy in hospital/GCRC

  22. Thymoglobulin: Anti-thymocyte Globulin (Rabbit) Production Process Immunogen Production Purification of IgG Rabbit Sera Production Fill/Finish

  23. Thymoglobulin: Anti-thymocyte Globulin (Rabbit) Target Antigens Adhesion & Cell Trafficking Immune Response Antigens Heterogeneous Pathways CD1a CD3/TCR CD4 CD6 CD7 CD8 CD16 CD19 CD20* CD25* CD28* CD30 CD32 CD40 CD80* CD86 CD152 (CTLA-4) HLA class I HLA DR β2-M 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 * Results differ among laboratories due to inconsistencies in monoclonal competition assays. Note: relative concentrations of antibodies targeting the listed antigens is not known. 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.

  24. B7 CD28 CD40 CD40L Daclizumab Basiliximab Mechanisms of Action- Anti-IL-2R Resting DC T-cell proliferation DC Maturation Activated T cells Signal 2: costimulation Signal 3: IL-2R, IL-15 T-cellGrowthFactors TCR MHC Signal 1: MHC/peptides Recognition by TCR

  25. High Affinity IL-2 Receptor b g a SL-04

  26. 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

  27. C-Peptide AUC

  28. Insulin Requirement

  29. Slope of Change over Time

  30. MMF B7 CD28 CD40 CD40L Daclizumab Basiliximab Mechanisms of Action-MMF/Anti-IL-2R Resting DC T-cell proliferation DC Maturation Activated T cells Signal 2: costimulation Signal 3: IL-2R, IL-15 T-cellGrowthFactors TCR MHC Signal 1: MHC/peptides Recognition by TCR

  31. Phase II trial: MMF and DZB P. Gottlieb, Denver Ages 8-45 Diagnosed within past 3 months Randomized trial N=126 Outcome: Insulin secretion at 2 years Oral MMF x 2 years Oral MMF x 2 years Oral Placebo x 2 years IV DZB x 2 doses IV placebo IV placebo RECRUITMENT DONE- RESULTS HERE MONDAY

  32. BELATACEPT B7 CD28 CD40 CD40L Mechanisms of Action- CD28 Blockade Resting DC T-cell proliferation DC Maturation Activated T cells Signal 2: costimulation Signal 3: IL-2R, IL-15 T-cellGrowthFactors TCR MHC Signal 1: MHC/peptides Recognition by TCR

  33. Full T-cell activation requires 2 signals APC Signal 1 T Cell Signal 2

  34. CD28 is critical for T-cell activation APC CD80 (B7-1) CD86 (B7-2) CD28 T Cell

  35. The absence of signal 2 results in T-cell anergy or apoptosis APC Signal 2 Signal 1 T Cell

  36. Mechanisms of Action- B cells B7 CD28 CD40 CD40L Resting DC B T-Cell Proliferation DC Maturation T-Cell Activation Signal 2: Costimulation Signal 3: IL-2R IL-15 T-CellGrowthFactors TCR MHC Signal 1: MHC/peptides Recognition by TCR Adapted with permission from Professor Dr. Walter Land and M. Schneeberger, University of Munich, Germany.

  37. 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)

  38. 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

  39. 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.

  40. 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.

  41. 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.

  42. 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.

  43. 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.

  44. 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 IgGk constant regions • First monoclonal antibody to be approved by the FDA for treatment of cancer

  45. Rituximab: Mechanism of Action • Rituximab selectively depletes B cells bearing the CD20 surface marker via: • Antibody-dependent cellular cytotoxicity (ADCC) • Complement-dependent cytotoxicity (CDC) • Induction of apotosis 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.

  46. Absolute CD19 (B cells) after Rituximab Cells/mm3 Days after Rituximab Dose

  47. Prevention/Treatment of Diabetes HuCD20-NOD Hu et al. J Clin Invest 117:3857-67, 2007

  48. Self APC Signal 1 Donor APC Signal 2 CD4+T cell Role of CD4+CD25+Foxp3+ Tregs in Immune Responses Indirect Pathway Activation Memory B cell help DTH CTL help Direct Pathway Effector Apoptosis Termination Anergy CD4+CD25+Foxp3+ Regulation Adapted from Najafian N, et al. Clin Dermatol. 2001;19:586.

  49. Prevention of Diabetes in HuCD20-NOD Xiu et al. The Journal of Immunology, 2008, 180: 2863–2875.

  50. Treatment of Diabetes in HuCD20-NOD Xiu et al. The Journal of Immunology, 2008, 180: 2863–2875

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