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NEW THERAPIES FOR SLE ,[object Object],[object Object],[object Object],[object Object]
2005 FDA Guidance Document for SLE ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
SLEDAI (Systemic lupus disease activity index) ,[object Object],[object Object],[object Object],[object Object],[object Object]
BILAG (British Isles Lupus Assessment Group) ,[object Object],[object Object],[object Object],[object Object],[object Object]
Clinical validation of the CLASI ,[object Object],[object Object],[object Object]
Newer agents for SLE ,[object Object],[object Object],[object Object],[object Object],[object Object]
Lupus Nephritis ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Houssiau F,  71 st  ACR , Boston 2007, ACR Clinical Symposium; Clarke A.  ibid , #503; Li T,  et al. ibid , #1255;Ginzler E, #L13 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Aspreva lupus management study (ALMS)
ALMS: Efficacy and Safety Results ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Ginzler E,  et al .  71 st  ACR , Boston 2007, #L13 38.8 (p=0.011) 38.5 (p=0.033) 54/64  (p=NS) 53 (p=NS) IVCy 60.9 60.4 56/53 56 MMF Hispanic (%) AA (%) Caucasian/Asian (%) Total (%)
Targets for New Therapies in SLE Peptides derived from nucleosomes, Sm Ag, Igs, TEVA (edratide) T cell regulation of autoantibody production Medimmune, Genentech anti-IFN-alpha; Coley blocks TLR7 and 9 Inhibition of interferon, toll receptors Expand CD4+CD25+ cells,  CD8+CD28- cells Promote regulatory cells mAbs to IL-10, sIL-6R, IL-6 Cytokines anti C5a (approved for PNH) Complement LJP 394; mAbs to CD20, CD22 antiBLyS, TACI-Ig, BAFF-RFc B cells, anti-dsDNA antibodies CTLA4 Ig; modified CD40L mAb T cells
How are T-cells activated? ,[object Object],[object Object],CD80/86:CD28 facilitates T-cell  activation, proliferation, survival  and  cytokine production  CD28 constitutively expressed on  T-cell surface; CD80/86 on APC binds CD28 on T-cell =  signal 2 Site of action of abatacept Antigen CD28 Activated T-cell
Survival of Lupus Mice Treated with CTLA4Ig and Anti-CD40L Wang et al.  J Immunol.  2002;168:2046–2053. Control CTLA4Ig/anti-CD40L CTLA4Ig Anti-CD40L Weeks % Alive 28 38 48 58 68 78 88 100 80 60 40 20 0
Phase 2 Trial of Abatacept ,[object Object],[object Object],[object Object],[object Object],[object Object],Source: www.clinicaltrials.gov. Accessed January 29, 2007.
T-lymphocyte co-stimulatory modulation: Importance of the T-cell subsets Adapted from Janeway CA Jr, et al. Immunobiology: The Immune System in Health and Disease.  6th e. New York, NY: Garland Science Publishing: 1994. p347 CTLA-Ig Less dependent CTLA-Ig More dependent Anti-viral / anti-tumor immunity CD8 T-cells: Peptide + class I CD4 T-cells: Peptide + class II Inflammation / Ab production T T Dougados M, et al. EULAR 2007, Barcelona, #SP0068
T-lymphocyte costimulatory modulation consequences ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Dougados M, et al. EULAR 2007, Barcelona, #SP0068
Selective co-stimulation modulators in clinical development ** * in Rilex, June 2005; * in Dillon 2006 Dougados M, et al. EULAR 2007, Barcelona, #SP0068 Tumors CD28 agonist Myeloma CC-5012 (CD28 activator) Renal cancer Leukemia Anti-CD28 (TGN1412) Tumors Anti-CLA-4 (Ipilimumab, ticilimumab) Activation Crohn's disease Multiple sclerosis Anti- α  2 integrine (natalizumab) RA BR3-Fc SLE RA Anti-BAF (AM6, G3) SLE, Multiple sclerosis RA, Lymphoma TACI-Ig SLE RA Anti-BAFF (belimumab) SLE Psoriasis Anti-CD80 Organ transplantation Anti-CD80/86 Organ transplantation LEA29Y (belatacept) Juvenile Chronic Arthritis, Multiple sclerosis RA (registration) SLE CTLA-4 Ig (abatacept) Inhibition Human diseases Co-stimulation modulator
Targeted therapeutics: Approaches in SLE Ng KP, et al. EULAR 2007, Barcelona, #OP0020 APC T B Y CTLA4-Ig  CD22 B-cell  toleragen  BlySS TACI-IG  CD20  IL-10 Peptide Antibody IL-10 Apoptotic material 1 2 Costimulatory  Factors,  eg, BlyS
Potential targets in B-cell lineage Antigen Independent Phase Antigen Dependent Phase Targets for BLyS/BAFF inhibitors Targets for Rituximab, Ocrelizumab, Ofatumumab CD45 (AKA B220) surface  marker Activated  B-cell Plasma cell Secreted IgG, IgA,  IgE, or IgM Mature  B-cell Pro-B-cell Pre-B-cell Immature  B-cell Surrogate light chain D H J H IgM IgM I g D Antigen IgM, IgD,  IgA, or IgE CD40L and cytokines CD40 V H D H J H V L   J L Adapted from Sell S, et al.  Immunology, Immunopathology, and Immunity . 6th ed. Washington, DC: ASM Press; 2001
Uncontrolled Data of Rituximab in  SLE and SS ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Ng KP,  et al. ACR,  Washington DC 2006, #536;  Tanaka Y ,  et al. ibid , #537;  Gunnarsson I ,  et al. ibid , #538;  Jónsdóttir T ,  et al. ibid , #539;  Luning Prak ET ,  et al. ibid , #540;  Dass S ,  et al. ibid , #541;  Pers JO ,  et al. ibid , #1770;  Gunnarsson I ,  et al. ibid , #2097
B-cell depletion is variable Anolik JH, et al. EULAR 2007, Barcelona, #SP0033 0.1 1 10 100 0 3 6 9 12 Months CD19+ (lymphocytes/uL) Non-depleters (n=6) Depleters (n=11) Recovery to 60% of baseline at 12 months Full recovery at 2–3 years in all but 1
Ocrelizumab: Humanized anti-CD20 mAb is effective in RA – 24 Week Phase 1/2 1 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],1.  Genovese M, et al. EULAR 2007, Barcelona, #SAT0008; 2. Manning W, et al. ibid, #SAT0018 ACR response EULAR response
Synthetic anti-CD 20 – TRU-015:  Ongoing Phase II RCT ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],ACR20 at Week 24 Burge DJ,  et al.   ACR,  Washington DC 2006, #463
Mechanism of Anti-CD20 (Rituximab) and Anti-CD22 (Epratuzumab) Monoclonal Antibodies ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Anti-CD20 MAb Rituximab Chimeric IgG1 κ Anti-CD22 MAb Epratuzumab Humanized IgG1 Carnahan et al.  Mol Immunol . 2007;44:1331–1341. CD22 CD20 B cell
B-cell–targeted therapies ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
B-cell growth factors Ligands Receptors BAFF-R BCMA TACI BLyS APRIL Heterotrimer Proteoglycans ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Issacs JD, et al.  EULAR 2007 , Barcelona #SP0069
Belimumab (lymphoStat-B) ,[object Object],[object Object],[object Object],[object Object],[object Object]
Systemic Lupus: Belimumab ,[object Object],[object Object],Ginzler E, et al. EULAR 2007, Barcelona, #OP0018
Belimumab reduced  CD20+ B cells by 61% at Week 76 p<0.01 for the comparison between all active vs placebo from Day 56 through Day 364 Furie R,  et al. ACR,  Washington DC 2006, #535; Wallace D,  et al. ibid , #2012; Stohl W,  et al. ibid , #1985
Novel combined endpoint* ,[object Object],[object Object],[object Object],[object Object],[object Object],Ginzler E, et al. EULAR 2007, Barcelona, #OP0018 * Accepted by Regulatory Authorities for Phase 3 Trials
Combined response rate for belimumab patients significantly higher  Ginzler E, et al. EULAR 2007, Barcelona, #OP0018 46% combined response rate for serologically active patients on belimumab vs 29% for placebo at Week 52 56% combined response rate for patients on belimumab at Week 76 * p=0.0059 at Week 52, p=0.02 at Week 56 0 10 20 30 40 50 60 70 0 28 84 140 224 280 336 392 476 532 Visit day Responder rate in  serologically active pts (%) Placebo Placebo to 10 mg/kg All active
Atacicept inhibits the function of BLys and APRIL ,[object Object],Atacicept Extracellular domain of TACI receptor Fc domain of human IgG rDNA  technology B-cell
Systemic Lupus: Atacicept (TACI-Ig) ,[object Object],[object Object],[object Object],[object Object],[object Object]
Phase I trials for lupus: Tociluzimab ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],1. Illei G,  et al. ACR,  Washington DC 2006, #L20;  2. Dall'Era M,  et al. ibid , #L19
Mechanism of LJP 394 (Abetimus) ,[object Object],[object Object],[object Object],[object Object],Alarcon-Segovia et al.  Arthritis Rheum . 2003;48:442-453. Furie.  Rheum Dis Clin North Am . 2006;32:149-156.  B cell B-cell receptor B-cell toleragen
Cumulative Renal Flare in Phase 3 Cumulative renal flares by week 32 59 82 98 118 153 Placebo 27 50 67 81 111 145 LJP394 88 64 48 32 16 Week 0 Patients
Tolerance Mechanisms: Edratide (TEVA)  Tsubata et al.  Autoimmunity . 2005;38:331-337. Bone Marrow Peripheral lymphoid organs Reactive to self antigens Self antigen Deletion T-cell zone Self antigen Deletion Anergy Receptor editing Self antigen Deletion Follicle B cell BCR B cell BCR B cell BCR B cell BCR B cell BCR
Innate Immune Responses in SLE ,[object Object],[object Object],[object Object],[object Object],IFNg IL-10 BlyS TNFa IL-1 IL-12 Activated  B cell Activated  T cell B cell T cell Mature DC Activated mono/macrophage Immature DC INCREASED IFN  Bacteria Viruses SLE DNA/IC CpG DNA ssRNA dsRNA Immune complexes in SLE bind TLR7 and 9
Induction of type I Interferon pathway through Toll-like receptors TLR3 TLR4 TLR7/8 TLR9 Inflammatory Cytokines Type I Interferon Inflammatory Cytokines Inflammatory Cytokines Type I Interferon Potential Endogenous Ligands: dsRNA ∞ RNA-containing Immune Complexes Fibronectin Products CpG DNA-containing Immune Complexes Exogenous Ligands: LPS ssRNA Demethylated CpG DNA dsRNA-containing Immune Complexes TRAM TIRAP Trf Trf MyD88 MyD88 MyD88
Toll-like Receptors in RA and SLE ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],1. Radstake TR, et al.  EULAR 2007 , Barcelona, #SP0136; 2. Magnusson M, et al.  ibid,  #SP0112; 3. Richez C, et al.  EULAR 2007 , Barcelona #OP0179; 4. Karonitsch TM, et al.  ibid,  #OP0178;  5. Means TK, et al.  J Clin Infect  2005;115:407 RA SLE
Hydroxychloroquine, “Antimalarials” are TLR Antagonists ,[object Object],[object Object],[object Object],[object Object],[object Object]
CPG 52364 showed dose-dependent inhibition of  TLR9-mediated IP-10 induction in mice Female adult BALB/c mice (n=5/gp) received different doses of CPG 52364 or chloroquine by IP injection. At 1 h post dose, animals received 100µg CpG-DNA  ODN subcutaneously.  Plasma was collected at 3 h post agonist injection and used for  IP-10 assay by ELISA.  Value are presented as percent mean TLR9 agonist activity.  
Hydroxychloroquine (HCQ) and Toll Receptors ,[object Object],[object Object],[object Object],Weeratna R,  et al. 71 st  ACR , Boston 2007. #1310
SLE is a Disease of TLR-Driven Amplification of  Autoimmunity   Dendritic Cells TLR7+ / 8+ / 9+ B cells TLR9+ / TLR7 Inducible Cytokine/Chemokine Induced Activation/Maturation And Damage Apoptotic debris Self-antigen Autoimmune Complex-Driven TLR Cellular Activation TLR signal Anti-self response Cytokine/chemokine Tissue Damage End Organ Failure Inflammation CPG 52364 TLR7/8/9 Antagonist X Complex uptake X CPG 52364 (Coley) is a TLR 7,8,9 antagonist in a Phase I trial with similar actions to hydroxychloroquine   Akira S,  et al .  Nat Imunol  2001;2:675;  Lipford G , et al. 71 st  ACR,  Boston 2007. #1596 T-cell NK cell
Interferons and Systemic Lupus Erythematosus ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],1 Hooks JJ,  et al .  New Engl J Med . 1979;301:5-8; 2 Crow M.  Arthritis Rheum.  2003;48:2396-2401; 3 Dall’era MC,  et al .  Ann Rheum Dis.  2005;64:1692-1697; 4 Ioannou Y, Isenberg DA.  Arthritis Rheum.  2000;43:1431-1442.
MEDI-545 (Medimmune/AstraZeneca) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Wallace D,  et al .  71 st  ACR,  Boston 2007. #1315 IFN-a IFNAR1 IFNAR2 P STAT2 P STAT2 P STAT1 P Tyk2 STAT1 P Jak1 IRF-9 IRF-9
MEDI-545 Reduces Type I IFN Gene Signature, Type I IFN–Induced Proteins in Skin, and Improves Disease Activity Day 14 Skin, day 0–28  5/17 29% 1/33 3% MEDI-545 Placebo 0 20 30 40 Pts, N 10 >3 point increase in SLEDAI score <3 point increase in SLEDAI score P =0.0136 Wallace D,  et al .  71 st  ACR,  Boston 2007. #1315 Type I IFN–induced proteins in skin Change in protein Change in transcript 20% 97% 75% 99% 87% 99% HERC5 ISG15 IP10 Improvement in disease activity Day 0 Day 14
MEDI-545 Can Normalize Type I IFN Gene Signature in Blood: Heat Map of Gene Expression Day Neutralization Wallace D,  et al .  71 st  ACR,  Boston 2007. #1315 Calculation based on top 25 type I IFN–inducible genes upregulated in whole blood of one patient treated with 30 mg/kg MEDI-545  (day 0, 1, 4, 7, 14)
Th1/Th2 Paradigm T-bet IL-5 IL-10 IL-13 IL-4 IL-6 Helminth protection (allergy, atopy, SLE) IL-4 IL-12 IL-18 Th 1  cell IFN-  LT-  IL-2 IL-22 Cell-mediated immunity Intracellular pathogens Autoimmunity IL-12R IL-18R Th 2  cell Schulze-Koops H,  et al. EULAR, 2006,  Amsterdam, #SP0130. Zhu J,  et al. Cell Res  2006;16:3 (-) (+) (-) (+) Naïve  T-cell STAT6 GATA3 CMAT
T cell subsets: Th17 and T reg  cells ,[object Object],[object Object],[object Object],FoxP3 T reg  cell Self Ag + TGF  IL-10 TGF  PROTECTION IL-17 IL-22 INFLAMMATION Self Ag + TGF   + IL-6 IL-23 (survival) IL-23R CTLA-4 TGF  AITR, GITR Naïve  T-cell ROR  t Th17 cell Betelli,  et al. Nature  2006;441:235; Ivanov,  et al. Cell  2006;26:1121;  Tesmer L,  et al. 70 th  ACR,  Washington DC,   2006. #297
T-regs in autoimmune disease ,[object Object],[object Object],[object Object],[object Object],Bonelli M, et al.  EULAR 2007 , Barcelona #FRI0080
Vitamin D and IL-10: An important potential link in SLE ,[object Object],[object Object],[object Object],[object Object],[object Object],1. Radbruch, et al.  EULAR 2007 , Barcelona;  2.  Kamen DL, et al. Autoimmune Rev 2006;5: 114–7
Vitamin D May Play a Role in SLE ,[object Object],[object Object],[object Object],Insufficient:  <30ng/ml of 25-0H vitamin D Deficiency:  <15ng/ml of 25-0H vitamin D Amital H,  et al. 71 st  ACR,  Boston 2007. #535; Toloza S,  et al. ibid.  #1117; Cantorna  et al .  Exp Biol Med , 2004
IL-18 and SLE ,[object Object],[object Object],[object Object],[object Object],Aringer M, et al.  EULAR 2007 , Barcelona, #OP0177 TN, IL-18 and SLE activity Serum TNF (pg/ml) 0 200 100 300 0 4 8 12 SIS t=0.76, p<0.0001 Serum IL-18 (pg/ml) 0 200 100 300 0 4 8 12 SIS t=0.38, p<0.02
Microparticles and lupus ,[object Object],[object Object],[object Object],[object Object],Huber L, et al.  EULAR 2007 , Barcelona #OP0180
Targets for New Therapies in SLE Peptides derived from nucleosomes, Sm Ag, Igs, TEVA (edratide) T cell regulation of autoantibody production Medimmune, Genentech anti-IFN-alpha; Coley blocks TLR7 and 9 Inhibition of interferon, toll receptors Expand CD4+CD25+ cells,  CD8+CD28- cells Promote regulatory cells mAbs to IL-10, sIL-6R, IL-6 Cytokines anti C5a (approved for PNH) Complement LJP 394; mAbs to CD20, CD22 antiBLyS, TACI-Ig, BAFF-RFc B cells, anti-dsDNA antibodies CTLA4 Ig; modified CD40L mAb T cells
New therapies for APS ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

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New Treatments for Lupus by Daniel J. Wallace, MD

  • 1.
  • 2.
  • 3.
  • 4.
  • 5.
  • 6.
  • 7.
  • 8.
  • 9. Targets for New Therapies in SLE Peptides derived from nucleosomes, Sm Ag, Igs, TEVA (edratide) T cell regulation of autoantibody production Medimmune, Genentech anti-IFN-alpha; Coley blocks TLR7 and 9 Inhibition of interferon, toll receptors Expand CD4+CD25+ cells, CD8+CD28- cells Promote regulatory cells mAbs to IL-10, sIL-6R, IL-6 Cytokines anti C5a (approved for PNH) Complement LJP 394; mAbs to CD20, CD22 antiBLyS, TACI-Ig, BAFF-RFc B cells, anti-dsDNA antibodies CTLA4 Ig; modified CD40L mAb T cells
  • 10.
  • 11. Survival of Lupus Mice Treated with CTLA4Ig and Anti-CD40L Wang et al. J Immunol. 2002;168:2046–2053. Control CTLA4Ig/anti-CD40L CTLA4Ig Anti-CD40L Weeks % Alive 28 38 48 58 68 78 88 100 80 60 40 20 0
  • 12.
  • 13. T-lymphocyte co-stimulatory modulation: Importance of the T-cell subsets Adapted from Janeway CA Jr, et al. Immunobiology: The Immune System in Health and Disease. 6th e. New York, NY: Garland Science Publishing: 1994. p347 CTLA-Ig Less dependent CTLA-Ig More dependent Anti-viral / anti-tumor immunity CD8 T-cells: Peptide + class I CD4 T-cells: Peptide + class II Inflammation / Ab production T T Dougados M, et al. EULAR 2007, Barcelona, #SP0068
  • 14.
  • 15. Selective co-stimulation modulators in clinical development ** * in Rilex, June 2005; * in Dillon 2006 Dougados M, et al. EULAR 2007, Barcelona, #SP0068 Tumors CD28 agonist Myeloma CC-5012 (CD28 activator) Renal cancer Leukemia Anti-CD28 (TGN1412) Tumors Anti-CLA-4 (Ipilimumab, ticilimumab) Activation Crohn's disease Multiple sclerosis Anti- α 2 integrine (natalizumab) RA BR3-Fc SLE RA Anti-BAF (AM6, G3) SLE, Multiple sclerosis RA, Lymphoma TACI-Ig SLE RA Anti-BAFF (belimumab) SLE Psoriasis Anti-CD80 Organ transplantation Anti-CD80/86 Organ transplantation LEA29Y (belatacept) Juvenile Chronic Arthritis, Multiple sclerosis RA (registration) SLE CTLA-4 Ig (abatacept) Inhibition Human diseases Co-stimulation modulator
  • 16. Targeted therapeutics: Approaches in SLE Ng KP, et al. EULAR 2007, Barcelona, #OP0020 APC T B Y CTLA4-Ig  CD22 B-cell toleragen  BlySS TACI-IG  CD20  IL-10 Peptide Antibody IL-10 Apoptotic material 1 2 Costimulatory Factors, eg, BlyS
  • 17. Potential targets in B-cell lineage Antigen Independent Phase Antigen Dependent Phase Targets for BLyS/BAFF inhibitors Targets for Rituximab, Ocrelizumab, Ofatumumab CD45 (AKA B220) surface marker Activated B-cell Plasma cell Secreted IgG, IgA, IgE, or IgM Mature B-cell Pro-B-cell Pre-B-cell Immature B-cell Surrogate light chain D H J H IgM IgM I g D Antigen IgM, IgD, IgA, or IgE CD40L and cytokines CD40 V H D H J H V L J L Adapted from Sell S, et al. Immunology, Immunopathology, and Immunity . 6th ed. Washington, DC: ASM Press; 2001
  • 18.
  • 19. B-cell depletion is variable Anolik JH, et al. EULAR 2007, Barcelona, #SP0033 0.1 1 10 100 0 3 6 9 12 Months CD19+ (lymphocytes/uL) Non-depleters (n=6) Depleters (n=11) Recovery to 60% of baseline at 12 months Full recovery at 2–3 years in all but 1
  • 20.
  • 21.
  • 22.
  • 23.
  • 24.
  • 25.
  • 26.
  • 27. Belimumab reduced CD20+ B cells by 61% at Week 76 p<0.01 for the comparison between all active vs placebo from Day 56 through Day 364 Furie R, et al. ACR, Washington DC 2006, #535; Wallace D, et al. ibid , #2012; Stohl W, et al. ibid , #1985
  • 28.
  • 29. Combined response rate for belimumab patients significantly higher Ginzler E, et al. EULAR 2007, Barcelona, #OP0018 46% combined response rate for serologically active patients on belimumab vs 29% for placebo at Week 52 56% combined response rate for patients on belimumab at Week 76 * p=0.0059 at Week 52, p=0.02 at Week 56 0 10 20 30 40 50 60 70 0 28 84 140 224 280 336 392 476 532 Visit day Responder rate in serologically active pts (%) Placebo Placebo to 10 mg/kg All active
  • 30.
  • 31.
  • 32.
  • 33.
  • 34. Cumulative Renal Flare in Phase 3 Cumulative renal flares by week 32 59 82 98 118 153 Placebo 27 50 67 81 111 145 LJP394 88 64 48 32 16 Week 0 Patients
  • 35. Tolerance Mechanisms: Edratide (TEVA) Tsubata et al. Autoimmunity . 2005;38:331-337. Bone Marrow Peripheral lymphoid organs Reactive to self antigens Self antigen Deletion T-cell zone Self antigen Deletion Anergy Receptor editing Self antigen Deletion Follicle B cell BCR B cell BCR B cell BCR B cell BCR B cell BCR
  • 36.
  • 37. Induction of type I Interferon pathway through Toll-like receptors TLR3 TLR4 TLR7/8 TLR9 Inflammatory Cytokines Type I Interferon Inflammatory Cytokines Inflammatory Cytokines Type I Interferon Potential Endogenous Ligands: dsRNA ∞ RNA-containing Immune Complexes Fibronectin Products CpG DNA-containing Immune Complexes Exogenous Ligands: LPS ssRNA Demethylated CpG DNA dsRNA-containing Immune Complexes TRAM TIRAP Trf Trf MyD88 MyD88 MyD88
  • 38.
  • 39.
  • 40. CPG 52364 showed dose-dependent inhibition of TLR9-mediated IP-10 induction in mice Female adult BALB/c mice (n=5/gp) received different doses of CPG 52364 or chloroquine by IP injection. At 1 h post dose, animals received 100µg CpG-DNA ODN subcutaneously. Plasma was collected at 3 h post agonist injection and used for IP-10 assay by ELISA. Value are presented as percent mean TLR9 agonist activity.  
  • 41.
  • 42. SLE is a Disease of TLR-Driven Amplification of Autoimmunity Dendritic Cells TLR7+ / 8+ / 9+ B cells TLR9+ / TLR7 Inducible Cytokine/Chemokine Induced Activation/Maturation And Damage Apoptotic debris Self-antigen Autoimmune Complex-Driven TLR Cellular Activation TLR signal Anti-self response Cytokine/chemokine Tissue Damage End Organ Failure Inflammation CPG 52364 TLR7/8/9 Antagonist X Complex uptake X CPG 52364 (Coley) is a TLR 7,8,9 antagonist in a Phase I trial with similar actions to hydroxychloroquine Akira S, et al . Nat Imunol 2001;2:675; Lipford G , et al. 71 st ACR, Boston 2007. #1596 T-cell NK cell
  • 43.
  • 44.
  • 45. MEDI-545 Reduces Type I IFN Gene Signature, Type I IFN–Induced Proteins in Skin, and Improves Disease Activity Day 14 Skin, day 0–28 5/17 29% 1/33 3% MEDI-545 Placebo 0 20 30 40 Pts, N 10 >3 point increase in SLEDAI score <3 point increase in SLEDAI score P =0.0136 Wallace D, et al . 71 st ACR, Boston 2007. #1315 Type I IFN–induced proteins in skin Change in protein Change in transcript 20% 97% 75% 99% 87% 99% HERC5 ISG15 IP10 Improvement in disease activity Day 0 Day 14
  • 46. MEDI-545 Can Normalize Type I IFN Gene Signature in Blood: Heat Map of Gene Expression Day Neutralization Wallace D, et al . 71 st ACR, Boston 2007. #1315 Calculation based on top 25 type I IFN–inducible genes upregulated in whole blood of one patient treated with 30 mg/kg MEDI-545 (day 0, 1, 4, 7, 14)
  • 47. Th1/Th2 Paradigm T-bet IL-5 IL-10 IL-13 IL-4 IL-6 Helminth protection (allergy, atopy, SLE) IL-4 IL-12 IL-18 Th 1 cell IFN-  LT-  IL-2 IL-22 Cell-mediated immunity Intracellular pathogens Autoimmunity IL-12R IL-18R Th 2 cell Schulze-Koops H, et al. EULAR, 2006, Amsterdam, #SP0130. Zhu J, et al. Cell Res 2006;16:3 (-) (+) (-) (+) Naïve T-cell STAT6 GATA3 CMAT
  • 48.
  • 49.
  • 50.
  • 51.
  • 52.
  • 53.
  • 54. Targets for New Therapies in SLE Peptides derived from nucleosomes, Sm Ag, Igs, TEVA (edratide) T cell regulation of autoantibody production Medimmune, Genentech anti-IFN-alpha; Coley blocks TLR7 and 9 Inhibition of interferon, toll receptors Expand CD4+CD25+ cells, CD8+CD28- cells Promote regulatory cells mAbs to IL-10, sIL-6R, IL-6 Cytokines anti C5a (approved for PNH) Complement LJP 394; mAbs to CD20, CD22 antiBLyS, TACI-Ig, BAFF-RFc B cells, anti-dsDNA antibodies CTLA4 Ig; modified CD40L mAb T cells
  • 55.