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.