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Biologic therapy for psoriasis

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Ahmed Amer
Ahmed Amer

This document discusses biologic agents used to treat psoriasis. It defines biologics as proteins extracted from tissues or synthesized through recombinant DNA techniques that mimic or block naturally occurring proteins. Early biologics included insulin, hematopoietic growth factors, and monoclonal antibodies used to prevent transplant rejection. Current biologics for psoriasis include TNF-α inhibitors (etanercept, adalimumab, infliximab), which bind and neutralize tumor necrosis factor; and ustekinumab, which targets the p40 subunit of interleukin-12 and -23. The document provides details on the mechanisms, dosing, and side effects of these biologic therapies.

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Dr. Ahmed Abdelmoaty MD Assistant Prof. Dermatology and Venerology Al- Azhar University Cairo Egypt
Definition ï‚— 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. ï‚— Molecules produced by living cells, which either mimic or block naturally occurring proteins, such as soluble receptors, antibodies, or fusion proteins.
Early used biologics ï‚— Insulin , a protein first extracted from pigs and now made as recombinant human insulin. ï‚— Hematopoietic support (eg, erythropoietin, granulocyte, and platelet growth factors). ï‚— 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 ï‚— Are molecules that are either exact replicas of normal human proteins or fragments thereof have specific physiological effects. ï‚— These drugs function by interacting with normal cellular receptors to induce their effects. ï‚— 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 ï‚— Are proteins that specifically bind to proteins on cell surfaces in the circulation or tissue. ï‚— This interaction alters activity of the target protein. ï‚— Monoclonal antibody inhibits effects of the protein, thus altering the course of disease.
Fusion Proteins ï‚— Are molecules that combine sections of different proteins. The first combines a human protein with a toxin. ï‚— Human protein binds to a cell and causes the entire complex to be internalized. ï‚— Once inside the cell, toxin is released, thereby killing the cell.
The second is similar to humanized monoclonal antibodies.
Biologic production ï‚— Injecting antigen into mice ï‚— Respond producing antibodies from B Cell ï‚— Which are identical ----- monoclonlity ï‚— In vitro propagation via ï‚— 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 ï‚— Murine ï‚— Antibodies of animal origin --- antigenic ï‚— 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 antibodies Only preserve the direct antigen binding site – CDRs – complementary determining region Suffix --- zumab ( efalizumab)
Fully human antibodies ï‚— No remaining element of animal origin ï‚— Suffix --- umab (adalimumab)
Murine
Chimeric antibodies antibodies that are approximately 65% human
Humanized antibodies
Fully human antibodies
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)
Tumor necrosis factor antagonists ï‚— TNF is a proinflammatory cytokine produced by a wide variety of cell types ï‚— Soluble cytokine (sTNF) and (transmembrane tmTNF). ï‚— Both sTNF and tmTNF are biologically active ï‚— TNF receptor 1 (TNFR1, p55) and TNF receptor 2 (TNFR2, p75).
Tumor necrosis factor antagonists Two groups of biologic agents that target TNF: ï‚— Monoclonal antibodies (adalimumab and infliximab), and ï‚— sTNF receptors (etanercept). ï‚— 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 lymphotoxin family [LTα3 (also known as TNF-β) and LTα2β1]
Etanercept ï‚— 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 ï‚— Onset of action is slower than that seen with the monoclonal antibodies ï‚— Improvement after 4 and 8 weeks after initiation of treatment. ï‚— Response is dose related ï‚— Continuous therapy provides better disease control and if treatment is stopped, disease relapses slowly:
Adalimumab ï‚— Highly effective treatment for chronic plaque psoriasis ï‚— Onset of action is rapid ï‚— Significant improvement within 2 weeks ï‚— Response is dose related ï‚— 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 ï‚— Patients must have severe disease as defined in (a) and fulfil one of the clinical categories outlined in (b): ï‚— (a) Severe disease is defined as a ï‚— PASI score of 10 or more ï‚— BSA of 10% or greater where PASI is not applicable) ï‚— DLQI > 10. ï‚— Disease should have been ï‚— Severe for 6 months, ï‚— Resistant to treatment and ï‚— The patient should be a candidate for systemic therapy.
Eligibility criteria (b) fulfill at least one of the following clinical categories ï‚— (i) at higher risk of developing drug-related toxicity ï‚— (ii) intolerant to or cannot receive standard systemic therapy ï‚— (iii) become unresponsive to standard therapy ï‚— (iv) have disease that is only controlled by repeated inpatient management ï‚— (v) have significant, coexistent, unrelated comorbidity ï‚— (vi) have severe, unstable, life-threatening disease (erythrodermic or pustular psoriasis) ï‚— (vii) have psoriatic arthritis eligible for treatment with anti- TNF agents, in association with skin disease
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
Contraindications ï‚— Should never be given a live vaccine, only killed vaccines. ï‚— Pulmonary malignancy or significant CHF
Side effects ï‚— Injection-site reaction (ISR) ï‚— Infusion reactions are ameliorated by peri- infusional corticosteroids. ï‚— Neutropenia, anemia, thrombocytopenia, and pancytopenia, ï‚— Development of a lupus-like syndrome ï‚— Development of antibodies ï‚— Rare instances of hepatotoxicity
Recommendation ï‚— For stable disease, particularly if not too severe (e.g. PASI >10 but <20), etanercept or adalimumab are often first options. ï‚— For patients requiring rapid disease control, adalimumab or infliximab may be considered first choice due to early onset of action. ï‚— For patients with unstable or generalized pustular psoriasis, 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.

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Biologic therapy for psoriasis

  • 1. Dr. Ahmed Abdelmoaty MD Assistant Prof. Dermatology and Venerology Al- Azhar University Cairo Egypt
  • 2. Definition ï‚— 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. ï‚— Molecules produced by living cells, which either mimic or block naturally occurring proteins, such as soluble receptors, antibodies, or fusion proteins.
  • 3. Early used biologics ï‚— Insulin , a protein first extracted from pigs and now made as recombinant human insulin. ï‚— Hematopoietic support (eg, erythropoietin, granulocyte, and platelet growth factors). ï‚— In solid organ transplantation, in which monoclonal antibodies designed to inhibit rejection.
  • 4. Types of biologic molecules  Recombinant human  Cytokines or  Growth factors  Monoclonal antibodies, and  Fusion proteins
  • 5. Recombinant Human Proteins ï‚— Are molecules that are either exact replicas of normal human proteins or fragments thereof have specific physiological effects. ï‚— These drugs function by interacting with normal cellular receptors to induce their effects. ï‚— 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. Monoclonal Antibodies ï‚— Are proteins that specifically bind to proteins on cell surfaces in the circulation or tissue. ï‚— This interaction alters activity of the target protein. ï‚— Monoclonal antibody inhibits effects of the protein, thus altering the course of disease.
  • 7. Fusion Proteins ï‚— Are molecules that combine sections of different proteins. The first combines a human protein with a toxin. ï‚— Human protein binds to a cell and causes the entire complex to be internalized. ï‚— Once inside the cell, toxin is released, thereby killing the cell.
  • 8. The second is similar to humanized monoclonal antibodies.
  • 9. Biologic production ï‚— Injecting antigen into mice ï‚— Respond producing antibodies from B Cell ï‚— Which are identical ----- monoclonlity ï‚— In vitro propagation via ï‚— Fusion with immortal tumor cell ( myeloma cell) ---- hybridoma cell
  • 10. Biologic production ï‚— This process is slow --- resulting in mixture containing --- ï‚— a- Hybridoma cell --- needed ï‚— B- B cell --- die spontaneously ï‚— 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. ï‚— Hybridma cell (antibodies + tumor cell) of animal origin ---- antigenic
  • 11. Final ï‚— Murine ï‚— Antibodies of animal origin --- antigenic ï‚— To reduce this antigencity ---- human part to be replaced ----- resulting in
  • 12. Chimeric antibodies ï‚— Comprise constent portion of human antibodies, ï‚— Only variable region are of animal origin. ï‚— Suffix – ximab ( infliximab)
  • 13. Humanized antibodies Only preserve the direct antigen binding site – CDRs – complementary determining region Suffix --- zumab ( efalizumab)
  • 14. Fully human antibodies ï‚— No remaining element of animal origin ï‚— Suffix --- umab (adalimumab)
  • 16. Chimeric antibodies antibodies that are approximately 65% human
  • 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. Tumor necrosis factor antagonists ï‚— TNF is a proinflammatory cytokine produced by a wide variety of cell types ï‚— Soluble cytokine (sTNF) and (transmembrane tmTNF). ï‚— Both sTNF and tmTNF are biologically active ï‚— TNF receptor 1 (TNFR1, p55) and TNF receptor 2 (TNFR2, p75).
  • 21. Tumor necrosis factor antagonists Two groups of biologic agents that target TNF: ï‚— Monoclonal antibodies (adalimumab and infliximab), and ï‚— sTNF receptors (etanercept). ï‚— All three agents specifically bind both soluble and transmembrane forms of TNF
  • 22. Act by ï‚— Blocking TNFR-mediated mechanisms and ï‚— Inducing tmTNF (reverse-signalling) events. ï‚— Etanercept also binds members of the lymphotoxin family [LTα3 (also known as TNF-β) and LTα2β1]
  • 23. Etanercept ï‚— 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. Etanercept ï‚— Target TNF- α ï‚— Type fully human fusion protein ï‚— Mode of action block of TNF- α ï‚— Dose 2/ 25 or 1/ 50 mg/ week subcut for ---- ï‚— PASI 75 by 12 weeks
  • 25. Etanercept ï‚— Onset of action is slower than that seen with the monoclonal antibodies ï‚— Improvement after 4 and 8 weeks after initiation of treatment. ï‚— Response is dose related ï‚— Continuous therapy provides better disease control and if treatment is stopped, disease relapses slowly:
  • 26. Adalimumab ï‚— Highly effective treatment for chronic plaque psoriasis ï‚— Onset of action is rapid ï‚— Significant improvement within 2 weeks ï‚— Response is dose related ï‚— PASI 75 at week 12
  • 27. Adalimumab ï‚— Type fully human monoclonal antibody ï‚— Dose 80 mg subcutaneously at week 0. 40 mg at week 1, and then every other week ï‚— Target TNF α ï‚— Mode of action neutralizes TNF α ï‚— Anti-adalimumab antibodies develop in 8.4% of patients.
  • 28. Infliximab ï‚— Type chimeric monoclonal antibody ï‚— Target TNF-α ï‚— Mode of action TNF inhibition which leads to a decreased amount of interleukins (IL-1, IL-6) released from inflammatory cells, ï‚— Dose IV 3-5 mg /kg at week 0, 2, 6.
  • 29. Eligibility criteria ï‚— Patients must have severe disease as defined in (a) and fulfil one of the clinical categories outlined in (b): ï‚— (a) Severe disease is defined as a ï‚— PASI score of 10 or more ï‚— BSA of 10% or greater where PASI is not applicable) ï‚— DLQI > 10. ï‚— Disease should have been ï‚— Severe for 6 months, ï‚— Resistant to treatment and ï‚— The patient should be a candidate for systemic therapy.
  • 30. Eligibility criteria (b) fulfill at least one of the following clinical categories ï‚— (i) at higher risk of developing drug-related toxicity ï‚— (ii) intolerant to or cannot receive standard systemic therapy ï‚— (iii) become unresponsive to standard therapy ï‚— (iv) have disease that is only controlled by repeated inpatient management ï‚— (v) have significant, coexistent, unrelated comorbidity ï‚— (vi) have severe, unstable, life-threatening disease (erythrodermic or pustular psoriasis) ï‚— (vii) have psoriatic arthritis eligible for treatment with anti- TNF agents, in association with skin disease
  • 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. Contraindications ï‚— Should never be given a live vaccine, only killed vaccines. ï‚— Pulmonary malignancy or significant CHF
  • 33. Side effects ï‚— Injection-site reaction (ISR) ï‚— Infusion reactions are ameliorated by peri- infusional corticosteroids. ï‚— Neutropenia, anemia, thrombocytopenia, and pancytopenia, ï‚— Development of a lupus-like syndrome ï‚— Development of antibodies ï‚— Rare instances of hepatotoxicity
  • 34. Recommendation ï‚— For stable disease, particularly if not too severe (e.g. PASI >10 but <20), etanercept or adalimumab are often first options. ï‚— For patients requiring rapid disease control, adalimumab or infliximab may be considered first choice due to early onset of action. ï‚— 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. ï‚— At present, there are five biological agents licensed for the treatment of psoriasis vulgaris. ï‚— (i) etanercept, a fully human soluble p75 TNF-α receptor fusion protein; ï‚— (ii) infliximab, a chimeric human-immune antibody to TNF-α; ï‚— (iii) adalimumab, a fully human recombinant antibody to TNF-α; ï‚— (iv) ustekinumab, a fully human recombinant antibody to the p40 component of IL-12/IL-23: ï‚— (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.