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