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Advances in B-Cell Biology in the Treatment of Autoimmune and Inflammatory Diseases

Advances in B-Cell Biology in the Treatment of Autoimmune and Inflammatory Diseases. Learning Objectives. Discuss recent advances in understanding how B-cell biology affects autoimmune rheumatic diseases (ARDs) Review new biologic agents that target B cells and their mechanisms of action

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Advances in B-Cell Biology in the Treatment of Autoimmune and Inflammatory Diseases

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  1. Advances in B-Cell Biology in the Treatment of Autoimmune and Inflammatory Diseases

  2. Learning Objectives Discuss recent advances in understanding how B-cell biology affects autoimmune rheumatic diseases (ARDs) Review new biologic agents that targetB cells and their mechanisms of action Identify how studies of B-cell–targeted therapy are changing our understandingof integrated immune responses and the pathogenesis of ARDs

  3. Outline • B-cell biology in autoimmune disorders • Overview of B-cell–targeting agents • Recent developments in B-cell targetingin rheumatoid arthritis (RA) • Recent development in B-cell targetingin other ARDs

  4. B DC T B TNF-a LT IL-6 FDC T DC T M ? Lymphoid organogenesis Antigen presentation and costimulation Inflammatory cytokines Auto- antibodies Immune complexes Multiple sclerosis Sjögren’s syndrome RA Multiple sclerosis SLE RA All autoimmune disorders Graves’ disease Myasthenia gravis Pemphigus vulgaris SLE (RA) SLE RA B B-Lineage Cells and Autoimmunity Mature Blast Bone Marrow Activation Immature Plasma cell T1 T2 Pro B Pre B Spleen FO MZ Plasmablast Memory GC DC, dendritic cell; FDC, follicular dendritic cell; FO, follicular; GC, germinal center;IL, interleukin; LT, lymphotoxin; Mφ, macrophage; MZ, marginal zone; SLE, systemiclupus erythematosus; TNF, tumor necrosis factor. Adapted from Martin F, Chan AC. Annu Rev Immunol. 2006;24:467-496 5

  5. Why Are Some Plasma Cells Short-Lived and OthersLong-Lived? • Plasma cells, which arise after new immune exposures, are continuously generated in lymphoid tissues, and perhaps in pathologic ectopic lymphoid tissues(eg, rheumatoid synovium) • There are different life expectancies of Ig-secreting plasmablasts (which can proliferate) and plasma cells(which cannot proliferate) • Newly generated plasma cells are released into the bloodstream, then migrate to the bone marrow • As long-term survival requires that they find a “niche,” they must displace “older” plasma cells from their survival niche for long-term survival Dörner T, Radbruch A. Immunity. 2007;27:384-392.

  6. T Complex Interactions Determine Plasma Cell Survival • Adhesion • CD138 • CD44, 18, 11a • E-/P-selectin • Chemokine systems • CXCR4/CXCL12 • Intracellular survival regulators • ↑ Bcl-2, Blimp1, XBP1, Aiolos • ↓ BACH2 and Pax5 Bone marrow GC B Competence Plasmablasts • Instruction of memory • B cells by T cells • CD40/154 • ICOS/ICOS-L • SAP Long-lived memory plasma cell • Soluble survival factors • IL-6 • IL-21 (?) • TNF, IL5 • BAFF/APRIL • Chemokine systems • CXCR4/CXCL12 (?) • Insoluble survival factors from • nurse cells • or stromal cells (within inflamed tissue) Dörner T, Radbruch A. Immunity. 2007;27:384-392. Tarlinton D et al. Curr Opin Immunol. 2008;20:162-169.

  7. Not All CD20+ B Cells Are Susceptible to Depletion • Deletion is most efficient in blood • CD20+ precursors and transitional and naïve B cells appear highly susceptible to deletion • CD20+ B1 cells, MZ B cells, and GC B cells are resistant (GC in GALT Peyer’s patches) • Most plasma cells are not directly affected by RTX (although in the tonsil a subset may express CD20) • Effect of RTX on memory B cells and plasmablasts • Little is known about RTX effects on these cells in lymphoid organs • IgG-producing plasma cells generally live longer than IgM producers GALT, gut-associated lymphoid tissue. Gong Q et al. J Immunol. 2005;174:817-826. Silverman GJ. Arthritis Rheum. 2006;54:2356-2367. Withers DR et al. Blood. 2007;109:4856-4864. Terstappen LW et al. Blood. 1990;76:1739-1747.

  8. Does Extent of Reduction in SynovialB Cells Explain Clinical Response? CD22 stainingof synovial tissue Before Treatment 4 Weeks After Treatment B-cell depletion Nondepletion Vos K et al. Arthritis Rheum. 2007;56:772-778.

  9. B cell T cell Plasma cell IL-1, IL-6, TNF-a IFN-g TNF-a IFN-g IL-17 RANKL RF, anti-CCP antibodies FLS Immune complexes Complement fixation Induce Mf secretion of proinflammatory cytokines Mf MMPs Cathepsins TNF-a IL-1 IL-6 MMPs Cathepsins TNF-a, IL-1, IL-6 Model of RTX-Induced RA Synovial Changes in Clinical RespondersBASELINE CCP, cyclic citrullinated peptide; FLS, fibroblast-likesynoviocyte; IFN, interferon; MMP, matrixmetalloproteinase; RANKL, receptor activator ofNF-κB ligand; RF, rheumatoid factor. Silverman GJ, Boyle DL. Immunol Rev. 2008;223:175-185. Responsible formarginal erosions and bone loss Osteoclast

  10. Model of RTX-Induced RA Synovial Changes in Clinical Responders4 WEEKS X Early synovial B-cell depletion is necessary but not sufficient! Trends toward ↓ in plasma cells in clinical responders (at 6 months) B cell X T cell Plasma cell IL-1, IL-6, TNF-a IFN-g TNF-a IFN-g IL-17 RANKL RF, anti-CCP antibodies FLS Immune complexes Complement fixation Induce Mf secretion of proinflammatory cytokines Mf MMPs Cathepsins TNF-a IL-1 IL-6 MMPs Cathepsins TNF-a, IL-1, IL-6 Responsible formarginal erosions and bone loss Osteoclast Silverman GJ, Boyle DL. Immunol Rev. 2008;223:175-185.

  11. Model of RTX-Induced RA Synovial Changes in Clinical Responders8 WEEKS Early synovial B-cell depletion is necessary but not sufficient! Trends toward ↓ in plasma cells in clinical responders Significant ↓ in Ig transcripts in ACR50/70 clinical responders(at 6 months) Trends toward ↓ in lymphocytic aggregates and T cells X B cell X T cell Plasma cell IL-1, IL-6, TNF-a IFN-g TNF-a IFN-g IL-17 RANKL RF, anti-CCP antibodies FLS Immune complexes Complement fixation Induce Mf secretion of proinflammatory cytokines Mf MMPs Cathepsins TNF-a IL-1 IL-6 MMPs Cathepsins TNF-a, IL-1, IL-6 Responsible formarginal erosions and bone loss Osteoclast Silverman GJ, Boyle DL. Immunol Rev. 2008;223:175-185.

  12. Significant synovial B-cell depletion Significant ↓ in plasma cells Significant ↓ in T cells and lymphocytic aggregates Significant ↓ in CD68+ Mf All in clinical responders at6 months X X B cell X T cell Plasma cell IL-1, IL-6, TNF-a IFN-g TNF-a IFN-g IL-17 RANKL RF, anti-CCP antibodies X FLS Immune complexes Complement fixation Induce Mf secretion of proinflammatory cytokines Mf MMPs Cathepsins TNF-a IL-1 IL-6 MMPs Cathepsins TNF-a, IL-1, IL-6 ? Responsible formarginal erosions and bone loss Osteoclast Model of RTX-Induced RA Synovial Changes in Clinical Responders16 WEEKS Silverman GJ, Boyle DL. Immunol Rev. 2008;223:175-185.

  13. Primary end point is clinical response at 24 weeks Effects on synovial cytokines/chemokines have not been evaluated at later time points Direct studies on osteoclasts after RTX are not currently available X X B cell X T cell Plasma cell IL-1, IL-6, TNF-a IFN-g TNF-a IFN-g IL-17 RANKL RF, anti-CCP antibodies X FLS Immune complexes Complement fixation Induce Mf secretion of proinflammatory cytokines Mf MMPs Cathepsins TNF-a IL-1 IL-6 MMPs Cathepsins TNF-a, IL-1, IL-6 ? Responsible formarginal erosions and bone loss Osteoclast Model of RTX-Induced RA Synovial Changes in Clinical Responders24 WEEKS Silverman GJ, Boyle DL. Immunol Rev. 2008;223:175-185.

  14. Insights From RA Synovial Biopsy Studies • There are great variations in the histopathologic changes inducedby RTX • Based on small open synovial biopsy studies, there may be a sequence of changes in the synovia that leads to clinical response1-6 • B-cell depletion at 4 weeks may predict clinical response; subsequent↓ in plasma cells and Ig transcripts may predict clinical response1,2,5 • RTX-induced depletion of B-lineage cells, with loss of plasma cells and immune complex formation, may induce clinical responses by multiple pathways • B-Cell Roadblock Hypothesis: As B cells are most susceptible to deletion in the blood, RTX benefits may derive from preventing reseeding of pathogenic B cells to the synovia7 • Kavanaugh A et al. Ann Rheum Dis. 2007;66(suppl 2):291 [abstract FRI0037]. • Rosengren S et al. Ann Rheum Dis. 2007;66(suppl 2):298 [abstract FRI0059]. • 3. Thurlings RM et al. Ann Rheum Dis. 2008;67:917-925. • 4. Dass S et al. Ann Rheum Dis. 2007;66(suppl 2):90 [abstract OP0123]. • 5. Teng YK et al. Arthritis Rheum. 2007;56:3909-3918. • 6. Teng Y et al. Ann Rheum Dis. 2007;66(suppl 2):439 [abstract SAT0034]. • 7. Silverman GJ, Boyle DL. Immunol Rev. 2008 223:1751-85.

  15. Conventional Immunosuppressive Therapy Can Deplete Peripheral Plasmablasts and Naϊve B Cells, but Not Memory B Cells Plasma cells/blasts 6.7% 2.5% 1.2% CD27 64.0% 72.1% 87.1% CD27+ memory B cells 29.2% 25.4% 11.7% CD19 07/21/03 07/28/03 09/09/03 Methylprednisolone Cyclophosphamide Odendahl M et al. J Immunol. 2000;165:5970-5979. Figure courtesy of T. Dörner (Berlin, Germany)

  16. Are There Predictive Biomarkers of Response to RTX Treatment in RA? • Open trial of 17 patients with refractory RA who received a first cycle of rituximab • 12 patients responded with good EULAR responsesa • 6 patients with an early relapse (weeks 24–40) • 6 patients with a late relapse (after week 40) • 5 patients were classified as nonresponders • 1 patient remained in remission after 1 cycle of treatment • 11/17 patients received a second cycle of rituximab • 2/11 were RF-negative, 3/11 were anti-CCP–negative Roll P et al. Arthritis Rheum. 2008;58:1566-1575. aResponse was defined as improvement in DAS28 ≥1.2. DAS28, Disease Activity Score including a 28-joint count; EULAR, European League Against Rheumatism.

  17. At Baseline, Higher CD27+ Memory B Cell Counts Correlated WithEarly Relapse in Clinical Responders After RTX Treatment CD27+ B cells/µL Before Therapy 60.0 memory CD27 50.0 40.0 30.0 20.0 naive 10.0 P = .045 IgD 0.0 Early Relapse Late Relapse Memory B cells are either IgD+ or IgD- (After Week 40) (Week 24–40) At Time of B-cell Regeneration, Clinical Nonresponders Had Higher Levels of IgD+ CD27+ Memory B Cells – Lack of Persistent Memory B Cell Reductions CD27+/IgD+ B cellsa 2.0 P = .019 CD19+/CD27+ B Cells/ml 0.0 Responder Nonresponder (n = 12) (n = 5) aFirst time-point of regeneration Roll P et al. Arthritis Rheum. 2008;58:1566-1575.

  18. Summary • In RA, levels of CD27+ memory B cells increase with disease duration1 • After RTX treatment, at time of B-cell regeneration, clinicalnonresponders had higher levels of IgD+ CD27+ memory B cells • Lack of lasting memory B cell reductions • Early relapse after the first RTX cycle was associated with higher CD27+ memory B cell counts prior to therapy and higher IgD+/CD27+ and IgD-/CD27+ B cell counts after first and second treatment cycle, compared with late-relapsing patients • Yet even for nonresponders after the first cycle, RTX retreatmentcan still be effective • Clinical response to anti-CD20 treatment may be primarilydependent on the reduction of blood memory B cells, and this may be linked to a reduction of plasmablasts 1. Fekete et al. J Autoimmun. 2007;29:154-163.

  19. Epratuzumab: A HumanizedAnti-CD22 Therapeutic Antibody • CD22 first appears on B cells at the stage of antigen responsiveness • CD22 acts as a coreceptor with the antigen receptor that can down-regulate antigen responses • Interacts with inhibitory 2,6-linked sialic acid–associated glycoproteins • Epratuzumab induces rapid CD22 internalization and phosphorylation • In clinical trials for ARD and NHL • Open phase I trial in 12 patients with SLE showed safety and some efficacy based on BILAG scores • All patients fulfilled ACR criteria • Majority of patients had low disease activity (median SLEDAI = 2) How does epratuzumab work? What are the effects on the human immune system? BILAG, British Isles Lupus Assessment Group; ACR, American College of Rheumatology;NHL, non-Hodgkin‘s lymphoma; SLEDAI, systemic lupus erythematosus disease activity index. Dörner T et al. Arthritis Res Ther. 2006;8:R74. doi:10.1186/ar1942. Jacobi AM et al. Ann Rheum Dis. 2008;67:450-457.

  20. Epratuzumab Preferentially Reduced Peripheral Blood Naϊve B Cells; Plasmablasts and CD27+ Memory B Cells Are Less Affected B cells absolute cell number CD27- naive B cells/ml CD27+ memory B cells/ml CD27++ plasmablasts/ml Jacobi AM et al. Ann Rheum Dis. 2008;67:450-457.

  21. Epratuzumab Modulates the Activation and Proliferation ofB Cells in Patients With SLE • Epratuzumab was shown to be safe in a phase I open trial • Surface levels of CD22 were rapidly down-modulated • Average reduction of 30% of total blood B-cell levels, that lasted for 12 weeks after last infusion • Reductions primarily in naïve B cells, trend to increase in plasmablasts. No change in memory B cells • Laboratory studies show epratuzumab causes impaired B-cell proliferative responses to in vitro experimental stimulationof T-cell–independent pathway • CD22-targeted therapy may provide mechanistic advantagesin patients with certain autoimmune diseases • More studies are warranted Jacobi AM et al. Ann Rheum Dis. 2008;67:450-457.

  22. Conclusions • Studies with RTX have demonstrated an attractive safety/efficacy profile in RA and encouraged the development of newer agents • A diversity of additional strategies for targeting B cells, as well as design of biologic agents, are currently under investigation • Different B-cell subsets, including naïve B cells, plasma cells/blasts, and memory B cells, appear to make different contributions to pathogenesis • The capacity to inhibit or delete each B-cell subset varies greatly based on the mechanism of action of the therapeutic agent • Investigations into B-cell–targeted therapy are providing new therapeutic options as well as helping to elucidate previously unknown immunologic mechanisms of pathogenesis.

  23. B-Cell–Directed Therapyfor RA RA, rheumatoid arthritis.

  24. Learning Objectives State the rationale of B-cell depletion for the management of RA and list at least 3 agents that are being studied in clinical trials Summarize the efficacy of B-cell–targeted therapy following DMARD and anti-TNF therapy failure Describe the safety of long-term and repeated courses of B-cell–targeted therapy and the nuances of fixed or on-demand retreatment Summarize the radiographic changes noted following B-cell–targeted therapy for RA DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor.

  25. CD20: A Target on B cells 297-AA membrane-associated phosphoprotein (33–37 kDa) Not shed: No known membrane/secreted molecular analogues Selective expression: Not expressed on stem cells, pro-B cells, plasma cells, dendritic cells Anti-CD20 binding: Does not rapidly modulate expression Does not cause substantial internalization Differences in epitope binding are of unclear clinical significance with regard to safety or efficacy Ofatumumab Ocrelizumab TRU-015 CD20 AA, amino acid. Kehrl JH et al. Immunol Today. 1994;15:432-436; Golay J et al. Blood. 2000;95:3900-3908.

  26. RTX (REFLEX): EULAR Responses Based on RF/Anti-CCP While significantly more patients receiving RTX demonstrated ACR20 and EULAR responses compared with placebo recipients, seronegative patients (for RF and anti-CCP) did not respond as well RF/Anti-CCP+(Either or Both)a RF/Anti-CCP−b aP > .0001 vs placebo, seropositive. bP = .05 vs placebo, seronegative. Anti-CCP, anti–cyclic citrullinated peptide;EULAR, European League Against Rheumatism;RF, rheumatoid factor. Tak PP et al.Ann Rheum Dis. 2007;66(suppl 2):338 [abstract FRI0192].

  27. Repeated Treatment With RTX Produces Sustained Efficacy in Patients With RA With an Inadequate Response to DMARDs Week 24 (n = 57) Patients (%) DMARD, disease-modifying antirheumatic drug; DAS28, Disease Activity Score including a 28-joint count. Emery P et al. Arthritis Rheum. 2007;56(9 suppl):S151-S152 [abstract 266].

  28. Patient-Reported Outcomes During RTX Treatment of Anti–TNF-a Refractory RA in Addition to ACR Responses a a a a Patients (%) Patients (%) Achieving MCID a a aP < .0001 vs placebo + MTX. MCID, minimum clinically important difference; FACIT-F, Functional Assessment of Chronic Illness Therapy–Fatigue; HAQ-DI, Health Assessment Questionnaire Disability Index; PCS, physical component score; MCS, mental component score. Cohen SB, et al. Arthritis Rheum 2006;54:2793-2806. Keystone E et al. Arthritis Rheum. 2008;59:785-793.

  29. Repeated Treatment With RTX Produces Sustained Efficacy in Patients With an Inadequate Response or Intolerance to TNF Inhibitors Week 24 (n = 96) Patients (%) Emery P et al. Arthritis Rheum. 2007;56(9 suppl):S151-S152 [abstract 266].

  30. REFLEX: Change in Radiographic Outcomes at Week 56 P = .0046 Mean Change JSN, joint space narrowing; TGS, total Genant-modified Sharp score. Keystone E et al. Ann Rheum Dis. 2007;66(suppl 2):431-432 [abstract SAT0011].

  31. REFLEX: Change in RadiographicEnd Points at Week 56 Change in Sharp–Genant Total Score atWeek 56 by Anti-CCP Status at Baseline1 ACR20 Nonresponders at Week 242 Mean Change Mean Change in X-ray Score (n = 11) (n = 78) Missing (n = 21) (n = 33) Negative (n = 85) (n = 129) Positive The effect of RTX in inhibiting joint damage was consistent for all subgroups examined(baseline: total Sharp score, DAS28, disease duration, CRP, HAQ, SJC, and TJC). The studywas not powered to detect treatment differences within each subgroup; however, numericallysimilar and consistent results were observed for nearly all subgroups analyzed. CRP, C-reactive protein; SJC, swollen joint count; TJC, tender joint count. 1. Cohen S et al. Ann Rheum Dis. 2007;66(suppl 2):428 [abstract SAT0002]. 2. Keystone E et al. Ann Rheum Dis. 2007;66(suppl 2):431-432 [abstract SAT0012].

  32. REFLEX: RTX Radiographic Findings in RA at 2 years X-rays at weeks 0, 24, 56, 104 Total Genant-modified Sharp score used Linear extrapolation used for missing week 104 x-rays (30% of patients) Effects on JSN and erosions were similar 87% of RTX patients who did not progress in year 1, did not progress in year 2 The data are confounded by multiple therapeutic changes 4 RTX(n = 187) Placebo(n = 281) 2.81 3 TGS 1.78 2 1.14 1 0.66 0 Year 1 Year 2 80 RTX Placebo 68 60 60 54 46 No  TGS (%) 40 20 0 Baseline to1 Year 1 Year to 2 Years Cohen S et al. Ann Rheum Dis. 2008;67(suppl 2):189 [abstract THU0167].

  33. RTX Fixed Retreatment vs On-Demand Retreatment of RA Fixed and on-demand retreatment with RTX showed equal efficacy and safety Fixed retreatment was more effective in moderate responders and nonresponders to the first course Nonresponders improved significantly only after fixed retreatment 70% 64% 60% 53% Fixed Retreatment 50% 40% 28% 30% 18% 20% On-Demand Retreatment 6% 10% 4% 0% ACR 20 ACR 50 ACR 70 Patients (%) Teng Y et al. Ann Rheum Dis. 2008;67(suppl 2):339 [abstract FRI0167].

  34. RTX (n = 101) Switch anti–TNF-α agent (n = 199) Switching Strategies When an Anti–TNF-α Fails: RTX or Alternate Anti–TNF-α Type of Prior Anti–TNF-α Failure Not Effective AEs 0 Not significant Significant IMPROVEMENT -0.5 -0.77 -0.86 -1 DAS 28 Δ From Baseline -1.03 -1.5 -1.55 -2 N = 300. Finckh A et al. Ann Rheum Dis. 2008;67(suppl 2):127 [abstract OP-0249].

  35. Subsequent RTX Treatment Courses: Incidence of Acute Infusion Reactions by Treatment Course Patients (%) • SIEs occurred in <1% of patients during course 1 and 2 • No SIEs were observed during course 3 or 4 All-exposure population by treatment course. SIE = serious infusion-associated event. van Vollenhoven RF et al. Arthritis Rheum. 2007;56(9 suppl):S147 [abstract 257].

  36. Mouse (red) Mouse (red) Design of B-Cell–Targeting Agents Chimeric antibody (Synthetic) fully human antibody Human variable regions Human IgG constant region Human Ocrelizumab (CD20) Ofatumumab (CD20) Belimumab (BAFF) Epratuzumab (CD22) Rituximab (CD20) SMIP Synthetic peptide Decoy receptors Human Human (green) Atacicept (BAFF and APRIL) (TACI-Ig) TRU-015 (CD20) BR3-FC (BAFF) Baminercept-alpha (LT-) AMG623 (BAFF)

  37. Therapeutic Approachesto B-Cell Depletion Memory Cell Immature B cell Transitional B cell Mature B cell Antigenstimulation Antibody-producing Plasma cells Pro- B Cell Stem Cell Pre- B Cell Epratuzumab (Anti-CD22) CD19 Modulates B cell function With limited depletion CD22 CD20 SLE Autoreactive B cells RA RTX (anti-CD20) Binds and eliminatesCD20-positive cells Other diseases Belimumab (antisoluble BAFF) Acts later in B-cell development Potently depletes Ig-secreting cells Atacicept (TACI-Ig) Neutralizes both BAFF and APRIL Acts broadly in B-cell development Potently depletes Ig-secreting cells SLE, systemic lupus erythematosus.

  38. Therapeutic Approaches to B-Cell Depletion: Clinical Trial Status aStatus as of July 17, 2008.

  39. Phase I/II dose-escalation RCT with OCR + MTX 175 patients in whom 1–6DMARDs failed ≥8 TJC and SJC plus CRP≥1 mg/dL or ESR ≥28 mm/h Single infusion of OCR(400, 1000, 1500, or2000 mg) or placebo No peri-infusionalcorticosteroids 1° end point: ACR20 atweek 24 Complete peripheral B-celldepletion Patients with incomplete response require 100 mg IV corticosteroids Ocrelizumab (OCR): Humanized Anti-CD20 mAb in RA ACR Results at Week 24 70 Placebo 58 58 60 OCR 400 OCR 1000 50 OCR 1500 38 40 34 OCR 2000 33 Patients (%) 32 27 30 25 23 19 20 14 13 9 10 3 0 0 ACR20 ACR50 ACR70 ESR, erythrocyte sedimentation rate; IV, intravenous; OCR, ocrelizumab; mAb, monoclonal antibody;RCT, randomized controlled trial. Tak PP et al. Ann Rheum Dis. 2008;67(suppl 2):127 [abstract OP-0250].

  40. CD20 – Ofatumumab: HumanAnti-CD20 IgG1 mAb – Phase II Study ACR20 ACR50 ACR70 60 49 50 46 41 40 Patients (%) b 30 26 26 a 19 20 15 • Conclusions • No apparent dose response • No limiting safety signals as yet 9 10 6 5 4 0 0 Placebo 300 700 1000 n = 55 n = 58 n = 57 n = 54 aP < .05; bP <.01 Østergaard M et al. Arthritis Rheum. 2007;56(9 suppl):S793-S794 [abstract 2086].

  41. TRU-015 in Patients With RA:Phase II Dose-Ranging Study 24-week double-blind RCT in patients with incomplete response to MTX 227 patients in United States ≥6 tender joints and swollen joints; RF+ Either increased ESR/CRPor morning stiffness >45 min 1 infusion, TRU-015 or placebo 200, 400, 800, or 1600 mg Premedicated 1 grade 3 AE on infusion day (400-mg group) Conclusion: 800 and 1600 mgof TRU-015 IV once statistically superior to placebo at week 24 aP < .05; bP = .003; cP = .008. Burge D et al. Abstract presented at: ACR/ARHP Annual Scientific Meeting; November 6–8, 2007; Boston, Massachusetts; abstract L7.

  42. LTβR-Ig (Baminercept) Human lymphotoxin-b receptor (LTb) extracellular domain fused to human IgG1 Fc receptor acts as a decoy receptor for LTb Effective in murine models of arthritis: Blocks induction of arthritis and decreases severity of arthritis in established disease B cells, T cells,NK cells Activated T cells Dendritic cells • Lymphotoxin a/b Pathway is • implicated in: • Liver, spleen, and lymph nodes • Gut mucosa and Peyer’s patches • LIGHT Pathway is implicated in: • Mucosal and hepatic inflammation LT LIGHT Baminercept alfa HVEM LTR T Cells B cells NK cells Control of Lymphoid Microenvironments • Costimulation of T-cell activity • Affects T-cell responsiveness (proposed) and enhanced survival HVEM, herpes virus entry mediator. Baldassare A et al. Ann Rheum Dis. 2008;67(suppl 2):86 [abstract OP-0122].

  43. 80 ACR20 ACR50 ACR70 67 70 60 50 50 50 50 40 40 Patients (%) 40 33 33 30 25 25 30 20 17 20 10 0 0 0 0 0 0 0 0 0 mg/kg PBO BAM 0.01 BAM 0.05 BAM 0.1 BAM 0.3 BAM 1.0 BAM 3.0 10 6 6 4 5 6 6 Sample size: LTβR-Ig (Baminercept) in RA • Placebo dose-finding Phase IIa RCT: 47 pts – IR ≥1 DMARD; +MTX • SC weekly injections x4 and observation to day 77: • 6 dose cohorts: 0.01, 0.05, 0.1, 0.3, 1 and 3 mg/kg BAM versus PBO • AEs >5%: PBO 55% and LTβR-Ig 67% • Headache: Placebo 9% and LTβR-Ig 19% • Flu-like symptoms in 25% within 24 h of first injection; ↓ with subsequent injections to 6–9% • Continued clinical responses after week 4 despite discontinuation of treatment • Phase IIb planned: 5, 50, 200 mg weekly Baldassare A et al. Ann Rheum Dis. 2008;67(suppl 2):86 [abstract OP-0122].

  44. Summary B-cell–directed therapy has demonstrated clinical and laboratory efficacy in RA Multiple other diseases potentially may be treated with B-cell–directed therapy Safety issues concerning long-term B-cell depletion are of concern, but data thus far are cautiously reassuring New strategies of B-cell targeting may provide more potent therapeutics in the future

  45. Assessing Immunocompetence in Patients Treated WithB-cell–Directed Therapies

  46. Learning Objectives Define immunocompetence and review the impact of B-cell–directed therapies on humoral immunity Summarize the safety of B-cell–directed therapies with regard to the following clinical scenarios: repeated use, safety of switching to DMARD or TNF inhibitor after RTX failure, effects on serum immunoglobulins, and serious infection rates State clinical considerations for immunizing patients who are candidates for B-cell–directed therapy DMARD, disease-modifying antirheumatic drug; RTX, rituximab; TNF, tumor necrosis factor.

  47. Outline Immunocompetence and the effects of B-cell–directed therapies Safety of B-cell–directed therapies Long-term safety of repeated use Effects on serum immunoglobulins Serious infection rates Safety of switching to DMARD or TNF inhibitor after RTX failure Immunization and B-cell–directed therapy Considerations for immunocompetence of newer B-cell– targeting agents BAFF, APRIL Progressive multifocal leukoencephalopathy (PML)in rheumatic diseases

  48. Defining Immunocompetence: Promises and Problems With Biologic Therapies Immunocompetence is broadly defined as the capacity of the integrated immune response to defend against infections and malignancies An increased rate of infections is the gold standard for detecting compromised immune function, but: Clinical trials are generally underpowered for rare events Data collected across clinical trials and databasesof such events are not uniform

  49. Immunocompetence andB-Cell– Directed Therapy • Humoral immunity is vital in protecting the host from bacterial infections • Patients deficient in Ab are prone to polysaccharide encapsulated bacterial infections • Experience in oncology fails to show that RTX adds risk of SIEs to traditional chemotherapy (except in HIV infections) Pro-B Pre-B Immature Transitional Naïve Memory CD20 RTX Plasmablast (short-lived) Plasma Cell (long-lived) Protective vspathogenic antibodies Protective vspathogenic antibodies Antimicrobial Anti-dsDNA RF and anti-CCPantibodies Antimicrobial Anti-dsDNA Anti-RBP antibodies(Ro, La, Sm/RNP) Survive weeks after RTX Survive months toyears after RTX RTX spares long-lived plasma cells,which are the primary source ofantimicrobial Abs Ab, antibody; CCP, cyclic citrullinated peptide; dsDNA, double-stranded DNA; HIV, human immunodeficiencyvirus; RF, rheumatoid factor; SIE, severe infectious event. Looney RJ, et al. Arthritis Rheum. 2008;58:5-14.

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