research targets and novel immunology-based therapeutic ... · mit dem schwerpunkt rheumatologie 1...

I.H. Tarner, M.D.

Lehrstuhl für Innere Medizin

mit dem Schwerpunkt Rheumatologie

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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.



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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.



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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.



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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.



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Novel Therapeutics: Targets

Targets in RA synovium: innate and adaptive immunity

RANKL

I.H. Tarner, M.D.



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Innate immunity: Complement system

Ricklin & Lambris, Nat Biotechnol 2007

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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.



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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.



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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.



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Short Intermission Phenotype of CIA

Grade 1

Grade 2

Grade 3

Grade 4

I.H. Tarner, M.D.



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Adaptive immunity: APC - T-Cell interaction

I.H. Tarner, M.D.



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MHCII TCR

CD28CD40L

CD80/86CD40

TACI

BCR

BLyS; APRIL

CD20CD22


clonal expansion,cytokines(IL-1, TNF, IL-6, IL-10...)autoantibodiesimmune complexesactivation of the complement system

I.H. Tarner, M.D.



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MHCII TCR

TACI

BCR

CD20CD22

CD28CD40L

CD80/86CD40


BLyS; APRIL

I.H. Tarner, M.D.



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MHCII TCR

TACI

BCR

CD20CD22

immune tolerance/anergy

CD28CD40L

CD80/86CD40


BLyS; APRIL

I.H. Tarner, M.D.



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MHCII TCR

TACI

BCR

CD20CD22

apoptosis/cell-lysis

immune tolerance/anergy

CD28CD40L

CD80/86CD40



BLyS; APRIL

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Cytokines: IL-1

RANKL

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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.



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Cytokines: TNF

RANKL

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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.



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Cytokines: IL-6

RANKL

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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


I.H. Tarner, M.D.



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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


TOWARD study, Genovese et al., A&R 2008

I.H. Tarner, M.D.



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Cytokines: IL-15

RANKL

IL-15

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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


Baslund et al., A&R 2005

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Cytokines: Inhibition of intracellular signalling

RANKL

IL-15

I.H. Tarner, M.D.



Pamapimod (RO4402257): p38 MAPK inhibitor– Rationale:

intracellular signaling via p38 MAPK:

• cell growth

• apoptosis• pro-inflammatory cytokines

orally bioavailable small molecule


I.H. Tarner, M.D.



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


I.H. Tarner, M.D.



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)


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.



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


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.



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APC - T-Cell interaction: Inhibition of costimulation

MHCII TCR

TACI

BCR

CD20CD22

BLyS

CD28CD40L

CD80/86CD40


I.H. Tarner, M.D.



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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

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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

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Depletion of B-cells

MHCII TCR

TACI

BCR

CD20CD22

CD28CD40L

CD80/86CD40


BLyS; APRIL

I.H. Tarner, M.D.



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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

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Rituximab (MabTheraTM): anti-CD20 mAb– Clinical data:

depletion of peripheral, BM and synovial B-cells synovial B-cells and ACPA predict response


Teng et al., A&R 2007

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Ocrelizumab: anti-CD20 mAb– Rationale: humanized, not chimeric antibody

– Clinical data: Phase I/II RCT: well tolerated, effective, low immunogenicity


ACTION study, Genovese et al., A&R 2008

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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


I.H. Tarner, M.D.



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Inhibition of B-cells

MHCII TCR

TACI

BCR

CD20CD22

BLyS

CD28CD40L

CD80/86CD40


I.H. Tarner, M.D.



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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.



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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


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.



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Inhibition of B-cells

MHCII TCR

TACI

BCR

CD20CD22

BLyS; APRIL

CD28CD40L

CD80/86CD40


I.H. Tarner, M.D.



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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


Tak et al., A&R 2008

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Inhibition of T-cells

RANKL

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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


I.H. Tarner, M.D.



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Bone destruction: RANKL

RANKL

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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.



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Inhibition of multiple cell types

RANKL

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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.



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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.



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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.



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...but worth the effort

Thank you for your attention!Merry Christmas!

research targets and novel immunology-based therapeutic ... · mit dem schwerpunkt rheumatologie 1...

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