biologic therapy for psoriasis
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Biologic Therapy for Psoriasis
Biologic Therapy for Psoriasis Dr. Ahmed Abdelmoaty MD Assistant Prof. Dermatology and Venerology Al- Azhar University Cairo Egypt1Definition 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. 2Early used biologicsInsulin , 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. 3Types of biologic moleculesRecombinant human Cytokines or Growth factors Monoclonal antibodies, and Fusion proteins 4Recombinant 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. 5Monoclonal 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. 6Fusion 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. 7The second is similar to humanized monoclonal antibodies.8Biologic 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 9Biologic 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
10Final Murine Antibodies of animal origin --- antigenic To reduce this antigencity ---- human part to be replaced ----- resulting in
11Chimeric antibodiesComprise constent portion of human antibodies, Only variable region are of animal origin. Suffix ximab ( infliximab)
12Humanized antibodiesOnly preserve the direct antigen binding site CDRs complementary determining region Suffix --- zumab ( efalizumab)
13Fully human antibodies No remaining element of animal origin Suffix --- umab (adalimumab)
antibodies that are approximately 65% human16Humanized antibodies
17Fully human antibodies
18Biologics AgentConstructMode of ActionUsual DosingHalf-lifeTNF-a antagonists Adalimumab Humira Human mAb to TNF-aBinds TNF-a40 mg SQ q 1-2 weeks12-14 daysEtanercept Enbrel Recombinant TNF-a receptor/IgG Fc fusion proteinBinds TNF-a, lymphotoxin-a50 mg SQ q week or 25 mg SQ biweekly4-5 daysInfliximab Remicade Chimeric mAb to TNF-aBinds TNF-a3-10 mg/kg IV q 4-8 weeks8-10 daysAlfacept Amevive Fusion protein Inhibits T cell activation7.5 mg iv or 15 mg im weekly Efalizumab Raptiva Humanized antibody Inhibits T cell activation50 mg sq weeklyIL-1 receptor antagonist AnakinraRecombinant IL-1 receptor antagonistBinds IL-1 receptors100 mg SQ qday6 hoursAnti-CD20 Ig Rituximab Rituxan Chimeric mAb to CD20Depletes CD20+ B cells1000 mg q 2weeks X 2 doses32-153 hours (mean 76.3 hours)CTLA-4 Ig Abatacept Orencia Chimeric CTLA-4/IgG Fc fusion proteinInhibits T cell activation10 mg/kg (500, 750, or 1000 mg) IV q 4weeks8-25 days (mean 13.1 days)19Tumor necrosis factor antagonistsTNF is a proinflammatory cytokine produced by a wide variety of cell typesSoluble cytokine (sTNF) and (transmembrane tmTNF).Both sTNF and tmTNF are biologically activeTNF receptor 1 (TNFR1, p55) and TNF receptor 2 (TNFR2, p75).20Tumor 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 TNF21Act byBlocking TNFR-mediated mechanisms and Inducing tmTNF (reverse-signalling) events.Etanercept also binds members of the lymphotoxin family [LT3 (also known as TNF-) and LT21]22EtanerceptIs a genetically engineered fusion protein composed of a dimer of the extracellular portions of human TNFR2 (p75) fused to the Fc domain of human IgG1.23EtanerceptTarget TNF- Type fully human fusion proteinMode of action block of TNF- Dose 2/ 25 or 1/ 50 mg/ week subcut for ----PASI 75 by 12 weeks24EtanerceptOnset of action is slower than that seen with the monoclonal antibodiesImprovement after 4 and 8 weeks after initiation of treatment.Response is dose relatedContinuous therapy provides better disease control and if treatment is stopped, disease relapses slowly:25AdalimumabHighly effective treatment for chronic plaque psoriasisOnset of action is rapidSignificant improvement within 2 weeksResponse is dose relatedPASI 75 at week 1226AdalimumabType fully human monoclonal antibody Dose 80 mg subcutaneously at week 0. 40 mg at week 1, and then every other weekTarget TNF Mode of action neutralizes TNF Anti-adalimumab antibodies develop in 8.4% of patients.
27Infliximab Type chimeric monoclonal antibody Target TNF- 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, 6.28Eligibility criteriaPatients 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.29Eligibility 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 disease30Pretreatment ScreeningComplete blood count, Assessment of hepatic and renal function, Tests for hepatitis B and C,UrinalysisChest radiographA purified protein derivative (PPD) test for TBPregnancy test ANA, anti-DNA, or antiphospholipid antibodiesRule out occult malignancy 31Contraindications Should never be given a live vaccine, only killed vaccines. Pulmonary malignancy or significant CHF
32Side effects Injection-site reaction (ISR)Infusion reactions are ameliorated by peri- infusional corticosteroids.Neutropenia, anemia, thrombocytopenia, and pancytopenia,Development of a lupus-like syndrome Development of antibodies Rare instances of hepatotoxicity
33Recommendation For stable disease, particularly if not too severe (e.g. PASI >10 but