New Treatments for Lupus by Daniel J. Wallace, MD


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A presentation by Daniel J. Wallace, MD from Lupus LA's 4th Annual Patient Education Conference at Cedars-Sinai in Los Angeles, CA.

Published in: Health & Medicine
  • I suffer from a very disabling Auto Immune condition. The current treatments are toxic. I found out on that Dr. Wallace was doing phase three studies of a non toxic treatment.i contacted the office by phone and email repeatedly and for over two weeks no one got back to me. They never answer the phone, merely leave you to a phone tree of names. WHen I finally got through to someone she said she could not do anything because Dr. Wallace was out of town, the time he was gone was extended for weeks. Finally this person who was supposedly the research intake person, Erin Avila, who had refused to be forthcoming or helpful in anyway, when pressed told me to send her my "medical records". No matter how many times i asked ,she would not tell me which and what kind of medical records, including what. I sent her all my rhumatology doctors records for the past year including chart notes and clinical docs. I tracked it and it had arrived at the office. However Ms. Avila, obviously did not want to do her job and denied receiving them, even though she had. My most recent records and all the clinical docs were then send via email. She said she had those but it was not enough. By six weeks had passed. I asked again in writing for the sixth time, DO you want only my Rhumatologist and how far back, Erin refused to answer clearly again,saying only "we want all your medical records: I asked .. for what period. She still would not answer me. Instead the same day, I ot the brush off, a nasty email from her that they were refusing to see me because i was not desparate and sick enough to put up with the endless mistreatment, lack of honesty and candor, that they clearly dish out to all their patients. This kind of discrimination and abuse is not uncommon when doctors have all the power over very sick people who have no options and no good treatments . And to abuse ones power, over people who are sick and have no options is as low down and dirty as it gets. I intend to report them to the drug company that is making the drug and to the Medical board. These people are heartless and rotten. Erin Avila, the nasty rude office manager, are both not fit to serve the public, they are so nasty. As far as Dr. Wallace is concerned, i was told by the office manager that this is his policy and he said to do it all. If so, he has no heart, he is not a healer, rather just another bad egg in the field.
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  • New Treatments for Lupus by Daniel J. Wallace, MD

    1. 1. NEW THERAPIES FOR SLE <ul><li>DANIEL J WALLACE MD </li></ul><ul><li>Clinical Professor of Medicine </li></ul><ul><li>Cedars-Sinai Medical Center </li></ul><ul><li>David Geffen School of Medicine at UCLA </li></ul>
    2. 2. 2005 FDA Guidance Document for SLE <ul><li>The drug is safe </li></ul><ul><li>Clinical indices must be improved (BILAG+ either SLEDAI, SLAM or ECLAM) </li></ul><ul><li>Clinical response index (e.g., RIFLE) </li></ul><ul><li>Quality of life improvement </li></ul><ul><li>ACR/SLICC Damage Index </li></ul><ul><li>Organ specific measures </li></ul><ul><li>Subpart H: surrogate markers or biomarkers </li></ul>
    3. 3. SLEDAI (Systemic lupus disease activity index) <ul><li>Evaluates 24 components and emphasizes organ activity as opposed to laboratory abnormalities </li></ul><ul><li>105 possible points---64 of which are central nervous system and 16 are renal </li></ul><ul><li>Anti DNA, C3, Leukopenia, Thrombocytopenia are the only blood determinations and if all abnormal account for only 6 points </li></ul><ul><li>Does not include: hemolytic anemia, pulmonary hypertension, TTP, mesenteric vasculitis, pulmonary hemorrhage </li></ul><ul><li>SLEDAI Flare Index requires a change of 4 points </li></ul>
    4. 4. BILAG (British Isles Lupus Assessment Group) <ul><li>8 organ systems with 86 items weighted as 0-4 (not present to new or improved) </li></ul><ul><li>Organ systems: constitutional, musculoskeletal, renal, nervous system, hematologic, cutaneous, cardiopulmonary, eye, gastrointestinal </li></ul><ul><li>Rated A-E (life threatening to not present) </li></ul><ul><li>BLIPS software </li></ul><ul><li>End points as new BILAG A or B </li></ul>
    5. 5. Clinical validation of the CLASI <ul><li>An ACR and dermatology group derived the CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) (J Inv Derm 2005; 125:889-94) for use in assessing skin scores in clinical trials (analagous to the PASI for psoriasis) fulfills the FDA guidance document’s requirements for validated organ specific measures in following lupus patients </li></ul><ul><li>Index contains weighted anatomic locations, activity (erythema, scale/hypertrophy), damage (dyspigmentation, scarring, atrophy, panniculitis), mucous membranes and alopecia </li></ul><ul><li>First attempt to validate it (abst #1010) in a pilot study of 9 patients at U of Penn given drug interventions was promising but needs much greater experience </li></ul>
    6. 6. Newer agents for SLE <ul><li>Mycophenolate mofetil </li></ul><ul><li>Topical pinecrolimus and tacrolimus </li></ul><ul><li>Tacrolimus </li></ul><ul><li>Leflunomide </li></ul><ul><li>Infliximab and other TNFi </li></ul>
    7. 7. Lupus Nephritis <ul><li>Cost </li></ul><ul><ul><li>Direct medical costs are 4x higher for lupus nephritis pts compared with SLE pts without nephritis ($19,250–$42,174/yr vs $4700–$10,015/yr) </li></ul></ul><ul><ul><li>Extra costs due to hospitalizations and/or dialysis </li></ul></ul><ul><li>Response to standard therapy </li></ul><ul><ul><li>80% respond to IV cyclophosphamide </li></ul></ul><ul><ul><li>35% relapse rate </li></ul></ul><ul><ul><li>10% dialysis </li></ul></ul><ul><li>Poor prognostic factors </li></ul><ul><ul><li>AA race does not respond as well to IV cyclophosphamide </li></ul></ul><ul><ul><li>Poor initial response </li></ul></ul><ul><ul><li>Renal relapse </li></ul></ul>Houssiau F, 71 st ACR , Boston 2007, ACR Clinical Symposium; Clarke A. ibid , #503; Li T, et al. ibid , #1255;Ginzler E, #L13 <ul><li>Efficacy and safety study to demonstrate superiority of MMF over IVCy in Lupus nephritis (WHO III, IV) </li></ul><ul><li>Induction protocol (370 pts randomized to one of two therapies for 24 wks) </li></ul><ul><ul><li>MMF 3 g/d (185 pts) </li></ul></ul><ul><ul><li>IV cyclophosphamide 0.5–1.0 g/m 2 monthly (185 pts) </li></ul></ul><ul><ul><li>All pts received prednisone 60 mg/d with taper </li></ul></ul><ul><li>Response: stable/improved Cr and improved proteinuria </li></ul>Aspreva lupus management study (ALMS)
    8. 8. ALMS: Efficacy and Safety Results <ul><li>Conclusions </li></ul><ul><ul><li>MMF equal to IVCy for induction </li></ul></ul><ul><ul><li>AA and Hispanics may respond better to MMF than to IVCy </li></ul></ul><ul><ul><li>Safety </li></ul></ul><ul><ul><ul><li>MMF: 24 AEs; 12 infections; 9 deaths (7 from infection) </li></ul></ul></ul><ul><ul><ul><li>IVCy: 13 AEs; 4 infections; 5 deaths (2 from infection) </li></ul></ul></ul>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 (%)
    9. 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. 10. How are T-cells activated? <ul><li>CD80/86:CD28 is one of the best characterized co-stimulatory pathways </li></ul><ul><ul><li>Signal 2 </li></ul></ul>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
    11. 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. 12. Phase 2 Trial of Abatacept <ul><li>Randomized, double-blind, placebo-controlled, phase 2 study </li></ul><ul><li>Abatacept compared with Placebo on a background of oral glucocorticosteroids for subjects with SLE and the prevention of subsequent lupus flares </li></ul><ul><li>Primary objective of this study will be to assess the proportion of subjects with new clinical flare of SLE (BILAG &quot;A&quot; or &quot;B&quot;) during the 1 year double-blind treatment period </li></ul><ul><li>Secondary objective of this study will be to assess proportion of subjects with a new clinical flare of SLE (BILAG A or B) within the initial 6 months of the double-blind treatment period and evaluate the proportion of subjects who during the study experienced a BILAG A or B flare </li></ul><ul><li>Expected Total Enrollment is 180 </li></ul>Source: Accessed January 29, 2007.
    13. 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. 14. T-lymphocyte costimulatory modulation consequences <ul><li>Activation of the co-stimulation </li></ul><ul><ul><li>Anti-tumoral effect? </li></ul></ul><ul><ul><li>Autoimmune disorders </li></ul></ul><ul><li>Inhibition of the costimulation? </li></ul><ul><ul><li>Pro-tumoral effect? </li></ul></ul><ul><ul><li>Prevention of autoimmune disorders? </li></ul></ul>Dougados M, et al. EULAR 2007, Barcelona, #SP0068
    15. 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. 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. 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. 18. Uncontrolled Data of Rituximab in SLE and SS <ul><li>Two placebo-controlled trials underway in SLE (SS?) (EXPLORER and LUNAR) </li></ul><ul><li>9 uncontrolled studies presented in lupus and Sjogren’s </li></ul><ul><li>New insights from in uncontrolled studies include: </li></ul><ul><ul><li>NK cell levels surge just as B-cell recovery begins </li></ul></ul><ul><ul><li>Persistence of B-cells predicts a poorer outcome </li></ul></ul><ul><ul><li>Drug may be more effective when used with CTX </li></ul></ul><ul><ul><li>In membranous nephritis, rebiopsy shows resorption of immune depositions </li></ul></ul><ul><ul><li>20% with SLE develop with HACA (3x that reported with RA) </li></ul></ul><ul><ul><li>Responses can last up to 1 y. 1/3 don’t require further immune suppressive Rx </li></ul></ul><ul><ul><li>16 patients with primary Sjogren’s: salivary gland B-cell morphology returned to baseline after 18 months (ISRs and serum sickness reported in some pts) </li></ul></ul><ul><ul><li>Drug is safe in children with lupus </li></ul></ul>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
    19. 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. 20. Ocrelizumab: Humanized anti-CD20 mAb is effective in RA – 24 Week Phase 1/2 1 <ul><li>237 patients: All RF+; IR to MTX: </li></ul><ul><ul><li>Ocrelizumab 10, 50, 200, 500, 1000 mg IV Day 1 and 15 or Pbo </li></ul></ul><ul><li>Dose dependent B-cell depletion and increases in serum BAFF ² </li></ul><ul><li>Most frequent AEs: infusion-associated HA, nausea, chills, pyrexia, dizziness </li></ul><ul><ul><li>SAEs and SIEs similar between active and placebo </li></ul></ul><ul><li>HAHAs Wk 24: 10mg: 19%; 50mg: 10%; 200mg: 0; 500mg: 0; 1000mg: 2.5% </li></ul><ul><li>Conclusions: </li></ul><ul><ul><li>No apparent dose response </li></ul></ul><ul><ul><li>progressing to phase 2/3 </li></ul></ul>1. Genovese M, et al. EULAR 2007, Barcelona, #SAT0008; 2. Manning W, et al. ibid, #SAT0018 ACR response EULAR response
    21. 21. Synthetic anti-CD 20 – TRU-015: Ongoing Phase II RCT <ul><li>CD20-directed SMIP (single-chain polypeptides), smaller than antibodies </li></ul><ul><li>Mediates ADCC and CDC </li></ul><ul><li>36 patients w/ active disease despite MTX </li></ul><ul><li>5 mg/kg IV x1 or 2.5 or 7.5 mg/kg IV q week x2 </li></ul><ul><li>Study ongoing; interim data </li></ul><ul><li>Generally well tolerated </li></ul><ul><li>No infectious or non-infectious SAEs </li></ul><ul><li>B-cell depletion in all cohorts </li></ul><ul><li>B-cell recovery starts at 16 weeks </li></ul>ACR20 at Week 24 Burge DJ, et al. ACR, Washington DC 2006, #463
    22. 22. Mechanism of Anti-CD20 (Rituximab) and Anti-CD22 (Epratuzumab) Monoclonal Antibodies <ul><li>Antibody-dependent cell-mediated cytotoxicity </li></ul><ul><li>Complement-dependent cytotoxicity </li></ul><ul><li>Apoptosis </li></ul><ul><li>Modest antibody-dependent cell-mediated cytotoxicity </li></ul><ul><li>No complement-dependent cytotoxicity </li></ul><ul><li>Immunomodulatory and antiproliferative effect </li></ul>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
    23. 23. B-cell–targeted therapies <ul><li>Anti-CD20 agents: </li></ul><ul><ul><li>Rapidly deplete peripheral B-cells via ADCC and CDC </li></ul></ul><ul><ul><li>First dose infusion reactions due to rapid cell death, cytokine release </li></ul></ul><ul><ul><li>Immunogenicity in part related to cell death/debris </li></ul></ul><ul><ul><li>Despite fully human or SMIP -single chain polypeptides, smaller than antibodies ; expect immunogenicity </li></ul></ul><ul><li>B-cell growth factors (BLyS/BAFF/APRIL) antagonists </li></ul><ul><ul><li>Slower depletion of B-cells </li></ul></ul><ul><ul><li>Peripheral and germinal center B-cells undergo apoptosis due to absence of growth factors </li></ul></ul><ul><ul><li>Onset of benefit generally occurs over 3-6 months </li></ul></ul><ul><ul><li>Less severe infusion reactions </li></ul></ul><ul><ul><li>Less immunogenicity </li></ul></ul>
    24. 24. B-cell growth factors Ligands Receptors BAFF-R BCMA TACI BLyS APRIL Heterotrimer Proteoglycans <ul><li>Increased B-cell survival Costimulation of B-cell prolferation </li></ul><ul><li>Ig class switch recombination </li></ul><ul><li>Enhanced APC function </li></ul><ul><li>Germinal center formation </li></ul><ul><li>Regulation of B-cell tolerance </li></ul><ul><li>Sequester APRIL at cell surface to improve TACI and/or BCMA signalling? </li></ul><ul><li>Mediate plasma cell trafficking </li></ul>Issacs JD, et al. EULAR 2007 , Barcelona #SP0069
    25. 25. Belimumab (lymphoStat-B) <ul><li>Fully-human monoclonal antibody </li></ul><ul><li>Selectively targets and inhibits soluble BLyS </li></ul><ul><ul><li>TNF family member that promotes B-cell differentiation, proliferation, and survival </li></ul></ul><ul><ul><li>Plays critical role in physiologic B-cell development and induces B cells to secrete immunoglobulins </li></ul></ul><ul><li>Inhibition of BLyS can result in autoreactive B-cell apoptosis </li></ul>
    26. 26. Systemic Lupus: Belimumab <ul><li>Phase 2: 52-week, randomized, double-blind, placebo-controlled trial. </li></ul><ul><li>n=449…but subset analysis using 71.5% of patients defined by ANA>1:80 or dsDNA >30 IU. Moderately ill SLE: baseline mean SELENA SLEDAI= 9.6. </li></ul>Ginzler E, et al. EULAR 2007, Barcelona, #OP0018
    27. 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. 28. Novel combined endpoint* <ul><li>> 4 point improvement in SELENA SLEDAI score </li></ul><ul><ul><li>AND </li></ul></ul><ul><ul><li>No new BILAG 1A/2B flares </li></ul></ul><ul><ul><li>AND </li></ul></ul><ul><ul><li>No worsening in Physician’s Global Assessment (<0.3 point increase) </li></ul></ul>Ginzler E, et al. EULAR 2007, Barcelona, #OP0018 * Accepted by Regulatory Authorities for Phase 3 Trials
    29. 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. 30. Atacicept inhibits the function of BLys and APRIL <ul><li>Atacicept is a fusion protein formed between the extracellular domain of the naturally occurring human TACI receptor and the Fc domain of human IgG1 </li></ul>Atacicept Extracellular domain of TACI receptor Fc domain of human IgG rDNA technology B-cell
    31. 31. Systemic Lupus: Atacicept (TACI-Ig) <ul><li>2 Phase I studies of PK and biologic activity </li></ul><ul><li>Appears tolerated and safety is favorable </li></ul><ul><li>Good signs of biologic effects on B-cells whether IV or SC </li></ul><ul><li>Interestingly, measured atacicept-BLys complexes in peripheral blood </li></ul><ul><li>Further development and trials are planned </li></ul>
    32. 32. Phase I trials for lupus: Tociluzimab <ul><li>anti-IL-6R mAb </li></ul><ul><li>Phase I: 16 patients, 6 doses over 12 weeks (3 dosing regimens) </li></ul><ul><li>Safety signals </li></ul><ul><ul><li>Significant decrease in absolute neutrophil count in 60% of patients at highest dose </li></ul></ul><ul><li>Significant decreases noted in IgG and ds DNA Abs </li></ul><ul><li>Significant improvement in SLEDAI and SLAM scores </li></ul>1. Illei G, et al. ACR, Washington DC 2006, #L20; 2. Dall'Era M, et al. ibid , #L19
    33. 33. Mechanism of LJP 394 (Abetimus) <ul><li>Novel synthetic putative B-cell toleragen </li></ul><ul><ul><li>Four double-stranded oligodeoxyribonucleotides plus non-immunogenic PEG carrier </li></ul></ul><ul><ul><li>Acts as anti-anti DNA to reduce anti-dsDNA antibodies in SLE patients </li></ul></ul><ul><ul><li>Awaiting results of phase III study with an endpoint of time to nephrotic flare </li></ul></ul>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
    34. 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. 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. 36. Innate Immune Responses in SLE <ul><li>Toll-like receptors 7 and 9 in immature DC activated by complexes of self protein + RNA (TLR7) and DNA (TLR9) </li></ul><ul><li>These complexes are normally rapidly cleared, but accumulate in SLE </li></ul><ul><li>Clearance defects in mice or humans -> SLE </li></ul><ul><li>Activation of TLR7/9 induces immature DC secretion of IFN- α immature DC induce T and B cell responses against the RNA and DNA and associated proteins </li></ul>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
    37. 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. 38. Toll-like Receptors in RA and SLE <ul><li>In RA </li></ul><ul><ul><li>increased TLRs 3, 4, 7 on dendritic cells (DC) 1 </li></ul></ul><ul><ul><li>increased viral ds-RNA in joints compared with OA 2 </li></ul></ul><ul><li>In mouse models arthritis </li></ul><ul><ul><li>TLR 2 deficiency decreased susceptibility to arthritis, </li></ul></ul><ul><ul><li>TLR4 deficiency decreased severity, erosions </li></ul></ul><ul><ul><li>Abs to TLR 4 prevented arthritis 1 </li></ul></ul><ul><li>DS-RNA arthritogenic when injected into mouse joint, mediated by type 1 IFN from DC 2 </li></ul><ul><li>CpG DNA sequences, common in bacterial DNA bind TLR 7 and 9 in DCs and B cells. </li></ul><ul><li>Lupus immune complexes bind TLR 7 and Fc γ on DC, releasing cytokine and IFN 3 </li></ul><ul><li>Antimalarials block the activation TLR 7 and 9 </li></ul><ul><li>IFN increase SLE flares and increased in SLE serum </li></ul><ul><li>IFN signaling molecule Stat1 upregulated in SLE 4 </li></ul><ul><li> Genentech, Coley and MEDI-545 clinical trials </li></ul>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
    39. 39. Hydroxychloroquine, “Antimalarials” are TLR Antagonists <ul><li>Hydroxychloroquine and other “antimalarials” have been used in treating SLE and RA for decades, but MOA was unknown </li></ul><ul><li>Recent discovery: these antimalarials are TLR7/8/9 antagonists at clinically relevant doses </li></ul><ul><li>New approach to treatment – develop improved TLR antagonists </li></ul><ul><ul><li>Small molecule </li></ul></ul><ul><ul><li>Orally available </li></ul></ul>
    40. 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. 41. Hydroxychloroquine (HCQ) and Toll Receptors <ul><li>TLRs 7, 8 and 9 are activated inappropriately by endogenous RNA and DNA in SLE. This is inhibited by HCQ, which was thought to work primarily by diminishing antigen presentation </li></ul><ul><li>Mice were treated with HCQ for 5 days. TLR9 activation was strongly inhibited (and to a lesser extent TLR 7). Ag presentation was incompletely blocked. </li></ul><ul><li>The TLR mechanism is more important than antigen presentation inhibition and TLR antagonists represent a novel approach for SLE therapeutics </li></ul>Weeratna R, et al. 71 st ACR , Boston 2007. #1310
    42. 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. 43. Interferons and Systemic Lupus Erythematosus <ul><li>Type I interferons (IFNs) may play a critical role in the pathogenesis of systemic lupus erythematosus (SLE) </li></ul><ul><ul><li>Serum IFN-α levels are elevated in patients with SLE 1 </li></ul></ul><ul><ul><li>Increased expression of type I IFN-induced genes in blood and involved tissues in SLE 2 </li></ul></ul><ul><ul><li>Correlation between IFN levels and expression of type I IFN-induced genes and SLE activity 1,3 </li></ul></ul><ul><ul><li>Development of SLE in patients undergoing IFN-α treatment 4 </li></ul></ul><ul><ul><li>Inhibition of IFN-α may provide therapeutic benefit in the treatment of SLE </li></ul></ul>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.
    44. 44. MEDI-545 (Medimmune/AstraZeneca) <ul><li>Fully human anti–IFN- α IgG1k monoclonal antibody </li></ul><ul><li>Inhibits IFN-a signaling through IFN- α receptor (IFNAR) </li></ul><ul><li>Double-blind, placebo-controlled phase I trial of single escalating dose, intravenous MEDI-545 (0.3–30 mg/kg) in patients ≥18 years old with SLE </li></ul><ul><ul><li>2:1 randomization, 84-day follow-up </li></ul></ul><ul><li>There was no safety signal observed </li></ul><ul><li>Effects of MEDI-545 on neutralization of type I IFN gene signature in blood and skin and on disease activity were explored </li></ul>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
    45. 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. 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. 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. 48. T cell subsets: Th17 and T reg cells <ul><li>Th17 cells are abundant in gut, maintain mucosal homeostasis </li></ul><ul><li>Upregulated in inflammatory diseases including MS, RA, IBD </li></ul><ul><li>IL-23 important for the maintenance of the Th17 phenotype </li></ul>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
    49. 49. T-regs in autoimmune disease <ul><li>CD4+CD25+ regulatory cells prevent the activation of autoreactive T-cells </li></ul><ul><li>T-cells from lupus prone mice are relatively resistant to the suppressive effect of CD4+CD25+  </li></ul><ul><li>Work at the NIH (Lipsky et al) suggests CD4+CD25+ upregulation is a potential therapeutic avenue in lupus management  </li></ul><ul><li>Active as opposed to inactive SLE is associated with less CD4+CD25+ activity (poster and picture represented on the slide </li></ul>Bonelli M, et al. EULAR 2007 , Barcelona #FRI0080
    50. 50. Vitamin D and IL-10: An important potential link in SLE <ul><li>IL-10 is a complex cytokine whose levels are elevated in SLE and has both pro- and anti-inflammatory effects </li></ul><ul><li>Vitamin D levels are decreased in SLE </li></ul><ul><li>Vitamin D independently promotes IL-10 secretion </li></ul><ul><li>Activated B cells produce Vitamin D which down regulates the immune response </li></ul><ul><li>Efforts to produce a Mab to IL-10 are potentially problematic </li></ul>1. Radbruch, et al. EULAR 2007 , Barcelona; 2. Kamen DL, et al. Autoimmune Rev 2006;5: 114–7
    51. 51. Vitamin D May Play a Role in SLE <ul><li>25-OH vitamin D inhibits Th1 cell proliferation, cytokine production, autoantibody production and APC activation in SLE patients; may be clinically relevant </li></ul><ul><li>124 Toronto women with SLE who underwent DEXA scanning had significantly lower levels of 25-OH vitamin D levels compared with other DEXA patients; this finding did not correlate with bone density. </li></ul><ul><li>Among 274 Israeli lupus patients, 38% had low vitamin D levels and higher SLEDAI and ECLAM scores. Hydroxychloroquine-treated patients had higher vitamin D levels, corticosteroids had no impact </li></ul>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
    52. 52. IL-18 and SLE <ul><li>A member of the TNF superfamily which supports the expansion of Th1 and NK cells </li></ul><ul><li>Mouse models of SLE overexpress IL-18 </li></ul><ul><li>Increased levels in SLE sera and renal tissue which correlates with TNF levels and disease activity </li></ul><ul><li>Administration of infliximab decreases expression of IL-18. Targeted therapies against IL-18 are in development </li></ul>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
    53. 53. Microparticles and lupus <ul><li>200-700 nm in size surrounded by phospholipid bilayers </li></ul><ul><li>Released by cell death to the surface; taken up by macrophages and induce apoptosis and T cell proliferation </li></ul><ul><li>40 SLE pts and matched controls— increased levels that correlated with SLEDAI scores </li></ul><ul><li>Also increased in Sjogren’s, vasculitis, antiphospholipid syndrome in other studies </li></ul>Huber L, et al. EULAR 2007 , Barcelona #OP0180
    54. 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. 55. New therapies for APS <ul><li>Biologics: LJP 1082 </li></ul><ul><li>Oral heparins </li></ul><ul><li>Rituximab </li></ul><ul><li>Glycoprotein IIb/IIIa specific antagonists </li></ul><ul><li>Tissue factor expression inhibitors </li></ul><ul><li>P38 MAPK inhibitors </li></ul><ul><li>Thromboxane A2 inhibitors </li></ul><ul><li>Anti C5a </li></ul>