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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
➡ Anakinra ➡ Ruplizumab; IDEC 131➡ Infliximab ➡ Abatacept➡ Adalimumab ➡ Rituximab➡ Etanercept ➡ Ocrelizumab➡ Certolizumab ➡ Epratuzumab➡ Golimumab ➡ Belimumab➡ Tocilizumab ➡ Efalizumab➡ AMG 714 ➡ Denosumab➡ Pamapimod ➡ Imatinib
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
4
New Drugs - New Names
Nifty endings: -mab:
monoclonal antibodies -ximab: chimeric Ab: Fab generated in mice & Fc of human origin
(e.g. infliximab: anti-TNF Ab) -zumab: humanized Ab: murine sequences are exchanged for human ones
(e.g. tocilizumab: anti-IL-6R Ab) -umab:
genetically engineered fully human Ab (e.g. belimumab: anti-BlyS Ab)
-cept: soluble receptor (e.g. abatacept: CTLA4-Ig, soluble receptor for CD80/86) -ra:
receptor antagonist (e.g. anakinra: IL-1ra) Letters and numbers:
refer to the manufacturer (e.g. AMG 714: Amgen compound 714)
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
5
Novel Therapeutics: Targets
Targets in RA synovium: innate and adaptive immunity
RANKL
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
6
Novel Therapeutics: Targets
Innate immunity: Complement system
Ricklin & Lambris, Nat Biotechnol 2007
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
7
Inhibition of Complement
C5 Inhibitors: Eculizmab (anti-C5 mAb); PMX53 (C5aR ligand)– Rationale:
C5a: chemotactic factor for C5aR+ monocytes and neutrophils
PMX53 inhibits cytokine production/chemotaxis in vitro
– Preclinical data: C5-/- DBA/1 mice are resistant to CIA; anti-C5 mAb prevents/treats CIA
PMX53 anti-arthritic in rats
– Clinical data:
Eculizumab:• approved for paroxysmal nocturnal hemoglobinuria• limited data on SLE; no data on RA
PMX53: phase Ib RCT• good tolerabilty, appropriate serum levels• no clinical benefit vs. placebo• no decrease in cellular infiltration or biomarkers
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
8
Inhibition of Complement
C5 Inhibitors: Eculizmab (anti-C5 mAb); PMX53 (C5aR ligand)– Clinical data:
PMX53
Parameter PMX53 (n=14) Placebo (n=7) p
mean change TJC -1.38 -1.43 0.98
mean change TJC -1.54 -3.57 0.23
mean change CRP -6.15 -3.43 0.65
mean change DAS28 -0.28 -0.28 0.98
ACR20 responders 0 1 0.35
EULAR responders (moderate)
2 1 1.0
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
9
Short Intermission
The CIA model in DBA/1 mice– DBA/1 mice:
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:
• systemic onset juvenile RA,• adult onset Still‘s disease,• periodic fever syndromes• gout• ?osteoarthritis (intraarticular)
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
18
Novel Therapeutics: Targets
Cytokines: TNF
RANKL
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
19
Inhibition of Cytokines TNF-Inhibitors
– 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
Inhibition of Cytokines
Baslund et al., A&R 2005
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
25
Novel Therapeutics: Targets
Cytokines: Inhibition of intracellular signalling
RANKL
IL-15
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
Pamapimod (RO4402257): p38 MAPK inhibitor– Rationale:
intracellular signaling via p38 MAPK:
• cell growth
• apoptosis• pro-inflammatory cytokines
orally bioavailable small molecule
Inhibition of Cytokines
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
Pamapimod (RO4402257): p38 MAPK inhibitor– Pre-clinical data:
specific inhibition of p38α and β inhibition of TNF, IL-1 and IL-6 production
reduced inflammation/bone loss in CIA analgesic in animal models inhibition of renal disease in MRL/lpr mice
Inhibition of Cytokines
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
Pamapimod (RO4402257): p38 MAPK inhibitor– Clinical data:
2 phase II RCT
• PA18604: MTX monotherapy vs. pamapimod monotherapy
• PA18439: pamapimod vs. placebo as add-on in MTX failures PA18439 prematurely discontinued due to lack of efficacy (acceptable safety)
Inhibition of Cytokines
PA18439Percentage of patients
Placebo (n=53)
25 mg BID (n=57)
75 mg BID (n=57)
50 mg QD (n=53)
150 mg QD (n=54)
300 mg QD (n=54)
ACR20 34 40 40 42 31 43
ACR50 15 9 16 19 9 24
PA18604Percentage of patients
MTX (n=53) 5= mg QD (n=52)
150 mg QD (n=51)
300 mg QD (n=48)
ACR20 45 23 18 31
ACR50 23 12 6 13
RocheInvestigatorWeb ConferenceOctober 2007
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
Le roi est mort, vive le roi: p38 MAPK inhibitor SCIO-469– Clinical data:
2 phase II RCT
• n = 302
• stable dose of (hydroxy-)chloroquine, minocycline, doxycycline Tolerability: skin rash; 60 mg TID: dose-limiting liver toxicity
Inhibition of Cytokines
Geneovese et al.,ACR 2008
Parameter at week 12 Placebo
SCIO-469
100 mg ER QD 30 mg IR TID 60 mg IR TID
ACR 20 24% 23% 26% 33%
ACR 50 9% 8% 4% 3%
SJC -27% -18% -18% -25%
TJC -38% -22% -32% -39%
CRP 8% -3% -10%* -1%*
HAQ -0.02 -0.12 -0.17 -0.19
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
30
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
Depletion of B-Cells
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
35
Rituximab (MabTheraTM): anti-CD20 mAb– Clinical data:
depletion of peripheral, BM and synovial B-cells synovial B-cells and ACPA predict response
Depletion of B-Cells
Teng et al., A&R 2007
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
36
Ocrelizumab: anti-CD20 mAb– Rationale: humanized, not chimeric antibody
– Clinical data: Phase I/II RCT: well tolerated, effective, low immunogenicity
Depletion of B-Cells
ACTION study, Genovese et al., A&R 2008
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
37
Epratuzumab: anti-CD22 mAb– Rationale:
CD22 expressed specifically on B-cells immune-mediated B-cell lysis humanized antibody (vs. rituximab = chimeric)
– Clinical data: open label studies:
• "moderately active" lupus (n=14): well tolerated, no formation of HACA, reduction of activity score by >50% in all patients
• primary Sjögren‘s (n=15): 67% achieved >20% improvement by week 32 (at least 2 parameters: ocular/oral sicca, fatigue, ESR)
ongoing in SLE:• 1 non-randomized phase III study, 1 RCT phase IIb• 2 phase III RCT were discontinued
no trials in RA
Depletion of B-Cells
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
38
Inhibition of B-cells
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
39
Belimumab (LymphoStat-BTM): anti-BLyS (BAFF) mAb– Rationale:
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)
Inhibition of B-Cells
McKay et al., ACR 2005
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
40
Belimumab (LymphoStat-BTM): anti-BLyS (BAFF) mAb– Clinical data:
Phase II RCT, subgroup analysis:
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
Inhibition of B-Cells
Tak et al., A&R 2008
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
43
Novel Therapeutics: Targets
Inhibition of T-cells
RANKL
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
44
Efalizumab (RaptivaTM): humanized anti-CD11a mAb– Rationale:
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
Inhibition of multiple cell types
Paniagua et al., JCI 2006
days after initial treatment
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
49
Summary
➡ C5 inhibition: eculizumab ? PMX53 ✖ ➡ p38-MAPK inhibition: SCIO-469 ✖
➡ anti-IL-1: Anakinra ☂ ➡ co-stimulation: Ruplizumab; IDEC 131 ✖
➡ anti-TNF: Infliximab ✔ ➡ co-stimulation: Abatacept ✔
➡ anti-TNF: Adalimumab ✔ ➡ B-cell depletion: Rituximab ✔
➡ anti-TNF: Etanercept ✔ ➡ B-cell depletion: Ocrelizumab ✔
➡ anti-TNF: Certolizumab ✔ ➡ B-cell depletion: Epratuzumab ?
➡ anti-TNF: Golimumab ✔ ➡ B-cell inhibition: Belimumab; Atacicept ?
➡ anti-IL-6R: Tocilizumab ✔ ➡ T-cell depletion: Efalizumab ✖/?
➡ anti-IL-15: AMG 714 ? ➡ anti-RANKL: Denosumab ✔
➡ p38-MAPK inhibition: Pamapimod ✖ ➡ anti-everything: Imatinib ✔
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
50
Conclusion• Rheumatology research has (re-)discovered the B-cells
– Rituximab thus far most promising
• Many interesting new targets– Clinical relevance remains to be proven
• Not all good ideas work– e.g. p38 MAPK
• Still a long way to go...
I.H. Tarner, M.D.
Lehrstuhl für Innere Medizin
mit dem Schwerpunkt Rheumatologie
51
...but worth the effort
Thank you for your attention!Merry Christmas!