I.H. Tarner, M.D. Lehrstuhl für Innere Medizin mit dem Schwerpunkt Rheumatologie 1 Research Targets and Novel Immunology-Based Therapeutic Concepts in Rheumatoid Arthritis MAItaG Clinical Lecture Series 12/13/2008 I.H. Tarner, M.D. Dpt. of Internal Medicine and Rheumatology
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I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
1
Research Targetsand Novel Immunology-Based
Therapeutic Conceptsin Rheumatoid Arthritis
MAItaG Clinical Lecture Series 12/13/2008
I.H. Tarner, M.D.Dpt. of Internal Medicine and Rheumatology
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
2
New Therapies - Why should we?
New = better?"Conventional" DMARDs New Immunomodulating Agents– Save lives (letality of Wegener‘s – target defined mechanisms of disease pre CYC: 90% within 2 years) – high level of evidence (RCT)– Remissions achieved in most instances – expensive– long-standing experience – have to stand the test of time– mechanism(s) of action mostly unclear, – highly potent immunomodulation– Problems in unresponsive cases = potentially high risk of adverse effects
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
3
What’s on the Menu?• Biologics are all the rage:
– Biologics are substances, that specifically target and modulate defined biologic molecules/mechanisms are "hypothesis-driven"
– Most are antibody molecules, or other proteins
• Examples of novel therapeutics:➡ Eculizumab; PMX53 ➡ SCIO-469
developed by C.C. Little, founder of Jackson Laboratory result of experiments on mouse fur color (DBA/1 & DBS/2):
• Dilute: gene locus responsible for "dilution" of fur color• Brown: self explanatory• Non-Agouti: mutation of agouti locus (loss of yellow bands in hair)
– Method Emulsify dissolved CII (100 µg/animal) 1 : 1 by volume in
• CFA (mineral oil w/ desiccated, ground M. tuberculosis) or• IFA (w/o M. tuberculosis)
Inject s.c. on d1 (in CFA) and d21 (in IFA)
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
10
Short Intermission Phenotype of CIA
Grade 1
Grade 2
Grade 3
Grade 4
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
11
Novel Therapeutics: Targets
Adaptive immunity: APC - T-Cell interaction
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
12
Adaptive immunity: APC - T-Cell interaction
MHCII TCR
CD28CD40L
CD80/86CD40
TACI
BCR
BLyS; APRIL
CD20CD22
Novel Therapeutics: Targets
clonal expansion,cytokines(IL-1, TNF, IL-6, IL-10...)autoantibodiesimmune complexesactivation of the complement system
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
13
Adaptive immunity: APC - T-Cell interaction
clonal expansion,cytokines(IL-1, TNF, IL-6, IL-10...)autoantibodiesimmune complexesactivation of the complement system
MHCII TCR
TACI
BCR
CD20CD22
CD28CD40L
CD80/86CD40
Novel Therapeutics: Targets
BLyS; APRIL
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
14
Adaptive immunity: APC - T-Cell interaction
clonal expansion,cytokines(IL-1, TNF, IL-6, IL-10...)autoantibodiesimmune complexesactivation of the complement system
MHCII TCR
TACI
BCR
CD20CD22
immune tolerance/anergy
CD28CD40L
CD80/86CD40
Novel Therapeutics: Targets
BLyS; APRIL
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
15
Adaptive immunity: APC - T-Cell interaction
MHCII TCR
TACI
BCR
CD20CD22
apoptosis/cell-lysis
immune tolerance/anergy
CD28CD40L
CD80/86CD40
Novel Therapeutics: Targets
clonal expansion,cytokines(IL-1, TNF, IL-6, IL-10...)autoantibodiesimmune complexesactivation of the complement system
BLyS; APRIL
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
16
Novel Therapeutics: Targets
Cytokines: IL-1
RANKL
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
17
Inhibition of Cytokines
IL-1ra Anakinra (KineretTM): recombinant IL-1ra
– Rationale: IL-1RI mediates immune cell activation IL-1 induces osteoclast activation IL-1 inhibition effective in animal models of RA
– Clinical data: reduced bone erosion in RA but variable experiences with clincal efficacy daily s.c. injections required, frequent injection site reactions new indications:
– Rationale: Pro-inflammatory role in RA, PsA, ASP, CD bone destruction: TNF induces osteoclast activation
– Agents: Infliximab (chimeric antibody), Adalimumab (fully human antibody), Etanercept (soluble fusion protein of two p75 receptor molecules), Certolizumab pegol: humanized Ab, PEG instead of an Fc portion (no in vitro complement activation, ADCC, or apoptosis)
Golimumab: fully human Ab, once monthly application
– Clinical data: established as second line treatment in RA, PsA, ASP, CD prevention of bone destruction in RA
increased risk of infections and malignancies (ongoing debate)
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
20
Novel Therapeutics: Targets
Cytokines: IL-6
RANKL
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
21
Tocilizumab (ActemraTM): anti-IL-6R Ab– Rationale: IL-6 originally described as
B-cell differentiating/stimulating factor inducer of acute phase reactants activator of neoangiogenesis, lymphocytes, synovial fibroblasts, osteoclasts, causes fever and fatigue required for many experimental autoimmune diseases, while anti-inflammatory in acute inflammation anti-IL-6 mAb causes accumulation of IL-6 immune complexes anti-IL-6R-Ab does not and also inhibits the effects of IL-6/sIL-6R complexes
Inhibition of Cytokines
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
22
Tocilizumab (ActemraTM): anti-IL-6R Ab– Clinical data: very effective in phase IV trials in RA; approval expected next year adverse effects: leukopenia, LFT elevation, lipid elevation
Inhibition of Cytokines
TOWARD study, Genovese et al., A&R 2008
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
23
Novel Therapeutics: Targets
Cytokines: IL-15
RANKL
IL-15
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
24
AMG714: human IgG1 anti-IL-15 Ab– Rationale:
IL-15 signals via common γ-chain:
• recruitment and activation of T-cells, maintenance of T memory
• slowing of apoptosis of RASF and EC• promotion of synovial cytokine and chemokine release
– Pre-clinical data: amelioration of inflammation and articular destrution in CIA using sIL-15Rα
– Clinical data: 1 phase I-II RCT low no. of patients, but promising no further trials in progress
APC - T-Cell interaction: Inhibition of costimulation
MHCII TCR
TACI
BCR
CD20CD22
BLyS
CD28CD40L
CD80/86CD40
Novel Therapeutics: Targets
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
31
Inhibition of CD40/CD40L interaction:– Rationale: CD40/CD40L costimulation induces differentiation of B-cells CD40L serum levels correlate with anti-dsDNA-Ab titers in SLE increased CD40 u. CD40L in renal parenchyma in LN
– Preclinical data in SLE: anti-CD40L Ab: prevention or improvement of nephritis
– Clinical Data in SLE: Ruplizumab: effective, but thromboembolic complications of
unclear cause IDEC 131: insuffcient effectiveness vs. placebo in phase II
- No data on RA
Inhibition of Costimulation
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
32
Abatacept
Treg
Inhibition of CD28/CD80 interaction: Abatacept (CTLA4-Ig; OrenciaTM)
– Clinical data: approved for treatment of RA
second line after DMARD failure not to be combined with TNF blockers b/o increase in serious infections several trials ongoing for other autoimmune diseases
Inhibition of Costimulation
Kremer et al., A&R 2008
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
33
Depletion of B-cells
MHCII TCR
TACI
BCR
CD20CD22
CD28CD40L
CD80/86CD40
Novel Therapeutics: Targets
BLyS; APRIL
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
34
Rituximab (MabTheraTM): anti-CD20 mAb– Rationale: CD20: unknown function, but B-cell specific (except plasma cells) effective B-cell depletion in B cell lymphoma
– Clinical data: approved for RA, effective in cases refractory to TNF blockers effective also in RF- RA, though less than in RF+ RA generally well tolerated; rate of infections comparable to other DMARDs case reports of progressive multifocal leukencephalopathy (JC-Virus):
• prevalence of latent JC infection: 80%• 76 documented cases of PML in 1.5 million rituximab patients• 5 cases in autoimmune disease (2 SLE, 2 vasculitis, 1 RA)• 37 cases in autoimmune disease w/o rituximab (40% SLE)• all had extensive immunosuppression
BLyS/BAFF stimulates proliferation, differentiation and Ab-production, inhibits apoptosis serum levels correlate with IgM-RF, anti-CCP and SJC in early RA increased levels in RA synovium
– Clinical data: Phase II RCT, only published in abstract form (ACR 2005):
• included anti-TNF non-responders
• add-on to stable 0-2 DMARDs (w/o biologics) + NSAID/steroids• ACR20 (week 24): 29% in all dosing groups vs. 16% in placebo
• significant reduction of RF and CD20+ B-cells (p<0.001)
New: LY2127399, fully human Ab, binds soluble and membrane-bound BAFF
Inhibition of B-Cells
subgroup
ACR20 response at week 24
placeboBelimumab dosage
all dosages combined 1 mg/kg 4 mg/kg 10 mg/kg
RF+7/58
(12%)53/180 (29%) N/A N/A N/A
RF- no significant difference between belimumab and placebo groups
anti-TNF naive
5/40(13%)
48/135(36%)
18/45(40%)
15/45(33%)
15/45(33%)
anti-TNF experienced no significant difference between belimumab and placebo groups
Genovese et al., ACR 2005
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
41
Inhibition of B-cells
MHCII TCR
TACI
BCR
CD20CD22
BLyS; APRIL
CD28CD40L
CD80/86CD40
Novel Therapeutics: Targets
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
42
Atacicept: TACI-Ig fusion protein binding BLyS and APRIL– Rationale:
inhibition of BLyS or APRIL binding to TACI on B-cells reduces Ig levels and B-cells numbers in SLE
– Clinical data: Phase Ib RCT, only published in abstract form (ACR 2008):
• dose-dependent reduction of total Ig, RF and anti-CCP Ab levels
• dose-dependent redution of B-cell numbers
• good tolerabilty
• not powered for clinical efficacy, yet trends in high-dose group:mean DAS28 reduction from 6.4 ± 1.3 to 5.1 ± 1.4≥ACR20 at week 12 in 6/19 (32%) vs. none in the placebo group
blocks interaction of LFA-1 with ICAM-1 blocks activation, adhesion and trafficking of T-cells
– Clinical data: approved for the treatment of psoriasis Phase II RCT in PsA:
• ACR20 in 28% of treatment group at week 12• ACR20 in 19% of placebo group at week 12
Retrospective case series of new-onset PsA within a mean of 15 weeks after efalizumab; also single case report no data on RA
Inhibition of B-Cells
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
45
Novel Therapeutics: Targets
Bone destruction: RANKL
RANKL
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
46
Inhibition of RANKL Denosumab: anti-RANKL antibody
– Rationale: RANKL induces differentiation, maturation and activation of osteoclasts high expression of RANKL in RA vs. normal synovium
– Clinical data: Phase II RCT (n=218) in MTX-treated RA
• less erosion, reduced bone turnover• no effect on inflammation• good tolerability
Cohen et al., A&R 2008
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
47
Novel Therapeutics: Targets
Inhibition of multiple cell types
RANKL
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
48
Imatinib– Rationale:
inhibits tyrosine kinases (abl, c-Kit, c-Fms, PDGFR) thus reducing• cytokine production by macrophages and mast cells• proliferation of RASF
– Preclinical data: effective in CIA: reduction/inhibition of
• synovitis, pannus and erosions• cytokine production by synovial mast cells• epitope spreading of autoreactive B-cells• anti-CII T-cell proliferation/cytokine production
– Clinical data: 3 case reports on successful RA treatment with imatinib Phase II trial of imatinib + MTX: completed but not published yet