Dr Papp's deck

1. 1
IL-17a blockade and the
treatment of psoriasis
K. Alexander Papp MD, PhD, FRCPC
Probity Medical Research,
Canada (US, Australia, Chile)

2. 2
Psoriasis
 Perspective

3. 3
Proposed Mechanism of Psoriasis Disease Initiation
and Maintenance
Nestle et al. N Engl J Med. 2009;361:496.

4. 4
Key Cells and Mediators in Psoriasis
Innate Immunity
Keratinocyte
Myeloid
dendritic cell
Natural
killer T cell
Plasmacytoid
dendritic cell
Macrophage
IL-1
IL-6
TNF-
TNF-
TNF-
IFN-
IFN-
Adapted from Nestle et al. N Engl J Med. 2009;361:496.

5. 5
Key Cells and Mediators in Psoriasis
Innate Immunity
Keratinocyte
Myeloid
dendritic cell
Natural
killer T cell
Plasmacytoid
dendritic cell
Macrophage
IL-1
IL-6
TNF-
TNF-
TNF-
IFN-
IFN-
Th1 cell
Th17 cell
IL-23
Keratinocyte
IL-17A/F
IL-22
IL-12
TNF-
IFN-
Adaptive Immunity
Activation
Adapted from Nestle et al. N Engl J Med. 2009;361:496.

6. 6
Key Cells and Mediators in Psoriasis
Innate Immunity
Keratinocyte
Myeloid
dendritic cell
Natural
killer T cell
Plasmacytoid
dendritic cell
Macrophage
IL-1
IL-6
TNF-
TNF-
TNF-
IFN-
IFN-
Th1 cell
Th17 cell
IL-23
Keratinocyte
IL-17A/F
IL-22
IL-12
TNF-
IFN-
Adaptive Immunity
Activation
Antimicrobial peptides
IL-1
IL-6
TNF-
S100
CXCL8
CXCL9
CXCL10
CXCL11
CCL20
Innate Immunity
Adapted from Nestle et al. N Engl J Med. 2009;361:496.

7. 7
Key Cells and Mediators in Psoriasis
Innate Immunity
Keratinocyte
Myeloid
dendritic cell
Natural
killer T cell
Plasmacytoid
dendritic cell
Macrophage
IL-1
IL-6
TNF-
TNF-
TNF-
IFN-
IFN-
Th1 cell
Th17 cell
IL-23
Keratinocyte
IL-17A/F
IL-22
IL-12
TNF-
IFN-
Adaptive Immunity
Activation
Antimicrobial peptides
IL-1
IL-6
TNF-
S100
CXCL8
CXCL9
CXCL10
CXCL11
CCL20
Innate Immunity
Adapted from Nestle et al. N Engl J Med. 2009;361:496.

8. 8
Role of IL-17

9. 9
Key Events in the History of IL-17 and TH171
1986: Mosmann,
Coffman and
colleagues propose
the TH1- TH 2 cell
paradigm
IL-17RA is cloned
First demonstration that
TH17 cells are
pathogenic in
autoimmunity;
TH17 cells are shown to
arise as a separate
lineage from TH1 and
TH 2 cells
IL-17RC is found to
be the co-receptor
for IL-17A and IL-
17F;
TH17 cells are
shown to produce
IL-21
1986 1993 1995 2003 2005 2006 2007 2009
CTLA8, later
renamed IL-17A, is
cloned
1. Gaffen SL. Nat Rev Immunol. 2009;9:556-568
IL-23 is shown to
stimulate CD4+ T cells
to produce IL-17
RORyt and STAT3 are shown
to drive TH17 cell
differentiation;
TGF-β and IL-6 are shown to
drive TH17 cell development;
TREG cells are shown to
arise in opposition to TH17
cells;
TH17 cells are shown to
produce IL-22
IL-17-specific antibodies
show efficacy in early
clinical trials for the
treatment of psoriasis

10. 10
Genetic Experiments in
Nature

11. 11

12. 12
Chronic mucocutaneous candidiasis in humans with
inborn errors of interleukin-17 immunity
 Puel A, et al Science 2011;
332(6025): 65-68

13. 13
Chronic mucocutaneous candidiasis in humans with
inborn errors of interleukin-17 immunity
 Puel A, et al Science 2011;
332(6025): 65-68
Recurrent or persistent infections
caused by Candida albicans and less
frequently Staphylococcus aureus

14. 14
Chronic mucocutaneous candidiasis in humans with
inborn errors of interleukin-17 immunity
 Puel A, et al Science 2011;
332(6025): 65-68 Recurrent or persistent infections
caused by Candida albicans and less
frequently Staphylococcus aureus
Autosomal recessive deficiency of
IL-17A

15. 15
Chronic mucocutaneous candidiasis in humans with
inborn errors of interleukin-17 immunity
 Puel A, et al Science 2011;
332(6025): 65-68 Recurrent or persistent infections
caused by Candida albicans and less
frequently Staphylococcus aureus
Autosomal recessive deficiency of
IL-17A
Autosomal dominant deficiencies of
IL-17F

16. 16
TH Cell Differentiation Overview:
IL-17 Is Produced by TH17 Cells Arising from CD4+ T Cell Progenitors1-9
TH1 TREG
IL-1,TGF-,
IL-6, IL-23
Physiologic Targets
Defense against
intracellular pathogens
IL-12,
IFN-
TH2
IL-4
Defense against extracellular pathogens
Allergy and asthma
Defense against extracellular pathogens
Autoimmunity
Epithelial immunity and healing
Tolerance
Immune homeostasis
Defense against extracellular
pathogens
IL-17A, IL-17F,
IL-17A/F,
IL-21, IL-22
Stress, injury
Recruitment
of neutrophils
Activated
APC
Naïve
CD4+T cell
IL-5, IL-13, IL-4
IL-10,IL-25
Eosinophils, basophils,
T cells, B cells, APCs
IFN-
TNF-α
IL-2
T cells, APCs
IL-17A,
IL-17F
IL-17A/F
IL-2,
TGF-
IL-10,
TGF-
T cells
TH17
Keratinocytes, neutrophils,
APCs, T cells
Innate
immune
cells
IL-25
APC = antigen-presenting cell; TGF- = transforming growth factor-beta; TREG = regulatory T.
1. Brand S. Gut. 2009;58:1152-1167. 2. Cools N, et al. Clin Dev Immunol. 2007;89195:1-11. 3. Miossec P, et al. N Engl J Med. 2009;361:888-898. 4. Lucey DR, et al. Clin
Microbiol Rev. 1996;9:532-562. 5. Gaffen SL. Nat Rev Immunol. 2009;9:556-568. 6. Abbas AK, et al. Cellular and Molecular Immunology. 6th ed. Philadelphia, Pa: Saunders.
2007:303-320. 7. Cua DJ, et al. Nat Rev Immunol. 2010;10:479-490. 8. van der Fits L, et al. J Immunol. 2009;182:5836-5845. 9. Létuvé S, et al. J Allergy Clin Immunol.
2006;117:590-596.

17. 17
IL-17 Cytokine Family
Gaffen. Nat Rev Immunol 2009;9(8):556-67(Updated 9: p 747).

18. 18
IL-17 Signaling - Ligand/Receptor Combinations
IL-17A IL-17A/F
IL-17F
1. Gaffen. Nat Rev Immunol 2009;9(8):556-67(Updated 9: p747).
2. Chang et al. Immunity 2011;35(4):611-21.
IL-17C
IL-17D
IL-17E/IL-25
IL-17B
??
??
FN1
FN2
SEFIR
TILL
CBAD IL-17RA
IL-17RC
IL-17RA
IL-17RB/
IL-25R
IL-17RA
IL-17RD/
SEF
IL-17RB/
IL-25R
IL-17RA
IL-17RE
IL-17RD/
SEF

19. 19
IL-17 Receptor A Has an Important Role for
Function of Multiple IL-17 Family Cytokines1-7
 IL-17 cytokines bind to and activate signaling through a family of receptors1-7
 IL-17 receptor A forms a complex with other receptor subunits to bind with different IL-17 cytokines1,3
 For example, IL-17A, IL-17F, and IL-17A/F bind to and activate signaling through a heteromeric
receptor complex comprised of IL-17 receptor A and IL-17 receptor C1-4,6,7
1. Toy D, et al. J Immunol. 2006;177:36-39. 2. Wright JF, et al. J Immunol. 2008;181:2799-2805. 3. Rickel EA, et al. J Immunol. 2008;181:4299-4310. 4. Chang
SH, et al. Cell Res. 2007;17:435-440. 5. Claudio E, et al. J Immunol. 2009;182:1617-1630. 6. Kuestner RE, et al. J Immunol. 2007;179:5462-5473. 7. Ramirez-
Carrozzi V, et al. Nat Immunol. 2011;12:1159-1166.

20. 20
Main Functions of IL-17A and IL-17F1-12*
 Neutrophil recruitment4-6
 Extracellular pathogen defense7,8
 IL-17A is critical for memory
response against intracellular
pathogens9
 Bone metabolism10,11
*Data regarding the IL-17A/F heterodimer are limited.12
1. Toy D, et al. J Immunol. 2006;177:36-39. 2. Wright JF, et al. J Immunol. 2008;181:2799-2805. 3. Chang SH, et al. Cell Res. 2007;17:435-440. 4. Hurst SD, et
al. J Immunol. 2002;169:443-453. 5. Kelly MN, et al. Infect Immun. 2005;73:617-621. 6. Fossiez F, et al. J Exp Med. 1996;183:2593-2603. 7. O’Connor W Jr, et
al. Nat Immunol. 2010;11:471-476. 8. Zelante T, et al. Eur J Immunol. 2007;37:2695-2706. 9. Pappu R, et al. Immunology. 2011;134:8-16. 10. Lubberts E, et al. J
Immunol. 2003;170:2655-2662. 11. Goswami J, et al. Eur J Immunol. 2009;39:2831-2839.12. Gaffen SL. Nat Rev Immunol. 2009;9:556-568.

21. 21
Main Functions of IL-17C1,2
 Neutrophil recruitment1,2
 Extracellular pathogen defense1,2
 Regulation of intestinal epithelial
inflammation (protective
function)1,2
 Overlapping functions with IL-
17A1,2
– Host defense
– Cytokine induction
G-CSF = granulocyte colony-stimulating factor.
1. Ramirez-Carrozzi V, et al. Nat Immunol. 2011;12:1159-1166. 2. Song X, et al. Nat Immunol. 2011;12:1151-1158.

22. 22
Main Functions of IL-251-8
 Promotes TH2 responses2-4
 In preclinical models, modulates
allergic responses and asthma2-6
 Protective immunity to extracellular
pathogens
(eg, parasitic infections)2-4,7,8
IL-25
IL-17RB IL-17RA
1. Rickel EA, et al. J Immunol. 2008;181:4299-4310. 2. Claudio E, et al. J Immunol. 2009;182:1617-1630. 3. Angkasekwinai P, et al. J Exp Med.
2007;204:1509-1517. 4. Angkasekwinai P, et al. Nat Immunol. 2010;11:250-257. 5. Zhao Y, et al. Int Arch Allergy Immunol. 2010;151:297-307. 6. Létuvé S, et
al. J Allergy Clin Immunol. 2006;117:590-596. 7. Hurst SD, et al. J Immunol. 2002;169:443-453. 8. Fallon PG, et al. J Exp Med. 2006;203:1105-1116.

23. 23
The IL-17 Family Includes Unique
Receptors and Cytokines1-9
Cytokines Source of Cytokine Receptors Expression of Receptors
IL-17A
IL-17F
IL-17A/F
heterodimer
IL-17C
IL-25
(IL-17E)
IL-17B
IL-17D
Ubiquitous (higher in hematopoietic tissues)
Most human tissues (preferentially on
nonhematopoietic tissues)
Ubiquitous (higher in hematopoietic tissues)
Selectively induced in epithelia by bacterial,
inflammatory stimuli
Ubiquitous (higher in hematopoietic tissues)
TH2 cells, TH9 cells, fibroblasts, basophils,
endocrine, kidney, and liver cells
TH2 cells, TH9 cells, fibroblasts, basophils,
endocrine, kidney, and liver cells
Unknown
• NKT cells
• LTi cells
• NK cells
• TH17 cells
• CD8+ T cells
• γδ T cells
• PMN cells (low concentration)
Epithelial cells (trachea,
colon, skin)
• TH2 cells
• NKT cells
• Alveolar MФs
• PMN cells (lower concentration)
Unknown
Unknown
IL-17RA
IL-17RC
IL-17RA
IL-17RE
IL-17RA
IL-17RB
IL-17RB
Unknown
• Eosinophils
• Mast cells
• Basophils
γδ = gamma-delta; LTi = lymphoid tissue inducer; Mϕs = macrophages; NK = natural killer; NKT = natural killer T;
PMN = polymorphonuclear.
1. Gaffen SL. Nat Rev Immunol. 2009;9:556-568. 2. Chang SH, et al. Cell Res. 2007;17:435-440. 3. Garley M, et al. Adv Med Sci. 2008;53:326-330. 4. Pappu R,
et al. Immunology. 2011;134:8-16. 5. Ramirez-Carrozzi V, et al. Nat Immunol. 2011;12:1159-1167. 6. Song X, et al. Nat Immunol. 2011;12:1151-1158. 7.
Moseley TA, et al. Cytokine Growth Factor Rev. 2003;14:155-174. 8. Ge D, et al. Int Arch Med. 2008;1:1-19. 9. Lee J, et al. J Biol Chem. 2001;276:1660-1664.

24. 24
The IL-17 Receptor and Cytokine
Family Is Implicated in Psoriasis1-4
 Data suggest pathophysiology in psoriasis may be mediated by
interactions between IL-17 cytokine-producing cells and target cells
expressing IL-17 receptor A…1
 …And lead to a cascade that results in inflammation and skin
manifestations1
Keratinocyte
proliferation and
differentiation
(thickness and
scaling)
Inflammation
Vessel activation,
angiogenesis
(erythema)
IL-17 producing cells
(T cells, neutrophils, mast cells)
Target Cells Expressing IL-17RA
(Keratinocytes, dermal fibroblasts and epithelial
cell, endothelial cells)
1. Raychaudhuri SP. Clin Rev Allerg Immunol. 2013;44:183-193. 2. Miossec P, et al. N Engl J Med. 2009;361:888-898. 3. Miossec P, et al. Nat Rev Drug Discov.
2012. 4. Ouyang W, et al. Immunity. 2008;28:454-467.

25. 25
IL-17A Has Pathogenic Effects on Keratinocytes
Mast
Cells
Neutrophils
IL-17A
IL-17A
1. Guttman-Yassky. J Allergy Clin Immunol 2011;127(6):1420-32.
2. Chiricozzi and Krueger. Expert Opin Investig Drugs 2013;22(8):993-1005.
3. Gaffen. Nat Rev Immunol 2009;9(8):556-67(Updated 9: p 747).
4. Lin et al. J Immunol 2011;187(1):490-500.
Th17
Cells
KC
IL-17A
Hyperproliferation and
acanthosis leading to psoriatic
plaques 1,2
Release proinflammatory
cytokines leading to increased
inflammation and recruitment
of Th17 cells and neutrophils1,2
KC
Other cell types (not shown) that secrete IL-17 include γδ T cells, macrophages3,4

26. 26
TH1- and TH17 -Associated Cytokines Are Present in
Psoriatic Plaques1,2
mRNA expression in
psoriatic plaques vs.
nonlesional psoriatic skin is:
– Increased 28- to 33-fold
(P < 0.01) for IL-17A,
IL-17C, and IL-17F
– Increased 9-fold (P < 0.01)
for IFN-γ mRNA
6000
5000
4000
3000
2000
1000
0
*
IL-17A
Nonlesional Lesional
IL-17A/RPLPO mRNA
6000
5000
4000
3000
2000
1000
0
* IL-17C
Nonlesional Lesional
IL-17C/RPLPO mRNA
7000
6000
5000
4000
3000
2000
1000
0
IL-17F *
Nonlesional Lesional
IL-17F/RPLPO mRNA
1600
1400
1200
1000
800
600
400
200
0
IFN- *
Nonlesional Lesional
IFN-/RPLPO mRNA
Pooled paired tissue samples from lesional and nonlesional psoriatic skin of subjects with moderate to severe chronic plaque psoriasis (n = 9).
*P < 0.01 compared with nonlesional psoriatic skin
RPLPO = housekeeping gene used as control in the analysis.
1. Johansen C, et al. Br J Dermatol. 2009;160:319-324. Figures: © 2009 John Wiley and Sons. © 2009 British Association of Dermatologists. 2. Zaba LC, et
al. J Exp Med. 2007;204:3183-3194.

27. 27
Targeting: IL-171
1. Adapted from Nestle et al. N Engl J Med. 2009;361:496.
2. Tausend et al. J Cutan Med Surg. 2014;18:156.
Th1 cell
Th17 cell
Keratinocyte
Myeloid
dendritic cell
IL-17A
Natural
killer T cell
Plasmacytoid
dendritic cell
IL-17R
Keratinocyte
Macrophage
Antimicrobial peptides
IL-1
IL-6
TNF-
S100
CXCL8
CXCL9
CXCL10
CXCL11
CCL20
Activation
Secukinumab
Ixekizumab2
Brodalumab2

28. Original Article
Secukinumab in Plaque Psoriasis — Results of
Two Phase 3 Trials
Richard G. Langley, M.D., Boni E. Elewski, M.D., Mark Lebwohl, M.D., Kristian
Reich, M.D., Ph.D., Christopher E.M. Griffiths, M.D., Kim Papp, M.D., Ph.D., Lluís
Puig, M.D., Ph.D., Hidemi Nakagawa, M.D., Ph.D., Lynda Spelman, M.B., B.S.,
Bárður Sigurgeirsson, M.D., Ph.D., Enrique Rivas, M.D., Tsen-Fang Tsai, M.D.,
Norman Wasel, M.D., Stephen Tyring, M.D., Ph.D., Thomas Salko, B.A., Isabelle
Hampele, Ph.D., Marianne Notter, M.S., Alexander Karpov, Ph.D., Silvia Helou, M.D.,
Ph.D., Charis Papavassilis, M.D., Ph.D., for the ERASURE and FIXTURE Study
Groups
N Engl J Med
Volume 371(4):326-338
July 24, 2014

29. Study Overview
• In two trials in patients with moderate-to-severe plaque psoriasis, the
anti–interleukin-17A monoclonal antibody secukinumab was more
effective than placebo and etanercept.
• Infectious complications occurred more often with secukinumab than
with placebo.

30. Speed of Response.
Langley RG et al. N Engl J Med 2014;371:326-338

31. Efficacy over Time.
Langley RG et al. N Engl J Med 2014;371:326-338

32. Demographic and Baseline Clinical Characteristics of the Patients.
Langley RG et al. N Engl J Med 2014;371:326-338

33. Efficacy End Points in ERASURE.
Langley RG et al. N Engl J Med 2014;371:326-338

34. Efficacy End Points in FIXTURE.
Langley RG et al. N Engl J Med 2014;371:326-338

35. Adverse Events during the Induction Period and the Entire 52-Week Study Period in FIXTURE.
Langley RG et al. N Engl J Med 2014;371:326-338

36. Conclusions
• Secukinumab was effective for psoriasis in two randomized trials,
validating interleukin-17A as a therapeutic target.

37. 37

38. 38
PASI 75 Response for IL-17 Inhibitors
72
Low Dose High Dose
67
Placebo Group
5 5 3
60
82
77
83
100
80
60
40
20
0
Patients achieving a
PASI 75 response, %
ERASURE FIXTURE AMAGINE-1
Secukinumab1
Phase 3
Time Point 12 weeks
Brodalumab2
Phase 3
12 weeks
Dose 150 mg, 300 mg 140 mg, 210 mg
UNCOVER
Ixekizumab3
Phase 3
100
80
60
40
20
160 mg starting dose, 80 mg every 2 or 4 weeks
1. Langley et al. N Engl J Med 2014;371:326-38.
2. Amgen and AstraZeneca. 2014. Phase 3 Study of Brodalumab [News release]. Accessed September 2, 2014.
3. Eli Lilly and Company. 2014. Phase 3 Study of Ixekizumab [News Release]. Accessed September 2, 2014.
12 weeks
0
Patients achieving a
PASI 75 response, %
Between
78% to 90%
of patients
achieved a
response

39. 39
Key Cells and Mediators in Psoriasis
Innate Immunity
Keratinocyte
Myeloid
dendritic cell
Natural
killer T cell
Plasmacytoid
dendritic cell
Macrophage
IL-1
IL-6
TNF-
TNF-
TNF-
IFN-
IFN-
Th1 cell
Th17 cell
IL-23
Keratinocyte
IL-17A/F
IL-22
IL-12
TNF-
IFN-
Adaptive Immunity
Activation
Antimicrobial peptides
IL-1
IL-6
TNF-
S100
CXCL8
CXCL9
CXCL10
CXCL11
CCL20
Innate Immunity
Adapted from Nestle et al. N Engl J Med. 2009;361:496.