Biologic therapy Spyridon Gkalpakiotis,MD,PhD Dermatovenereology department Third faculty of medicine,Charles University,Prague
Biologic therapy
Spyridon Gkalpakiotis,MD,PhDDermatovenereology departmentThird faculty of medicine,Charles
University,Prague
Biologic therapy• Biologics are formed in the human body• Formed by:-recombinant DNA technology-hybridoms-blood-from human cells• Biologics are
- Large molecules - Applied usually by injection
Less side effects than traditional systemic therapeutics
Therapy of psoriasis and psoriatic arthritis with biologicsTherapy of psoriasis and psoriatic arthritis with biologics
Humira®Humira®(adali-(adali-mumab)mumab)
Enbrel®Enbrel®(etanerce(etanercept)pt)
Stelara®Stelara®(Ustekinu(Ustekinumab)mab)
RemicadeRemicade®®(infliximab(infliximab))
PsoriasisPsoriasis
Psoriasis-Psoriasis-ArthritisArthritis
Humira®Humira®(adali-(adali-mumab)mumab)
Enbrel®Enbrel®(etanerce(etanercept)pt)
Stelara®Stelara®(Ustekinu(Ustekinumab)mab)
RemicadeRemicade®®(infliximab(infliximab))
MechanisMechanismm
anti TNF-a anti TNF-a proti IL12/23
AplicationAplication s.c s.c
anti TNF-a
s.c i.v
Role of TNF in psoriasis
• Creation of tumor necrosis factor (TNF) is increased in psoriasis
• Elevated serum TNF• Increased concentrations of TNF in psoriatic
lesion• TNF levels correlate with scores of the
Psoriasis Area and Severity Index (PASI)• Decreased TNF correlates with clinical
manifestations
Efektorová aktivita Efektorová aktivita zprostředkovaná TNF-zprostředkovaná TNF-
TNF-TNF- se neváže na svůj se neváže na svůj receptor: nevytváří se receptor: nevytváří se signálsignál
TNF-TNF- receptor receptor
ProzánětlivýProzánětlivýcytokincytokinTNF-TNF- YSolubilní Solubilní
receptorreceptorTNF-TNF-
MonoklonálníMonoklonálníProtilátkaProtilátkaAntiAnti––TNF-TNF-
No antagonist of TNF with antagonist of TNF
Prozánětlivé signályProzánětlivé signály
TNF-TNF- receptor receptor
Choy ES, Panayi GS. N Engl J Med. 2001;334:907-916.
InfliximabInfliximab
Mouse Fv(binding site for TNF))
Human (IgG1)
Human kappa
Chimeric human -Chimeric human -mouse monoclonal mouse monoclonal antibody anti-TNFantibody anti-TNF
Infliximab
Aplication i.v ( 5mg/kg) – 0,2,6 and then every 8 weeksAplication i.v ( 5mg/kg) – 0,2,6 and then every 8 weeks
Side effects – headache, elevaion of liver enzymes, infectionsSide effects – headache, elevaion of liver enzymes, infections
InfusionInfusion reactions !!
PASI 75 až u 80% pacientůPASI 75 až u 80% pacientů
References: 1. Gottlieb, A.B, et al., Poster, 61st Annual AAD Meeting, 2003 2. Centocor, Inc. Summary of Product Characteristics. 1999.
EtanerceptEtanercept ■ Etanercept is a fusion protein
Composition of the ligand, which binds to the receptor for TNF■attached to the Fc portion of human IgG1
■ Approved for childhood psoriasis
Application: 25mg 2x a week sc or 50 mg 1x a ■week event. 50mg 2x a week (12weeks)
AdalimumabAdalimumab Complete human monooclonal antibody
anti–TNF-a Aplication: s.c baseline 80mg, 40mg after a
week and then 40mg every 2 weeksVH
Light
chai
n
CL
CH1
CH3
CH2
Fc
Fab
Heavy
chai
n
VL
Bain B, Brazil M. Nat Rev Drug Discov. 2003;2:693-694.
Lidskýpeptid
S-SS-S
S-SS-S
New biologic therapy- Block subinit of p40, which is part of IL-12 a IL-23
IL-23
IL-12TNF-IFN-
TNF- IL-17
IL-22
T cell
Je utlumena diferenciace a klonální pomnožení
subsetů Th1a Th17
Protilákta váže na podjednotku p40 IL-12 a
IL-23, zabraňuje navázání na její buněčné receptory
1. Gately MK, et al. Annu Rev Immunol. 1998;16:495-521. 2. Wilson NJ, et al. Nat Immunol. 2007;8(9):950-7. 3. Nickoloff BJ, Nestle FO. J Clin Invest. 2004;113(12):1664-75. 4. Nestle FO et al. J Invest Dermatol. 2004; 123:xiv-xxv.
Th1
Th17
Snížení hladinyzánětlivých cytokinů
Ustekinumab
• The complete human antibody against the IL-12/IL-23
• Applications s.c• Baseline, 4 weeks and then 1 every 12 weeks
Dose: 1 to 100 kg inj. 45mg, 2inj over 100 kg
Pappu R.J Clin Immunol (2010) 30:185–195
N Engl J Med 2012;366:1181-9.
Pappu R.J Clin Immunol (2010) 30:185–195
Brodalumab
N Engl J Med 2012;366:1190-9.
Which biologic? • Individual• According speed of effect • According way of administration
• European S3-Guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol. 2009, vol.23(2)
• British Association of Dermatologists' guidelines for biologic interventions for psoriasis 2009. Br J Dermatol. 2009 Nov;161(5):987-1019
Why biologic therapy
• High effect • Less adverse events• Long-term therapy
Future