Rheumatoid arthritis Part 1, case based approach with application of the late...
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
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)
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