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Biologic therapy for psoriasis

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Biologic therapy for psoriasis

  1. 1. Dr. Ahmed Abdelmoaty MD Assistant Prof. Dermatology and Venerology Al- Azhar University Cairo Egypt
  2. 2. 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.
  3. 3. 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.
  4. 4. Types of biologic molecules  Recombinant human  Cytokines or  Growth factors  Monoclonal antibodies, and  Fusion proteins
  5. 5. 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.
  6. 6. 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.
  7. 7. 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.
  8. 8. The second is similar to humanized monoclonal antibodies.
  9. 9. 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
  10. 10. 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
  11. 11. Final  Murine  Antibodies of animal origin --- antigenic  To reduce this antigencity ---- human part to be replaced ----- resulting in
  12. 12. Chimeric antibodies  Comprise constent portion of human antibodies,  Only variable region are of animal origin.  Suffix – ximab ( infliximab)
  13. 13. Humanized antibodies Only preserve the direct antigen binding site – CDRs – complementary determining region Suffix --- zumab ( efalizumab)
  14. 14. Fully human antibodies  No remaining element of animal origin  Suffix --- umab (adalimumab)
  15. 15. Murine
  16. 16. Chimeric antibodies antibodies that are approximately 65% human
  17. 17. Humanized antibodies
  18. 18. Fully human antibodies
  19. 19. BAgentiologiCocnstrusct 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)
  20. 20. Tumor necrosis factor antagonists  TNF is a proinflammatory cytokine produced by a wide variety of cell types  Soluble cytokine (sTNF) and (transmembrane tmTNF).  Both sTNF and tmTNF are biologically active  TNF receptor 1 (TNFR1, p55) and TNF receptor 2 (TNFR2, p75).
  21. 21. Tumor necrosis factor antagonists Two 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
  22. 22. Act by  Blocking TNFR-mediated mechanisms and  Inducing tmTNF (reverse-signalling) events.  Etanercept also binds members of the lymphotoxin family [LTα3 (also known as TNF-β) and LTα2β1]
  23. 23. 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.
  24. 24. 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
  25. 25. 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:
  26. 26. 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
  27. 27. 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.
  28. 28. 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.
  29. 29. 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.
  30. 30. 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
  31. 31. Pretreatment Screening 1. Complete blood count, 2. Assessment of hepatic and renal function, 3. Tests for hepatitis B and C, 4. Urinalysis 5. Chest radiograph 6. A purified protein derivative (PPD) test for TB 7. Pregnancy test 8. ANA, anti-DNA, or antiphospholipid antibodies 9. Rule out occult malignancy
  32. 32. Contraindications  Should never be given a live vaccine, only killed vaccines.  Pulmonary malignancy or significant CHF
  33. 33. Side 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
  34. 34. 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 pustular psoriasis, limited evidence indicates that infliximab is effective and may be considered first choice amongst the biologics
  35. 35.  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.