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

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

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

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

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

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

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

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

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

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

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.

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

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

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