Immunopharmacology
Drug Classes
1. Immunosuppressant
a. Glucocorticoids
i. Agents
1. Corticosteroids
a. Prednisolone – oral
b. Methylprednisolone – parenteral
b. Interleukin Synthesis Inhibitors
i. Agents
1. Calcineurin Inhibitors
a. Cyclosporine
b. Tacrolimus
2. mTOR (Mammalian Target of Rapamycin) Inhibitor
a. Sirolimus/Rapamune
c. Immunosuppressive Antiproliferative/Antimetabolite
Agents
i. Agents
1. Antimetabolites
a. Purine Analogue
i. Azathioprine/6-Mercaptopurine
2. Antiproliferative/Alkylating Agent
a. Nitrogen Mustard
i. Cyclophosphamide
3. Inosine Monophosphate (IMP) Dehydrogenase Inhibitor
a. Mycophenolate Mofetil
d. Immunosuppressive Antibodies
i. Murine (Rat) Monoclonal Antibody
1. Muromonab-CD3/OKT3
ii. Antilymphocyte Globulin (ALG)
iii. Antithymocyte Globulin Rabbit (ATG)
iv. IL-2 Receptor Antibodies
1. Basiliximab
2. Daclizumab
v. Miscellaneous Antibodies
1. Rh(D) Immune Gobuline
a. Given to Rh (-) mother delivering Rh (+) child
2. Rh0 (D) Immune Globulin
a. Given to suppress antibody production by Rh(-)
mother after delivering Rh(+) baby
b. Given within 72 hours after birth of Rh(+) baby
i. Prevent hemolytic anemia in future pregnancy
3. Abciximab
a. Binds to surface receptor of activated platelets
b. Given after Coronary Angioplasty to prevent
restenosis
4. Rituximab
a. Attacks CD20 on
i. Pre-B lymphocytes
ii. Mature B lymphocytes
2. Immunostimulants
a. Thymic Hormones
i. Improve primary immune deficiency in children
b. Synthetic Stimulant
i. Levamisole
1. Stimulates
a. Phagocytosis
b. Production of T cells cytokines
c. Adjuvant of Bacterial Origin
i. Bacillus Calmette-Guerin (BCG)
1. Viable strain of Mycobacterium bovis
2. Enhances macrophages activity
3. Given in
a. Cancer of the bladder
b. Melanomas
3. Immunomodulators
a. Immunostimulatory Cytokines
i. Interleukins
1. IL-2
a. Enhance antitumor activity of
i. Natural Killer Cell
ii. Cytotoxic T cell
ii. Colony Stimulating Factor
1. Granulocyte Colony Stimulating Factor (G-CSF)
a. Given in neutropenia
2. Granulocyte Macrophage Colony Stimulating Factor
(GM-CSF)
a. Given to bone marrow transplant patients
iii. Interferons
1. Interferon Alpha – produce by Leukocytes
a. Antiviral
b. Antiproliferative
c. Given in
i. Malignant melanoma
ii. Renal cell carcinoma
iii. Hairy cell leukemia
iv. Kaposi’s sarcoma
2. Interferon Beta – produce by Fibroblast
a. Antiviral
b. Antiproliferative
c. Given in
i. Relapsing type Multiple Sclerosis
3. Interferon Gamma – produce by Lymphocytes
a. Stimulates
i. Natural Killer Cells
ii. Macrophages
b. Given in
i. Chronic Granulomatous Disease
b. Cytokine Inhibitors
i. TNF Inhibitors
1. TNF Receptor Analogue
a. Etanercept
i. Use in Rheumatoid Arthritis
2. Chimeric Human anti-TNF Monoclonal Antibody
a. Infliximab
3. Human IL-1 Receptor Antagonist
a. Anakinra
Agents
1. Prednisolone – oral
2. Methylprednisolone – parenteral
Immunosuppressants
Glucocorticoid
Mechanism of Action
1. Inhibits Phospholipase A2 in which involve in the
formation of Arachidonic Acid; precursor of
a. Cyclooxygenase, in return will form
i. Prostaglandin
b. Lypooxygenase, in return will from
i. Leukotriene
2. Inhibits Glucocorticoid Response Element (GRE) of
DNA
Consequences to that
1. Affects macrphages activity by
a. ↓macrophage phagocytic activity
b. Inhibit function in antigen recognition
2. Depress complement pathway
3. ↓proliferation of lymphocytes (T cells)
4. Inhibit cytotoxic activity of Cytotoxic T cells
5. ↑ in T suppressor
a. Differentiation
b. Maturation
6. Disrupts cooperation between B cell and T cell
Adverse Effects
Due to high dose usage of
steroid
1. Supression of HypothalmicPituitary Adrenal Axis (HPA)
function
2. Osteoporosis
3. Hypertension
4. Weight gain
5. Hyperglyceamia
6. Euphoric personality
changes
7. Cataract
Agents
Cyclosporine
1. Can be given
a. Alone
b. Combination with
i. Azathioprine
ii. Prednisolone
iii. Other anticancer
drugs
Drug Drug Interaction
 Cyclosporine alters
the activity of CYP450
enzymes through
o Inducing
o Inhibiting
Tacrolimus


Structure similar to
that of Macrolide
o Erythromycin
Used concomitantly
with Prednisolone
Interleukin Synthesis Inhibitors
Calcineurin Inhibitors
Pharmacokinetics
Mechanism of Action
Adverse Effects
Absorption
 Variable degree of oral
absorption
 Can be given orally
Distribution
 Lypophilic cyclic peptide
 Readily distributed across
body compartment
Metabolism
 Extensively undergoes
hepatic metabolism
Excretion
 Billiary excretion
1. Calcineurin is a Phosphatase enzyme required to
Dephosphorylate cytosolic Nuclear Factor of Activated
T cells (NFATc)
a. Dephosphorylation of NFATc will allow it to enter
nucleus
b. This will then a promote reaction that requires for
cytokine synthesis
2. Cyclosporine will bind to a binding protein called
Immunophilin
a. Cyclosporine-Immunophilin complex will further
bind to Calcineurin forming another complex of
Cyclosporine-Calcineurin complex
b. This complex is dysfunctional which therefore
inhibits
i. Transcription of IL-2 gene
ii. Cytokine expression
1. IL-3
2. Interferon Gamma
1.
2.
3.
4.
Nephrotoxicity
Hepatotoxicity
Hirsutism
Neurotoxicity
Absorption
 Readilly absorp orally
 Given
o Orally
o Parenterally
Distribution
 Primarilly distributed in the
Erythrocytes
 99% bound to plasma protein
o Albumin
o α acid glycoprotein
 Extensively distributed to other
tissues
 Passes breast milk
Metabolism
 Undergoes CYP450 metabolism
Excretion
 Billiary excretion – primary
 Renal – small fraction
1. Cyclosporine will bind to a binding protein
called FK-Binding Protein (FKBP-12)
a. Tacrolimus – FKBP-12 complex will further
bind to Calcineurin forming another
complex of Tacrolimus-Calcineurin
complex
b. This complex is dysfunctional which
therefore inhibits
i. Transcription of IL-2 gene
ii. Cytokine expression
1. IL-3
2. Interferon Gamma
1. Nephrotoxicity
2. Nuerotoxicity
a. Tremor
b. Headache
c. Motor
disturbances
d. Seizures
3. ↑risk of lymphomas
4. Hypersensitivity
reaction
5. Hyperglyceamia
6. GI upsets
7. Hypertension
Agents
Sirolimus/Rapamune

Structurally similar to
that of Macrolide
o Erythromycin
Properties of Sirolimus
1. Selective blockade of
cytokine signal
transduction
2. Inhibitor of T cells
a. Division
b. Proliferation
3. Potent and effective
immunosuppressor
4. Potent synergy with
other
immunosuppressor
Interleukin Synthesis Inhibitors
mTOR (Mammalian Target of Rapamycin) Inhibitor
Pharmacokinetics
Mechanism of Action
Absorption
 Low absorption after
oral admin
Distribution
 Widely distributed
across body
compartments
 92% bound to plasma
protein
o Albumin
 Long half life of 60
hours
Metabolism
 Undergoes CYP450
metabolism
Excretion
 Renal clearence
1. mTOR is a protein kinase
2. It plays an important role in IL-2 receptor
responses
3. When IL-2 binds to its receptor on the T
cells, mTOR will be activated
a. mTOR will initiate a cascade effect
including Cyclin Dependent Kinases
which will then promote T cell
i. Proliferation
ii. Differentiation
4. Sirolimus will binds to Immunophilin and
this Sirolimus-Immunophilin complex will
inhibit the mTOR actvitiy resulting in
a. IL-2 dependent cell cycle
b. Harrasting the cell progression from
G1-S phase
Consequences to that
 ↓lymphocytes proliferation and
differentiation
 Inhibits antibody production
 ↓mesenchymal cell proliferation
o Vascular smooth muscle cells
o Endothelial cells
o Fibroblasts
Adverse Effects
1.
2.
3.
4.
Thrombocytopenia
Hyperlipidaemia
Rash
↑possibility to develop renal
failure in combination with
Cyclosporine
Agents
Mycophenolate Mofetil
Immunosuppressive Antiproliferative/Antimetabolite Agents
Inosine Monophosphate (IMP) Dehydrogenase Inhibitor
Pharmacokinetics
Mechanism of Action
Derivative of Mycophenolic
Acid
 Derived from a fungus
o Penicillium stoloniferum

Agents
Muromonab-CD3 (OKT3)



Produced through Hybridoma
technology (hybridization
technology)
Directed against CD3 of T cells
As it is originated from rat,
body tends to produce antiMuromonab antibodies
against it.
Absorption
 Readily absorb after oral
admin
Distribution
 May displace drug from
plasma proteins
Metabolism
 Undergoes CYP450
metabolism
Excretion
 Renal clearence
1. Inhibits the Inosine
Monophosphate (IMP)
Dehydrogenase enzyme
2. This enzyme involves in the de
novo synthesis of Purine
3. Inhibition of this will lead to
a. Suppressing proliferation of
i. T cells
ii. B cells
b. Supressing macrophages
activity
Immunosuppressive Antibodies
Murine (Rat) Monoclonal Antibody
Pharmacokinetics
Mechanism of Action
Absorption
1. Muromonab will bind to
 Can not be absorped orally
CD3 protein on the T cells
 Given only through IV
2. This will inhibit lymphocyte
admin
function as access to
Metabolism
antigen recogition site is
 Undergoes extensive
blocked
CYP450 metabolism
3. Subsequently depletes
Excretion
circulating T cells, thus
 Billiary excretion
reducing T cells
involvement in immune
response
Adverse Effects
1. Diarrhea
2. Leukopenia
3. Cytomegalovirus
infection
4. ↑incidence of
lymphoma and other
malignancies
Adverse Effects
1. Hypersensitivity reactions
a. Chills
b. Fever
c. Thrombocytopenia
d. Erythema
2. Anaphylactic shock
3. CNS effects
a. Seizures
b. Encephalopathy
Due to its extensive side
effects (considering its foreign
in nature), it is seldom being
used compared to Basiliximab
and Daclizumab
Immunosuppressive Antibodies
Thymoglobulin
Mechanism of Action
Agents
Antithymocyte Globulin Rabbit 1. Antibody binds to surface of the circulating T cells


Antibodies derived from rabbit
Due to its foreigness, body
produces anti-ATG antibodies to
fight against it.
Agents
Basiliximab (Simulect®)



Chimeric murine monoclonal
antibodies
Given only through IV
Serum half life of about 7 days
Daclizumab (Zenapax®)


Humanized monoclonal
antibodies
Fromed by spilicing the murine
complimentary portions of light
and heavy chain
o Fused it with Human Fab
framework
o Then associates with Human
IgG Fc segment
2. This will then leads to
a. Complement mediated destruction
b. Antibody depedent cytotoxicity
c. Apoptosis
d. Opsonisation
3. Antibody bounded T cells will be destroyed in the
a. Liver
b. Spleen
IL-2 Receptor Antibodies
Mechanism of Action
1. Binds to IL-2 receptor alpha subunit on activated T cell
2. This will then block further activation of other T cells leading
to inhibition of clonal expansion of T cells
Advantages of Chimeric Vs Humanized
1. ↓immunogenecity (foreigness) without sacrificing affinity
2. Allow complement fixation to occur by using Human Fc
region instead of murine
3. Humanization of Fab region my reduce affinity as it wont
attack self antigen
a. Baciliximab has ↑affinity to IL-2 receptor compared to
Daclizumab
Adverse Effects
1.
2.
3.
4.
Chills
Fever
Leukopenia
Thrombocytopenia
Adverse Effects
1. GIT upsets
2. No antibodies production
against Basiliximab
3. Very well tolerated