Innovatív immunsuppressios lehetőségek Dr. Nagy György főorvos Budai Irgalmasrendi Kórház, I sz. Reumatológiai Osztály, Budapest

Innovatív immunsuppressios lehetőségek SLE-ben Dr. Nagy György Semmelweis Egyetem III. sz. Belgyógyászati Klinika, I. Reumatológiai és Fizioterápiás Tanszéki Csoport, Budapest Semmelweis Egyetem, Genetikai, Sejt- és Immunbiológia Intézet Budai Irgalmasrendi Kórház XVIII. DEBRECENI NEPHROLOGIAI NAPOK országos továbbképző tanfolyam 2013. május 29.

Szisztemás lupus erythematosus Jacoud's arthropátia Discoid lupus Alopécia Diffúz proliferatív glomerulonephritis Myelitis transversa retina vasculitis Stroke

Terápiás lehetőségek SLE-ben IFN-α sifalimumab tocilizumab belimumab kostimuláció abatacept rituximab ocrelizumab epratuzumab BG9588 Chan VS et al: cellular and molecular immunology 2013. 133-142

Terápiás lehetőségek SLE-ben IFN-α sifalimumab tocilizumab belimumab kostimuláció abatacept rituximab ocrelizumab epratuzumab BG9588 Chan VS et al: cellular and molecular immunology 2013. 133-142

CD19, CD20 és CD22 expresszió B-sejt érés során1 B sejt fejlődés CD19, CD20 és CD22 expresszió B-sejt érés során1 Adapted from Sell S et al. Immunology, Immunopathology, and Immunity. 6th ed. Washington,; Roitt I et al. Immunology. 6th ed. Philadelphia, PA: Mosby; 2001. Tedder TF et al. J Immunol. 1985; 135:973-979. Rituximab a CD20 antigénhez kötődik 1. Roitt et al, eds. Immunology. 6th ed. Chapter 8. 2001. Rituxan® (Rituximab) PI. February 28, 2006.

Rituximab hatásmechanizmus: antitestek effektor funkciója Komplement aktiváció ADCC

Rituximab hatékonysága SLE-ben, EXPLORER (fázis II/III) vizsgálat A, Mean British Isles Lupus Assessment Group (BILAG) index global scores over time. B, Kaplan‐Meier curve showing the time to moderate/severe flare over 52 weeks. Scr = screening; HR = hazard ratio. © This slide is made available for non-commercial use only. Please note that permission may be required for re-use of images in which the copyright is owned by a third party. Arthritis & Rheumatism 222-233, 28 DEC 2009 DOI: 10.1002/art.27233

Terápiás lehetőségek SLE-ben IFN-α sifalimumab tocilizumab belimumab kostimuláció abatacept rituximab ocrelizumab epratuzumab BG9588 Chan VS et al: cellular and molecular immunology 2013. 133-142

BAFF szerepe a B limfocita aktivációban BAFF, (BLyS) B limfocita túlélést és aktivációt szabályozza termeli:monocita, DC, T limfocita BAFF TG egér- SLE, anti DNS NZBXNZW; MRL-lpr/lpr egér, magas BAFF szint BAFF gátlás hatékony SLE állatmodellekben B sejt autoimmunitás küszöb szabályozása Zhang, et al. J Immunol 2001;166:6-10

Belimumab (BAFF/BLyS) gátlás a belimumab humán monoklonális IgG1 antitest, terápiás javallatok kiegészítő kezelésként javallt aktív fázisban levő, autoantitest pozitív szisztémás lupus erythematosusban szenvedő felnőtt betegeknek Nature Botechnology 30, 69–77 (2012) doi:10.1038/nbt.2076

BLISS-52 and BLISS-76 Pooled Systemic lupus erythematosus response index (SRI) változás belimumab kezelés mellett (fázis III vizsgálatok) Placebo plus SOC Belimumab 10mg/kg plus SOC 60 40 20 + + # + # # # # * Responders (%) 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Study week #P <0.001, +P <0.01, *P <0.05 1. Cervera R, et al. EuroLupus 2011 Abstr O12. 2. Petri M, et al. ACR 2010 Abstr 452. 12

Belimumab 10mg/kg plus SOC vs placebo plus SOC: 19.8% difference Phase 3 Subgroup: Low C and Positive Anti-dsDNA at Baseline Systemic lupus erythematosus response index (SRI) változás belimumab kezelés mellett (alacsony komplement, anti DNS+ alcsoport Placebo plus SOC Belimumab 10mg/kg plus SOC Belimumab 10mg/kg plus SOC vs placebo plus SOC: 19.8% difference 60 40 20 # # # # # # * # # # 51.5% P <0.001 31.7% * + Responders (%) 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Study week #P <0.001, +P <0.01, *P <0.05 van Vollenhoven RF, et al. Ann. Rheum Dis (2012) 13

Anti DNS és C3, C4 szint belimumab kezelés mellett BLISS-52 and BLISS-76 Pooled Anti DNS és C3, C4 szint belimumab kezelés mellett 60 50 40 30 20 10 Placebo plus SOC 10 mg/kg Belimumab 10mg/kg plus SOC # # # Normalised (%) # IgG Anti-dsDNA C3 C4 #P <0.001 aAbnormal at baseline and assessed at Week 52. Hiepe F, et al.EULAR 2011 Abstr 14

Terápiás lehetőségek SLE-ben IFN-α sifalimumab tocilizumab belimumab kostimuláció abatacept rituximab ocrelizumab epratuzumab BG9588 Chan VS et al: cellular and molecular immunology 2013. 133-142

T limfociták által termelt faktor szabályozza a B limfociták antitest termelését

IL-6 fiziológiás szerepe Immunreguláció és gyulladás → B sejt differenciáció és autoantitest termelés → Th17 sejt differenciáció, regulatorikus T sejtek gátlása → osteoclast aktiváció, osteoblast funkció gátlása → akut fázis fehérjék szintjének emelkedése Egyéb pleiotróp hatások → májsejtek hepcidin termelése  → akut fázis fehérjék termelése  → hypothalamus-hypophysis-mellékvese tengely működésének szabályozása

IL-6 jelátvitel SOCS: suppressors of cytokine signaling JAK kináz aktivitást gátol Kishimoto Arthritis Research & Therapy 2006 8(Suppl 2):S2   doi:10.1186/ar1916

Tocilizumab SLE-ben (fázis I vizsgálat) Clinical efficacy of treatment with 2 mg/kg, 4 mg/kg, or 8 mg/kg of tocilizumab from baseline to week 14 in patients with systemic lupus erythematosus (SLE). a, Swollen joint counts at baseline, week 6, week 14 (end of tocilizumab treatment), and week 20 (end of followup) in 7 SLE patients who had arthritis at baseline. In all 7 patients, there was an improvement in arthritis, as determined by the swollen joint count, with tocilizumab treatment, with complete resolution in 4 patients. Data are shown as box plots. Each box represents the 25th to 75th percentiles, the lines within the boxes represent the median (50th percentile), and the lines outside the boxes represent the 10th and 90th percentiles. Solid circles indicate outliers. P values comparing the end of treatment data with the baseline data were determined by Wilcoxon's signed rank test. b, Scores on the modified Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (mSELENA–SLEDAI) and the Systemic Lupus Activity Measure (SLAM) at baseline, weeks 6, week 14 (end of tocilizumab treatment), and week 20 (end of followup) in the 15 SLE patients evaluated for efficacy. There was improvement in overall disease activity over the course of treatment, with the mSLEDAI and SLAM scores showing a significant decrease at the end of treatment. Values are the mean and SD. P values were determined by repeated‐measures analysis of variance. © This slide is made available for non-commercial use only. Please note that permission may be required for re-use of images in which the copyright is owned by a third party. Arthritis & Rheumatism, pages 542-552, 28 JAN 2010 DOI: 10.1002/art.27221

Terápiás lehetőségek SLE-ben IFN-α sifalimumab tocilizumab belimumab kostimuláció abatacept rituximab ocrelizumab epratuzumab BG9588 Chan VS et al: cellular and molecular immunology 2013. 133-142

T limfociták SLE-ben Perl A, Gergely P, Nagy G, Koncz A, Banki K. Trends Immunol 2004. pp. 360-367.

T limfocita aktiváció Activated T cell Antigen presenting cell (APC) Major histocompatibility complex (MHC) CD80/86 co-stimulatory pathway Signal 1 CD28 T-cell receptor (TCR) Activated T cell Macrophage B cell T-cell activation occurs through the following steps: First, antigen is processed and presented to the T cell by the major histocompatibility complex (MHC) on the surface of the antigen presenting cell (APC) Although several possible antigens have been suggested as pathogenic triggers in rheumatoid arthritis, a specific antigen has yet to be identified The antigen is then recognised by the T cell through interaction of the MHC on the APC with the T-cell receptor or TCR (signal 1) T-cell mediated immunity. In: Janeway CA Jr, Travers P, Walport M, Shlomchik MJ. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science Publishing; 2005; 8: 319–65. Yamada A, Salama AD, Sayegh MH. The role of novel T cell co-stimulatory pathways in autoimmunity and transplantation. J Am Soc Nephrol 2002; 13(2): 559–75. Choy E, Panayi GS. Cytokine pathways and joint inflammation in Rheumatoid Arthritis. NEJM 2001; 344: 907–916, Smolen JS, Steiner G. Therapeutic strategies for Rheumatoid Arthritis. Nat Rev Drug Discov 2003; 2: 473–488 Cytokine release including TNF-, IL-1, & IL-6 Inflammation and destruction 1Janeway et al. Immunobiology: The immune system in health and disease 2005;8:319–65. 2Yamada et al. J Am Soc Nephrol 2002; 13(2): 559–75 3Choy, Panayi, NEJM 2001;344: 907–916, 4 Smolen, Steiner, Nat Rev Drug Discov 2003;2: 473–488

T limfocita aktiváció Activated T cell Antigen presenting cell (APC) Major histocompatibility complex (MHC) CD80/86 Signal 2 CD28 T-cell receptor (TCR) Activated T cell Macrophage B cell T-cell activation does not take place with signal 1 alone. A second signal is required and is provided via the engagement of CD80/86 on antigen presenting cells (APCs) with CD28 on T cells This produces positive co-stimulatory signals (signal 2) and facilitates full T-cell activation, proliferation, survival and cytokine production Following co-stimulation, T cells proliferate and differentiate, releasing potent cytokines and chemokines Fontenot AP, Gharavi L, Bennett SR, Canavera SJ, Newman LS, Kotzin BL. CD28 co-stimulation indepredence of target organ versus circulating memory antigen-specific CD4+ T cells. J Clin Invest 2003; 112: 776–84 T-cell mediated immunity. In: Janeway CA Jr, Travers P, Walport M, Shlomchik MJ. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science Publishing; 2005; 8: 319–65 Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol 2002; 2(2): 116–26 Yamada A, Salama AD, Sayegh MH. The role of novel T cell co-stimulatory pathways in autoimmunity and transplantation. J Am Soc Nephrol 2002; 13(2): 559–75. Choy E, Panayi GS. Cytokine pathways and joint inflammation in Rheumatoid Arthritis. NEJM 2001;344: 907–916 Smolen JS, Steiner G. Therapeutic strategies for Rheumatoid Arthritis. Nat Rev Drug Discov 2003; 2: 473–488 Cytokine release including TNF-, IL-1, & IL-6 Inflammation and destruction 1Fontenot et al. J Clin Invest 2003: 112: 776–84. 2Janeway et al. Immunobiology 2005; 8: 319–65, 3Sharpe et al. Nat Rev Immunol 2002; 2(2): 116–26.; 4 Yamada et al. J Am Soc Nephrol 2002; 13(2): 559–75, 5 Choy, Panayi.NEJM 2001;344: 907–916, Smolen, Steiner, Nat Rev Drug Discov 2003; 2: 473–488

CTLA4-IgG gátolja a CD28-B7 interakciót T-limfociták CTLA4-IgG gátolja a CD28-B7 interakciót T-sejt antigén prezentáló sejt TCR MHC + peptide CD28 CD80/86

Abatacept szerkezete CTLA-4 IgG1 ORENCIA (CTLA-4Ig) External ORENCIA is a soluble fusion protein consisting of an extracellular domain of human CTLA-4 linked to the modified Fc portion of human IgG1 CTLA-4 IgG1 ORENCIA (CTLA-4Ig) External Cell membrane Internal ORENCIA is a recombinant human fusion protein comprising the extracellular domain of human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and a fragment of the heavy chain (Fc) domain of human immunoglobulin G1 (IgG1) CTLA-4 has high affinity for CD80/86, two components of the second activation signal. It also has high avidity for these components1 CTLA-4 is structurally similar to CD28. When CD28 binds to CD80/86 the co-stimulatory T-cell activation signal is induced. However, when CTLA-4 binds to CD80/86 it provides a negative signal and the co-stimulatory pathway is blocked1 Affinity: tendency for a compound to combine with other compounds by chemical reaction Avidity: degree of affinity of an antibody for an antigen Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 1991; 174(3): 561–9 Not complement-fixing IgG1 = immunoglobulin G1. CTLA4=cytotoxic T-lymphocyte-associated antigen-4; Ig=immunoglobulin. Linsley. J Exp Med 1991; 174(3): 561–9

Abatacept SLE-ben (fázis IIb vizsgálat) Proportion of patients with a new flare of systemic lupus erythematosus (SLE) after the start of the steroid dosage taper and over 12 months, in the entire population of patients who were randomized and treated, as well as in the 3 subgroups of SLE manifestations at study entry. A, Flare (adjudicated) as determined by a British Isles Lupus Assessment Group (BILAG) index of A or B. B, Flare (adjudicated) as determined by a BILAG score of A only. C, Flare as determined by the physician's assessment. Analyses are based on the intent‐to‐treat population. Values are the percentage, with within‐group 95% confidence intervals. Values at the top of the bars are the actual percentages represented. Values in the table at the bottom are the number of patients in each group. © This slide is made available for non-commercial use only. Please note that permission may be required for re-use of images in which the copyright is owned by a third party. Arthritis & Rheumatism pages 3077-3087, 8 JUN 2010 DOI: 10.1002/art.27601

Terápiás lehetőségek SLE-ben IFN-α sifalimumab tocilizumab belimumab kostimuláció abatacept rituximab ocrelizumab epratuzumab BG9588 Chan VS et al: cellular and molecular immunology 2013. 133-142

Sifalimumab (human Anti–Interferon‐α monoklonlális AT) SLE-ben, fázis I vizsgálat Change from baseline in disease activity, as determined by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in patients with SLE (modified intent‐to‐treat population). A, Combined sifalimumab group (n = 121) and placebo group (n = 40). B, Combined sifalimumab group (n = 121) and placebo group (n = 40) adjusted for burst steroids in excess of that permitted in the protocol. Patients' baseline values were imputed for the value after excess steroid use (dose and duration). C, Subgroup of patients with a high type I interferon (IFN)–inducible gene signature (using a 4‐gene panel) at baseline (n = 92 in the sifalimumab group and n = 30 in the placebo group). D, Subgroup of patients with a high type I IFN–inducible gene signature at baseline adjusted for burst steroids in excess (dose or duration) of that permitted in the protocol (and as described in B) (n = 92 in the sifalimumab group and n = 30 in the placebo group). Values are the mean. © This slide is made available for non-commercial use only. Please note that permission may be required for re-use of images in which the copyright is owned by a third party. A sifalimumab vs placebo B sifalimumab vs placebo szteroid lökéskezelésre korrigálva C sifalimumab vs placebo I interferon (IFN)–indukálható gén mintázat csoport D sifalimumab vs placebo I interferon (IFN)–indukálható gén mintázat csoport, szteroid lökéskezelésre korrigálva Arthritis & Rheumatism pages 1011-1021, 28 MAR 2013 DOI: 10.1002/art.37824

Tartósan magas anti-IFNα szint hogyan érhető el? vakcináció elvben biztosíthat tartósan magas anti-IFNα szintet IFNα önmagában nem immunogén IFNα kinoid vakcináció poliklonális AT termelődés, fertőzések ?

TNF-blokkolók alkalmazása mellett jelentkező autoimmun betegségek A TNF gátolja egészséges kontrollokból származó PBMC IFNα termelését A TNF gátolja SLE-s betegekből származó PBMC IFNα termelését TNF blokkolás mellett fokozott lehet az IFN-α termelés PNAS 2005 March 1; 102(9): 3372–3377.

Összegzés biológiai terápia SLE-ben B limfocita T limfocita citokinek (BAFF, IL-6, IFNα) mellékhatások kiegészítő kezelés további célpontok (kinázgátlók)

Köszönöm a figyelmet

B limfocita mint terápiás célpont Nature Clinical Practice Neurology (2008) 4, 557-567 34

SRI Endpoint SRI composite endpoint combines the strengths of three commonly used indices SRI verifies improvement in disease activity without worsening in other organs that translates into a real clinical benefit for the patient 35 1. Navarra S et al. ACR 2009. Abstr LB1. 2. Furie RA et al. Arthritis Rheum. 2009;61:1143-51.