Immunotherapy in autoimmune disease 高雄醫學大學附設醫院 過敏免疫風濕內科 歐燦騰
Immunotherapy 免疫療法(immunotherapy)近來蓬勃發展，除了最 早期用在對過敏性疾病的減敏治療外，目前在癌 症治療、自體免疫疾病、心臟血管疾病、胸腔疾 病、神經系統疾病、眼科疾病、骨質疏鬆、及器 官移植等，都獲得長足的進步。
Biomed Pharmacother. 2017 Aug;92:615-633
免疫療法治療：自體免疫疾病 類風溼性關節炎 僵直性脊椎炎 乾癬性關節炎 ANCA-associated vasculitis ulcerative vasculitis and Crohn’s disease IgG4-related disease Neuromyelitis optica spectrum disorder Multiple sclerosis SLE Sjogren’s syndrome
Immunotherapy in RA
Biomed Pharmacother. 2017 Aug;92:615-633
Integrated Immune Response and Pathogenesis of RA APC – B cells – Dendritic cells – Macrophages
RF, anti-CCP
IL-4 IL-6 IL-10
B
IL-6, TNFα, IFNγ, IL-10, lymphotoxin
T APC
PC
IL-2 IFNγ
MΦ
TNFα IL-17 RANKL Pannus
Immune complexes Complement fixation Attract inflammatory cell infiltrates
TNFα, IL-1, IL-6, metalloproteinases OC
FLS C
Articular cartilage
Production of metalloproteinases and other effector molecules Migration of polymorphonuclear cells Erosion of bone and cartilage
Adapted from Smolen and Steiner. Nature Rev Drug Discovery. 2003;2;473; Choy and Panayi. N Engl J Med. 2001;344:907., Silverman and Carson. Arthritis Res Ther 2003; 59(suppl 4):S1.
Trends in Molecular Medicine, 2016, 22 (03) 214~229
Cytokine Signaling Cytokine
Cytokine Receptor
Signal
Modified from Choy and Panayi. N Engl J Med 2001;344:907–916
Targeting TNF Receptor Interactions: Neutralization of Cytokines
Soluble receptor construct
Monoclonal antibody
No signal Modified from Choy and Panayi. N Engl J Med 2001;344:907–916
Pathogenesis of RA B-cell Rituximab Plasma cell
Synovial tissue T-cell Abatacept
RF and other autoantibodies
Adalimumab Macrophage
Etanercept Infliximab Certolizumab pegol TNF IL-1 Golimumab RANKL
Anakinra
IL-6
MMPs
Tocilizumab
Fibroblast
Cartilage damage
Osteoclast Bone erosion
Chondrocyte Bone
Cartilage
Central Role of TNFα in RA TNFα
Pannus/Synovitis Osteoclasts
Chondrocytes Synoviocytes
Bone resorption
Bone erosion Kirwan JR, J Rheumatol 1999;7:720–725
Joint inflammation
Cartilage degradation
Pain Joint swelling
Joint space narrowing
Anti-Tumor Necrosis Factor (anti-TNF) Monoclonal antibody Infliximab (Remicade) Adalimumab (Humira) Golimumab (Simponi) Soluable receptor Etanercept (Enbrel)
GO-FORWARD
5 Years Safety and Efficacy of Golimumab in RA Patients • 313/444 pts continued treatment through Wk 252 (71% retention) • 131 withdrawals (64 for AE, 25 LOE, 6 lost to FU, 3 deaths, 33 others)
Percent of patients (%)
Efficacy at Week 256 100 80
90 90 89 88 76 76 77 75
60
47
52 54
48 46 42 45
47 38
40 23
29
43 28
25
60
55
23
46
27 28
20 0 ACR20
ACR50
PBO/GLM + MTX
ACR70 GLM 100 mg + PBO
DAS28-CRP EULAR Resp.
DAS28-CRP <2.6
GLM 50 mg + MTX
SDAI <3.3
vdH-S score <0
GLM 100 mg + MTX
Keystone et al. [abstract]. EULAR 2013 AB0267
Anti-CD20 Rituximab: B-cell depletion
以CD20為標的抗原 細胞表面的CD20分子只會表現 在B細胞成熟過程中的一個B細 胞亞群。CD20不會在幹細胞、 pro-B細胞或漿細胞(plasma cells)上表現。
Rituximab的作用機轉 Rituximab的選擇性對象為表現CD20的一個B細胞亞群，而幹細 胞、proB細胞與漿細胞則不受影響。MabThera可藉由三種不同的 作用機轉來去除循環中的週邊B細胞： 補體媒介之B細胞溶解 細胞媒介之細胞毒性 細胞凋亡的誘發。
顯示各個時間點的ACR與DAS28反 應。可以看到，從第8週開始， rituximab就可以顯著改善病情，效果 並可持續整個研究到第24週(Cohen et al. 2006a)
The selective costimulation molecules Abatacept, CTLA-4Ig (Orencia)
How are T Cells Activated? CD80/86:CD28 is the best characterized co-stimulatory pathway â&#x20AC;&#x201D;
Signal 2 APC
CD28 is constitutively expressed on T cells and binds to CD80/86
Activated T cell
Chambers CA, et al. Cold Spring Harb Symp Quant Biol 1999;64:303â&#x20AC;&#x201C;12
CD80/86:CD28 facilitates T-cell activation, proliferation, survival and cytokine production
CTLA-4 Downregulates CD28-mediated T-cell Activation CTLA-4 binds to CD80/86 with higher avidity than CD28
APC
CTLA4 prevents the interaction of CD28 with CD80/86 and produces co-inhibitory signals PreviouslyA ctivated Tcell
Chambers CA, et al. Cold Spring Harb Symp Quant Biol. 1999;64:303â&#x20AC;&#x201C;312.
The Fc Region of Abatacept has been Rationally Designed to Prevent ADCC and CDC Abatacept’s Fc region has been modified: —
—
—
Does not bind to the Fc receptors CD16 and CD32, and binds weakly to high-affinity CD64 Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) not observed with abatacept 1 ADCC and CDC are associated with cell lysis2 CTLA-4
IgG-1 abatacept
Extracellular Cell membrane Intracellular
Modified Fc
1Davis
DM et al. J Rheum Manuscript in press; 2Golay et al. Blood 2000 15;95(12):3900–8.
Abatacept: Normalizing Aberrant Immune Responses APC
Upstream modulation
abatacept Decrease T-cell activation and proliferation Decrease pro-inflammatory cytokine secretion from activated synovial macrophases
Naïve T-cell
RANK-L
MΦ
Decrease autoantibody production (e.g. RF) reduces clonal expansion
TNF-a
IL-1
IL-6 TNF-α IL-1
B
IL-6 Autoantibodies, e.g. RF
IL-6
RANK Osteoclast
Chondrocyte
MMPs
Downstream impact Reduction in inflammatory cytokines toward normal levels
ACR Responses at 6 and 12 Months AIM Placebo + MTX (n=214) Abatacept + MTX (n=424)
6 Months 80
80
*
*
12 Months
73.1
60
60
40
39.7
*
39.9
* 16.8
20
19.8
Patients (%)
Patients (%)
67.9
* 48.3
40
39.7
* 28.8 18.2
20
6.5 0
ACR20
ACR50
ACR70
*P<0.001 vs placebo; ACR = American College of Rheumatology. Kremer et al. ACR, 2004. Presentation L2.
6.1 0
ACR20
ACR50
ACR70
IL-6
IL-6 in RA: Articular Effects Antibody production
B-cell
Synoviocytes
VEGF Macrophage
IL-6
Endothelial cells Pannus formation
MMPs1 T-cell
RANKL
Neutrophil Joint destruction Mediation of chronic inflammation Dayer J-M & Choy E. Rheumatology 2010; 49:15−24. 1. Smolen J, et al. Nat Rev Drug Disc 2003; 2:473−488.
Osteoclast activation Bone resorption VEGF = vascular endothelial growth factor; MMPs = matrix metalloproteinases.
IL-6 in RA: Systemic Effects Acute-phase proteins (e.g. CRP)
The acute-phase response
IL-6 Hepcidin production
Anaemia
Alterations in iron homeostasis
Thrombocytosis
Inflammation
Increased cardiovascular risk
Hypothalamicpituitary-adrenal (HPA) axis
Dayer J-M & Choy E. Rheumatology 2010; 49:15â&#x2C6;&#x2019;24.
Systemic osteoporosis
Fatigue and mood
CRP = C-reactive protein.
Actemra® (Tocilizumab)
A recombinant humanized anti-human IL-6 receptor monoclonal antibody – Molecular weight: approximately 148 kDa.
Binds to membrane-bound and soluble forms of IL-6R to – Blocks IL-6 binding to its receptor – Blocks IL-6 signalling and gene activation
Smolen JS, et al. Arthritis Res Ther. 2006;8(Suppl 2):S5.
Robust ACR50 response rates (at Week 24) (Global studies) MTX-naïve/free
ACTEMRA 8 mg/kg + MTX (n=205)
ACTEMRA 8 mg/kg + DMARDs (n=803)
ACTEMRA 8 mg/kg + MTX (n=170)
MTX monotherapy (n=286)
Placebo + MTX (n=204)
Placebo + DMARD (n=413)
Placebo + MTX (n=158)
Patients (%)
44
44 37.6
34 31
27 29
30 20 9
10 0
1Jones
TNF-IR
ACTEMRA 8 mg/kg monotherapy (n=284)
50 40
DMARD-IR
4
AMBITION1
OPTION2
TOWARD3
2Smolen J, et al. Lancet 2008;371:987-97, G, et al. Ann Rheum Dis 2010;69:88-96, 4Emery P, et al. Ann Rheum Dis 2008;67:1516–1523. Rheum 2008;58:2968-80,
RADIATE4
3Genovese
M, et al. Arthritis
29
JAK3 inhibitor Tofacitinib
JAK Pathways 1 Cytokine binding to its cell surface receptor leads to receptor polymerization and autophosphorylation of associated JAKs
2
Activated JAKs phosphorylate the receptors that dock STATs
JAK
JAK
P
STAT
STAT
STAT P
3 Activated JAKs phosphorylate STATs, which dimerize and move to the nucleus to activate new gene transcription
P
STAT
STAT
Gene transcription
P 31
JAK=Janus kinase; STAT=signal transducer and activator of transcription. Figure adapted from Shuai K, et al. Nat Rev Immunol. 2003;3:900-911. This non-CME program was developed and is being offered by Pfizer Inc.
31
Trends in Molecular Medicine, 2016, 22 (03) 214~229
The Biological Significance of Signaling Through Different JAK Combinations
FUNCTION3
JAK1
JAK3
• Growth/ maturation lymphoid cells • Differentiation/ homeostasis T cells, NK cells • B cell class switching • Inflammation
JAK1
TYK2
JAK1
TYK2 JAK2
JAK1
JAK2
JAK2
TYK2
JAK2
JAK2
• Erythropoiesis
• Antiviral
• Naive T cell differentiation
• Inflammation
• T cell homeostasis
• Antitumor
• Inflammation • Granulopoiesis
• Antiviral • Inflammation
• Innate immunity
• Myelopoiesis
• Differentiation/ proliferation of Th17 cells
• Megakaryocyte/ platelet production
• Inflammation
• Growth • Mammary development
*Type II cytokine receptors such as those for IL-10, IL-19, IL-20, and IL-22 as well as gp130 subunit sharing receptors for IL-6 and IL-11 mainly signal through JAK1, but also associate with JAK2 and TYK2.2 †IL-10/IL-22 may have pro- or anti-inflammatory activities depending on the cellular environment and/or disease state.4 1. O’Sullivan LA, et al. Mol Immunol. 2007;44(10):2497-506; 2. Ghoreschi K, et al. Immunol Rev. 2009;228:273-287; 3. Vijayakrishnan L, et al. Trends Pharmacol Sci. 2011;32:25-34; 4. Sanjabi S, et al. Curr Opin Pharmacol. 2009;9(4):447-453.
This non-CME program was developed and is being offered by Pfizer Inc.
33
An Important Subset of Pro-inflammatory Cytokines Utilize JAK Pathways Key cytokines in the pathogenesis of RA1 IFNα and IFNβ IL-6 IL-7 IL-10 IL-12 IL-15 IL-21 IL-23 IL-1 IL-17 IL-18 TGF-β TNF
Key cytokines in RA that utilize JAK2,3 IFNα and IFNβ IL-6 IL-7 IL-10 IL-12 IL-15 IL-21 IL-23
IFN=interferon; IL=interleukin; JAK=Janus kinase; TGF=transforming growth factor; TNF=tumor necrosis factor. 1. McInnes IB, et al. Nat Rev Immunol. 2007;7:429-442; 2. O’Sullivan LA, et al. Mol Immunol. 2007;44(10):2497-2506; 3. Riese RJ, et al. Best Pract Clin Res Rheumatol. 2010;24:513-526. This non-CME program was developed and is being offered by Pfizer Inc.
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N Engl J Med 2012;367:495-507.
Systemic lupus erythematosus
Trends Mol Med. 2017 Jul;23(7):615-635
Trends Mol Med. 2017 Jul;23(7):615-635
Autoimmun Rev. 2017 Sep 9. pii: S1568-9972(17)30230-6
Sjogrenâ&#x20AC;&#x2122;s syndrome
Annu Rev Med. 2017 Jan 14;68:331-343
ANCA-associted vasculitis
Friedrich Wegener Friedrich Wegener (April 7, 1907~ July 9, 1990, Lübeck) was a German pathologist who is notable for his description of a rare disease. Although this disease was known before Wegener's description, from the 1950s to the 2000s, it was called by the name Wegener's granulomatosis. Wegener joined the Nazi Party in 1932. As a relatively high-ranking military physician, he spent some of World War II in a medical office three blocks from the Łódź Ghetto, a Jewish ghetto in Łódź, Poland. There is speculation that he participated in experiments on concentration camp inmates. The American College of Chest Physicians (ACCP) awarded Wegener a “master clinician” prize in 1989. After his Nazi past was discovered in 2000, the ACCP rescinded the prize and, separately, a campaign was begun to rename Wegener's granulomatosis to ANCA-associated granulomatous vasculitis. More recently, several journals proposed the name 'granulomatosis with polyangiitis' in a 2011 editorial
Clin Exp Rheumatol 2014; 32 (Suppl. 82): S112-S117
GPA/MPA間差異
Differences in the organs affected between GPA and MPA Granulomatosis with polyangiitis (GPA)
d
Microscopic polyangiitis (MPA)
傳統療法副作用
Cyclophosphamide (CYC) • Renal and bladder toxic effects • bone marrow suppression • Infection • Viral and fungal infection • Pneumocystis carinii • Transitional cell carcinoma of the bladder • Infertility
Azathioprine (AZA) • Current treatment standards mitigate some CYP toxicity by switching severe patients to Azathioprine (AZA) after induction • Prior to AZA initiation, thiopurine methyltransferase screening should be used to detect patients at risk of severe haematological and hepatic toxicity
Methotrexate (MTX) Management of CYP toxicity • CYP dosing must be adjusted for age, weight and renal function • Options when CYP toxicity presents • Further dose adjustment • Termination of CYP dosing • Switch to different drugs 1Langford, 2010; 2Talar-Williams et
al. 2001;
11Walko &
McLeod 2009
• Methotrexate (MTX) should not be used for patients with substantial renal dysfunction (glomerular filtration rate <50 mL/min)
Glucocorticoid
al. 1996; 3Hoffman et al. 1992; 4de Groot et al. 2009; 5Bosch et al. 2007; 6Hamour et al. 2010; 7Falk & Jennette 2010; 8Stone, 2010; 9Jayne et al. 2003; 10Evans et
RAVE
Rituximab vs. CYC (RAVE) Rituximab Works Better in Relapsing Patients Rituximab
Patients achieving complete remission (%)
80
p=0.67
70 60
60.4
CYC p=0.01
64.6
50
66.7
42
40 30 20 10 0 Newly diagnosed (n=96)
Relapsing disease (n=101)
RTX vs CYC in patients with relapsing disease at baseline Stone et al. New Eng J Med (2010) 363 (3): 221
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Thanks for your attentions
Cytokine 74 (2015) 101â&#x20AC;&#x201C;107