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.

1. Dr. Ahmed Abdelmoaty MD
Assistant Prof. Dermatology and Venerology
Al- Azhar University
Cairo Egypt

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. 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. Types of biologic molecules
 Recombinant human
 Cytokines or
 Growth factors
 Monoclonal antibodies, and
 Fusion proteins

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. 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. 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. The second is similar to humanized monoclonal
antibodies.

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. 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. Final
 Murine
 Antibodies of animal
origin --- antigenic
 To reduce this
antigencity ---- human
part to be replaced -----
resulting in

12. Chimeric antibodies
 Comprise constent
portion of human
antibodies,
 Only variable region are
of animal origin.
 Suffix – ximab (
infliximab)

13. Humanized antibodies
Only preserve the direct
antigen binding site –
CDRs – complementary
determining region
Suffix --- zumab (
efalizumab)

14. Fully human antibodies
 No remaining element
of animal origin
 Suffix --- umab
(adalimumab)

15. Murine

16. Chimeric antibodies
antibodies that are approximately 65%
human

17. Humanized antibodies

18. Fully human antibodies

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
 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
 Should never be given a live vaccine, only killed
vaccines.
 Pulmonary malignancy or significant CHF

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. 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.  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.