Biologic therapy for psoriasis
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Transcript of Biologic therapy for psoriasis
Definition Biologic agents are proteins that possess pharmacologic
activity and can be extracted from animal tissue or, much more commonly, synthesized in large quantities through recombinant DNA techniques.
Molecules produced by living cells, which either mimic or block naturally occurring proteins, such as soluble receptors, antibodies, or fusion proteins.
Early used biologics Insulin , a protein first extracted from pigs and
now made as recombinant human insulin.
Hematopoietic support (eg, erythropoietin, granulocyte, and platelet growth factors).
In solid organ transplantation, in which monoclonal antibodies designed to inhibit rejection.
Types of biologic molecules Recombinant human
Cytokines or
Growth factors
Monoclonal antibodies, and
Fusion proteins
Recombinant Human Proteins Are molecules that are either exact replicas of normal
human proteins or fragments thereof have specific physiological effects.
These drugs function by interacting with normal cellular receptors to induce their effects.
These effects are often limited to normal physiological function of the protein as is the case with recombinant insulin and type 1 diabetes mellitus.
Monoclonal Antibodies Are proteins that specifically bind to proteins on
cell surfaces in the circulation or tissue.
This interaction alters activity of the target protein.
Monoclonal antibody inhibits effects of the protein, thus altering the course of disease.
Fusion Proteins Are molecules that combine sections of
different proteins.
The first combines a human protein with a toxin.
Human protein binds to a cell and causes the entire complex to be internalized.
Once inside the cell, toxin is released, thereby killing the cell.
Biologic production Injecting antigen into mice Respond producing antibodies from B Cell Which are identical ----- monoclonlity In vitro propagation via Fusion with immortal tumor cell ( myeloma cell) ----
hybridoma cell
Biologic production This process is slow --- resulting in mixture containing ---
a- Hybridoma cell --- needed B- B cell --- die spontaneously C- myeloma cell --- removed actively --- by adding – substrate (
HAT) which metabolized by B cell and hybridoma cell due to presence of HGPRT enzyme but lacking of myelmoa cell to this enzyme it killed.
Hybridma cell (antibodies + tumor cell) of animal origin ---- antigenic
Final Murine
Antibodies of animal origin --- antigenic
To reduce this antigencity ---- human part to be replaced -----resulting in
Chimeric antibodies Comprise constent
portion of human antibodies,
Only variable region are of animal origin.
Suffix – ximab ( infliximab)
Humanized antibodiesOnly preserve the direct
antigen binding site –CDRs – complementary
determining region
Suffix --- zumab ( efalizumab)
Biologics Agent Construct Mode of Action Usual Dosing Half-life
TNF-a antagonists
Adalimumab
Humira
Human mAb to TNF-a Binds TNF-a 40 mg SQ q 1-2 weeks 12-14 days
Etanercept
Enbrel
Recombinant TNF-a receptor/IgG
Fc fusion protein
Binds TNF-a, lymphotoxin-a 50 mg SQ q week or 25 mg SQ
biweekly
4-5 days
Infliximab
Remicade
Chimeric mAb to TNF-a Binds TNF-a 3-10 mg/kg IV q 4-8 weeks 8-10 days
Alfacept
Amevive
Fusion protein Inhibits T cell activation 7.5 mg iv or 15 mg im weekly
Efalizumab
Raptiva
Humanized antibody Inhibits T cell activation 50 mg sq weekly
IL-1 receptor antagonist
Anakinra Recombinant IL-1 receptor
antagonist
Binds IL-1 receptors 100 mg SQ qday 6 hours
Anti-CD20 Ig
Rituximab
Rituxan
Chimeric mAb to CD20 Depletes CD20+ B cells 1000 mg q 2weeks X 2 doses 32-153 hours (mean 76.3 hours)
CTLA-4 Ig
Abatacept
Orencia
Chimeric CTLA-4/IgG Fc fusion
protein
Inhibits T cell activation 10 mg/kg (500, 750, or 1000 mg)
IV q 4weeks
8-25 days (mean 13.1 days)
Tumor necrosis factor antagonists
TNF is a proinflammatory cytokine produced by a wide variety of cell types
Soluble cytokine (sTNF) and (transmembranetmTNF).
Both sTNF and tmTNF are biologically active
TNF receptor 1 (TNFR1, p55) and TNF receptor 2 (TNFR2, p75).
Tumor necrosis factor antagonistsTwo groups of biologic agents that target TNF:
Monoclonal antibodies (adalimumab and infliximab), and
sTNF receptors (etanercept).
All three agents specifically bind both soluble and transmembrane forms of TNF
Act by Blocking TNFR-mediated mechanisms and
Inducing tmTNF (reverse-signalling) events.
Etanercept also binds members of the lymphotoxinfamily [LTα3 (also known as TNF-β) and LTα2β1]
Etanercept Is a genetically engineered fusion protein composed of
a dimer of the extracellular portions of human TNFR2
(p75) fused to the Fc domain of human IgG1.
Etanercept Target TNF- α
Type fully human fusion protein
Mode of action block of TNF- α
Dose 2/ 25 or 1/ 50 mg/ week subcut for ----
PASI 75 by 12 weeks
Etanercept Onset of action is slower than that seen with the
monoclonal antibodies
Improvement after 4 and 8 weeks after initiation of treatment.
Response is dose related
Continuous therapy provides better disease control and if treatment is stopped, disease relapses slowly:
Adalimumab Highly effective treatment for chronic plaque psoriasis
Onset of action is rapid
Significant improvement within 2 weeks
Response is dose related
PASI 75 at week 12
Adalimumab Type fully human monoclonal antibody
Dose 80 mg subcutaneously at week 0. 40 mg at week 1, and then every other week
Target TNF α
Mode of action neutralizes TNF α
Anti-adalimumab antibodies develop in 8.4% of patients.
Infliximab Type chimeric monoclonal antibody
Target TNF-α
Mode of action TNF inhibition which leads to a decreased amount of interleukins (IL-1, IL-6) released from inflammatory cells,
Dose IV 3-5 mg /kg at week 0, 2, 6.
Eligibility criteria Patients must have severe disease as defined in (a) and
fulfil one of the clinical categories outlined in (b): (a) Severe disease is defined as a
PASI score of 10 or more BSA of 10% or greater where PASI is not applicable) DLQI > 10.
Disease should have been Severe for 6 months, Resistant to treatment and The patient should be a candidate for systemic therapy.
Eligibility criteria(b) fulfill at least one of the following clinical categories (i) at higher risk of developing drug-related toxicity (ii) intolerant to or cannot receive standard systemic therapy (iii) become unresponsive to standard therapy (iv) have disease that is only controlled by repeated inpatient management (v) have significant, coexistent, unrelated comorbidity (vi) have severe, unstable, life-threatening disease (erythrodermic or pustular
psoriasis) (vii) have psoriatic arthritis eligible for treatment with anti- TNF agents, in
association with skin disease
Pretreatment Screening1. Complete blood count, 2. Assessment of hepatic and renal function, 3. Tests for hepatitis B and C,4. Urinalysis5. Chest radiograph6. A purified protein derivative (PPD) test for TB7. Pregnancy test 8. ANA, anti-DNA, or antiphospholipid antibodies9. Rule out occult malignancy
Contraindications Should never be given a live vaccine, only killed
vaccines.
Pulmonary malignancy or significant CHF
Side effects Injection-site reaction (ISR)
Infusion reactions are ameliorated by peri- infusionalcorticosteroids.
Neutropenia, anemia, thrombocytopenia, and pancytopenia,
Development of a lupus-like syndrome
Development of antibodies
Rare instances of hepatotoxicity
Recommendation For stable disease, particularly if not too severe (e.g. PASI >10
but <20), etanercept or adalimumab are often first options.
For patients requiring rapid disease control, adalimumab or infliximab may be considered first choice due to early onset of action.
For patients with unstable or generalized pustularpsoriasis, limited evidence indicates that infliximab is effective and may be considered first choice amongst the biologics
At present, there are five biological agents licensed for the treatment of psoriasis vulgaris.
(i) etanercept, a fully human soluble p75 TNF-α receptor fusion protein;
(ii) infliximab, a chimeric human-immune antibody to TNF-α; (iii) adalimumab, a fully human recombinant antibody to TNF-α; (iv) ustekinumab, a fully human recombinant antibody to the p40
component of IL-12/IL-23: (v) alefacept, a fusion protein of lymphocyte function associated
antigen-3 and IgG that inhibits T-cell activation—this is not licensed in the UK.