Transcript IMMUNOPHARMACOLOGY

‫اعداد الصيدالني‬
‫علي محسن هاشم‬
IMMUNOPHARMACOLOGY
Major Steps in Immune
Responses
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1- Antigen recognition
2- IL-1 production
3- IL-2 and other cytokine expression
4- lymphocyte proliferation &
differentiation
MAJOR STEPS IN IMMUNE RESPONSES
Antigen
IL-2
CD8 T cell
1
cytotoxic
T cells
4
2
3
IL-1
IL-2
antigen
presenting
cell
(macrophage,
dendritic cell)
CD4
T helper
cell
primed
CD4
T helper
cell
4
IL-2
B cell
plasma
cells
SITES OF ACTION OF
IMMUNOSUPPRESSIVE DRUGS
Antigen
1
X
A
IL-2
CD8 T cell4
X
E
C
X
2
B IL-1
antigen
presenting
cell
X
D
X
3
IL-2
CD4
T helper
cell
D
primed
CD4
T helper
cell
4
X
cytokines
cytotoxic
T cells
plasma
cells
Inhibitors of Immune Response
(site of action)
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A- Immune Globulin (antigen recognition)
B- Corticosteroids (IL-1 production, cell
proliferation)
C- OKT3 ,ATG (T cell receptors/surface prot.)
D- Cyclosporine, Tacrolimus, (1L-2 gene expr.),
Sirolimus (IL-2 signal transduction)
E- Rapamycin, Mycophenolate (T cell prolif.),
Azathioprine,Cyclophosphamide (all cell prolif.)
Major Classes of
Immunosuppressant Drugs
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Glucocorticoids
Calcineurin inhibitors
Cytotoxic agents: include azathioprine ,
cyclophosphamide ,leflunomide ,hydroxychloroquine,
other cytotoxic agents vincristine, MTX,cytarabine
_
Biologics (Antibodies)
Clinical uses of immunosuppressive agents
-Autoimmune disease:
Idiopathic thrombocytopenic purpura (ITP):Prednisone, vincristine,
occasionally cyclophosphamide, mercaptopurine, or
azathioprine; commonly high-dose gamma globulin
Autoimmune hemolytic anemia : Prednisone, cyclophosphamide,
chlorambucil, mercaptopurine, azathioprine, high-dose
gamma globulin .
Acute glomerulonephritis: Prednisone,mercaptopurine ,
cyclophosphamide .
Acquired factor XIII antibodies :Cyclophosphamide plus factor XIII
Autoreactive tissue disorders (autoimmune diseases including
systemic lupus erythematosus, rheumatoid arthritis,
scleroderma, dermatomyositis, mixed tissue disorder,
multiple sclerosis, Wegener's granulomatosis, chronic
active hepatitis, lipoid nephrosis, inflammatory bowel
disease.): Prednisone, cyclophosphamide, methotrexate,
interferon-α and -β, azathioprine, cyclosporine, infliximab,
etanercept, adalimumab .
-Isoimmune disease(Hemolytic disease of the newborn):Rho(D)
immune globulin .
-Organ transplantation
Renal & heart : Cyclosporine, azathioprine, prednisone, ALG,
OKT3, tacrolimus, basiliximab, daclizumab, sirolimus .
Liver :Cyclosporine, prednisone, azathioprine, tacrolimus,
sirolimus
bone marrow:Cyclosporine, cyclophosphamide, prednisone,
methotrexate, ALG .
-Prevention of cell proliferation (Coronary stents) : sirolimus .
Cyclosporine
(Neoral, Gengraf)
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Structure
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lipophilic cyclic peptide
Mechanism
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inhibits transcription of IL-2 gene plus other
lymphokine genes (IL-3, gamma interferon)
site of action is a binding protein that inhibits
calcineurin (a phosphatase) which is necessary for
the activation of a T-cell-specific transcription factor
Cyclosporine (Neoral)
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Pharmacokinetics
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variable, incomplete oral absorption
extensive hepatic metabolism, excreted in bile
used alone or in combination with prednisone and
azathioprine (or other antineoplastic drugs)
Adverse Effects
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nephrotoxicity, hepatotoxicity, hirsutism,HTN ,
hyperglycemia, hyperK,convulsion,gum hypertrophy.
Drug interactions due to induction and inhibition of
hepatic cytochrome P450
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Cyclosporine may be used alone or in combination
with other immunosuppressants, particularly
glucocorticoids.
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Used successfully as the sole immunosuppressant
for cadaveric transplants of the kidney, pancreas,
and liver, and cardiac transplants as well.
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In combination with methotrexate, cyclosporine is a
standard prophylactic regimen to prevent graft–
versus-host disease .
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Cyclosporine has also proved useful in a variety of
autoimmune disorders, including uveitis,
rheumatoid arthritis, psoriasis, and asthma.
Tacrolimus (FK506)
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Structure
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macrolide (structure like erythromycin)
Mechanism
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similiar to cyclosporine except binds to different
protein that inhibits calcineurin (a phosphatase
enzyme involved in gene transcription of IL-2,
gamma interferon and other cytokines)
Tacrolimus(FK506)
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Bioavailability
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given by IV infusion or orally
used concomitantly with corticosteroids
Adverse Effects
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nephrotoxicity, increased risk of lymphomas,
hypersensitivity, hyperglycemia, GI
complaints, hypertension, neurotoxicity
(tremor, headache, motor disturbances,
seizures)
Sirolimus (Rapamune)
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Structure
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macrolide similiar to tacrolimus
Mechanism
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binds to immunophilin protein that binds to a key
regulatory kinase required for T cell activation
(new unique mechanism to inhibit T lymphocyte
activation by IL-2)
different site of action than cyclosporine and
tacrolimus
Sirolimus (Rapamune)
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Inhibits mammalian target of rapamycin
(mTOR)
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mTOR is a protein kinase that plays pivotal role in
IL-2 receptor responses
IL-2 binds to its receptor on T cells and leads to
mTOR activation
mTOR initiates cascade of events (including cyclin
dependent kinases) that promote T lymphocyte
proliferation and differentiation
Inhibition of mTOR blocks IL-2 dependent cell-cycle
progression at G1→S phase transition
Consequences of TOR Action
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Lymphocyte cell proliferation &
differentiation
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T cells
B cells
Antibody production
Mesenchymal cell proliferation
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Vascular smooth muscle cells
Endothelial cells
Fibroblasts
Properties of TOR Inhibitors
such as Sirolimus (Rapamune)
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Selective blockade of cytokine signal
transduction
Inhibition of T cell division and proliferation
Potent and effective immunosuppression
Potential for synergy with other
immunosuppressants
Sirolimus (Rapamune)
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other theoretical actions include
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blockade of B cell Ig synthesis
inhibition of antibody-dependent cellular toxicity
inhibition of lymphocyte activated killer cells
inhibition of natural killer cells
inhibition of immune and nonimmune cell
proliferation (via inhibition of growth factor
signaling) (may explain antitumor actions)
Sirolimus (Rapamune)
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Bioavailability
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low oral absorption
hepatic metabolism by CYP4503A4 (drug
interactions may occur)
long half-life (60 hours)
Adverse Effects
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thrombocytopenia, hyperlipidemia, rash
lacks direct end organ toxicity but increased
incidence impaired renal function when combined
with cyclosporine
Mycophenolate Mofetil (CellCept)
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Structure
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derivative of mycophenolic acid
Mechanism
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inhibits inosine monophosphate dehydrogenase
involved in de novo synthesis of purines
selectively suppressess T- and B-cell proliferation
Also suppresses some macrophage functions (may
explain anti-inflammatory actions)
Mycophenolate Mofetil
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Pharmacokinetics
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oral absorption and hepatic metabolism
Adverse Effects
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diarrhea, leukopenia and CMV infections
increased incidence of lymphomas and other
malignancies
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Thalidomide inhibits TNFα,reduces
phagocytosis by neutrophils,↑production of IL10,alters adhesion mol. expression &enhances
cell mediated immunity via interaction with T
cell
Indications for leprosy and multiple myeloma
Side effects: teratogenicity, neuropathy,
fatigue, constipation, deep vein thrombosis
Thalidomide analogs have been obtained based
on its antiangiogenic and immunomodulatory
properties.(Immunomodulatory derivatives of
thalidomide are termed IMiDs.)
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Lenalidomide (Revlimid) - as the first
commercially derivative.It is only available in a
restricted distribution to avoid its use during
preg.
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CC-4047 (Actimid) is another IMiD that is being
investigated for the treatment of myelodysplastic
syndrome, myeloma, and prostate cancer.
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Another group of thalidomide analogs, selective
cytokine inhibitory drugs (SelCIDs), are
phosphodiesterase type 4 inhibitors with potent
anti-TNF- activity but no T-cell co-stimulatory
activity. Several SelCIDs are currently under
investigation for clinical use.
Corticosteroid
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Prednisone used most often orally
Methylprednisolone used parenterally
Numerous available preparations
Corticosteroid action
Inhibition of IL-1 and TNF gene expression and synthesis
Decreased activation of T lymphocytes by decreasing IL-1 release
Decreased neutrophil functions esp chemotaxis
Decreased antibody production (high doses)
Decreased release of kinins and proinflammatory eicosanoids
(prostaglandins and leukotrienes)
Corticosteroid Immunosuppression
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Decreased cell-mediated immune reactions that
mediate rejection of organ transplants
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Mechanisms:
_ decreased activation of T lymphocytes by
inhibition of IL-1 synthesis by macrophages
_ decreased lymphocyte mobilization out of
lymphoid organs (lymphopenia)
New Immunosuppressants
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Mizoribine (investigational)
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Brequinar (investigational)
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Inhibitor of de novo pyrimidine synthesis
15-Deoxyspergualin (investigational)
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Inhibitor of purine nucleotide synthesis
Antimonocytic that decreases MHC antigen
expression
Pimecrolimus (Elidel)
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Calcineurin inhibitor like cyclosporine
Approved for topical treatment of eczema
New Class of Immunosuppressant
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FTY720 (prodrug: requires phosphorylation)
Sphingosine 1-phosphate receptor (S1P-R)
agonist
Reduces recirculation of lymphocytes from
lymphatic system to the blood
Lymphocyte homing action which reversibly
sequesters host lymphocytes into lymph nodes
Useful in combination therapy but not alone
Toxicity: lymphopenia, decreased heart rate
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Biologics(antibodies):-
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Antilymphocyte & Antithymocyte
Antibodies
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Immune Globulin Intravenous (IGIV)
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RhO(D) Immune Globulin Micro-Dose
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Hyperimmune Immunoglobulins
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Monoclonal Antibodies (MABS)
Antibodies Used for Acute Rejection of Organ Transplants
-Antilymphocyte & Antithymocyte Antibodies
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Antisera directed against lymphocytes. ALG and
antithymocyte globulin (ATG) are now in clinical use in
many medical centers, especially in transplantation
programs. The antiserum is usually obtained by
immunization of large animals such as horses or sheep with
human lymphoid cells.
ALG and ATG are useful for suppressing certain major compartments
(ie, T cells) of the immune system and play a definite role in the
management of solid organ and bone marrow transplantation
-OKT3 (Muromonab-CD3)
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Murine monoclonal antibody to CD3 on T cell & thymocytes
inhibits cytotoxic T killer cell function
opsonizes circulating T lymphocytes and enhances their
removal
used to prevent or reverse acute graft rejection
Antithymocyte Globulin-Rabbit
(Thymoglobulin)
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Rabbit gamma immune globulin
preparation
Composed of antibodies to variety of T
cell markers
Mechanisms
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removal of T cells from circulation
modulation of T cell activation, homing and
cytotoxicity
decreases cytokine induced reactions
Adverse Effects of Antibody Preps
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Hypersensitivity reactions may occur with
nonhuman antibodies resulting in chills, fever,
thrombocytopenia, erythema, pruritis
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Problem with murine MAB OKT3 is formation
of anti-OKT3 antibodies limit its action so only
given by IV infusion for 7-14 days
.
Immune Globulin Intravenous (IGIV)
This immunoglobulin preparation (usually IgG) is prepared from
pools of thousands of healthy donors, and no specific antigen is
the target of the "therapeutic antibody“& have a normalizing
effect upon the patient's immune networks
IGIV in high doses (2 g/kg) has proved effective in a
variety of different conditions ranging from
immunoglobulin deficiencies to autoimmune disorders
to HIV disease to bone marrow transplants
It is used in Kawasaki's disease, reducing systemic
inflammation and preventing coronary artery aneurysms.
it also used in SLE & refractory ITP
Possible mechanisms of action of IGIV include a reduction of T
helper cells, increase of suppressor T cells, decreased
spontaneous immunoglobulin production, Fc receptor blockade,
increased antibody catabolism, and idiotypic-anti-idiotypic
interactions with "pathologic antibodies."
Rho(D) Immune Globulin
_
used to suppress immune response of Rh(neg.) mother after
delivery of Rh (pos.) baby
_ Given within 24-72 hours after birth of Rh(pos.) baby,the
mother's own antibody response to the foreign Rho(D)positive cells is suppressed because the infant's red cells
are cleared from circulation before the mother can generate
a B-cell response against Rho(D),to prevent hemolytic
anemia of the newborn that may occur in subsequent preg.
The usual dose of Rho(D) immune globulin is 2 mL
intramuscularly, containing approximately 300 mcg
anti-Rho(D) IgG.
Adverse reactions are infrequent,local discomfort at the
injection site or, rarely, a slight temperature elevation.
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Rho(D) immune globulin is a concentrated (15%) solution of
human IgG containing a higher titer of antibodies against the
Rho(D) antigen of the red cell.
Hyperimmune Immunoglobulins
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Hyperimmune immunoglobulin preparations are IGIV
preparations made from pools of selected human or
animal donors with high titers of antibodies against
particular agents of interest such as viruses or toxins.
Various hyperimmune IGIVs are available for treatment
of respiratory syncytial virus, cytomegalovirus, varicella
zoster, human herpesvirus 3, hepatitis B virus, rabies,
tetanus, and digoxin overdose.
Intravenous administration of the hyperimmune globulins is a
passive transfer of high titer antibodies that either reduces risk
or reduces the severity of infection
MONOCLONAL ANTIBODYS
NOMENCLATURE
Murine
Chimeric
Rituximab
Muromonab
Daclizumab
Humanized
Monoclonal
Antibody
MONOCLONAL ANTIBODY STRUTURE
Mouse
Chimeric
Human
Humanized
Advantages of Chimeric and
Humanized Antibodies
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Reduce immunogenicity without sacrificing
affinity
Allow complement fixation to occur by using the
human Fc region instead of murine Fc
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Resulting in ADCC and activation of phagocytic
cells
Humanization of Fab fragment may decrease
binding affinity compared to initial murine antibody
Baciliximab has higher affinity for IL-2 receptor
than Daclizumab
Antitumor MABs
1.Alemtuzumab humanized MAB binds to CD52 found on
normal and malignant B and T lymphocytes, NK cells,
monocytes, macrophages, and granuloctes
Alemtuzumab is approved for the treatment of B-cell chronic
lymphocytic leukemia in patients who have been treated with
alkylating agents and have failed fludarabine therapy,it deplete
leukemic and normal cells by direct antibody-dependent lysis
S.E:lymphopenia and neutropenia, anemia, and thrombocytopenia
2. Bevacizumab binds to vascular endothelial growth factor
(VEGF) and inhibits VEGF from binding to its receptor,
especially on endothelial cells. It is an antiangiogenic drug
inhibit growth of blood vessels (angiogenesis) in tumors. It is
approved for first-line treatment of patients with metastatic
colorectal cancer alone or in combination with 5-FU-based
chemotherapy.
S.E: hemorrhage, GI perforations, and wound healing problems

3.Cetuximab chimeric MAB binds to epidermal growth factor
receptor (EGFR) & inhibits tumor cell growth by a variety of
mechanisms, including decreases in kinase activity, matrix
metalloproteinase activity, and growth factor production, and
increased apoptosis. It is indicated for use in patients with
metastatic colorectal cancer whose tumors overexpress EGFR.
4. Gemtuzumab is a humanized MAB specific for CD33
found on leukemic blast cells in 80–90% of patients with acute
myelogenous leukemia (AML).In the clinical formulation,
gemtuzumab is coupled to the cytotoxic agent, ozogamicin,
which is an antibiotic with antitumor activity.Gemtuzumab is
approved for the treatment of patients 60 years and
older in first relapse with CD33 acute myelogenous
leukemia who are not considered candidates for other
types of cytotoxic chemotherapy
S.E: severe myelosuppression,especially neutropenia,others
hepatotoxicity and various hypersensitivity reactions.
5.Rituximab binds to CD20 molecule on normal and malignant
B lymphocytes and is approved for the therapy of patients with
relapsed or refractory low-grade or follicular, B-cell nonHodgkin's lymphoma.
The mechanism of action includes complement-mediated lysis,
antibody-dependent cellular cytotoxicity, and induction of
apoptosis in the malignant lymphoma cells.
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Adverse reactions:
Serious adverse events include cardiac arrest, tumor lysis syndrome
Infections:Hepatitis B reactivation,Other viral infections Progressive
multifocal leukoencephalopathy (PML)
Other anti CD20 monoclonal antibodies being developed:
Ocrelizumab, humanized B-cell depleting agent.
Ofatuzumab a fully-human B-cell depleting agent.
6.Trastuzumab humanized MAB binds to the
extracellular domain of the human epidermal growth
factor receptor HER-2/neu. This antibody blocks the
natural ligand from binding and down-regulates the
receptor. Trastuzumab is approved for the treatment of
metastatic breast cancer in patients whose tumors
overexpress HER-2/neu. As a single agent it induces
remission in about 15–20% of patients; in combination
with chemotherapy, it increases response rate and
duration as well as 1-year survival.
MABs Used to Deliver Isotopes to Tumors
1.Arcitumomab is a murine F(ab')2 fragment from an
anti-carcinoembryonic antigen (CEA) antibody labeled
with technetium 99m (99mTc) that is used for imaging
patients with metastatic colorectal carcinoma
(immunoscintigraphy) to determine extent of disease.
CEA is often upregulated on tumor in patients with
gastrointestinal carcinomas.
2. Capromab pendetide is a murine monoclonal
antibody specific for prostate specific membrane
antigen. It is coupled to isotopic indium (111In) and is
used in immunoscintigraphy for patients with biopsyconfirmed prostate cancer and post-prostatectomy in
patients with rising prostate specific antibody level to
determine extent of disease.
.
3.Ibritumomab tiuxetan is an anti-CD20 murine MAB
labeled with isotopic yttrium (90Y) or 111In. The
radiation of the isotope provides the major antitumor
activity. Ibritumomab is approved for use in patients
with relapsed or refractory low-grade, follicular, or Bcell non-Hodgkin's lymphoma, including patients with
rituximab-refractory follicular disease.
4.Nofetumomab is a mouse MAB coupled to 99mTc that
is used for diagnostic purposes to determine extent of
disease and to stage patients with small cell lung
cancer. It binds a 40 kD antigen found on many tumor
cell types, but also on some normal cells.
5. Tositumomab is another anti-CD20 MAB and is
complexed with iodine 131 (131I).It is used in two-step
therapy in patients with CD20-positive, follicular nonHodgkin's lymphoma whose disease is refractory to
rituximab and standard chemotherapy. Toxicities are
severe thrombocytopenia and neutropenia.
MABs Used as Immunosuppressants and AntiInflammatory Agents
#ANTI-TNF- α MABS block TNF-α(a proinflammatory
cytokine) from binding to TNF receptors on inflammatory cell
surfaces results in suppression of downstream inflammatory
cytokines such as IL-1 and IL-6 and adhesion molecules involved
in leukocyte activation and migration.They are includes
_ Adalimumab is a completely human MAB approved for
use in RA ,administered as single doses subcutaneously,
every other week.
_ Etanercept is a dimeric fusion protein,it is approved
for adult RA, polyarticular-course juvenile RA, and
psoriatic arthritis. It may be used in combination with
methotrexate.Administered subcutaneously, twice weekly
_ Infliximab is a chimeric MAB ,it is approved for use in
Crohn's disease, ulcerative colitis,RA, ankylosing spondylitis,
and psoriatic arthritis.It is given by i.v infusion every 8 weeks.
#Abatacept is a fusion protein composed of the
extracellular domain of CTLA-4 fused to human IgG Fc.
CTLA-4 is a costimulatory molecule found on T cells
that binds to CD80 and CD86 on APC.It blocks
activation of T cells by binding to CD80 or 86 so that
CD28 on T cells cannot bind and stimulate the T cell
and lead to cytokine release. Abatacept is approved for
patients with severe RA who have failed other DMARDS
#Alefacept is an engineered protein consisting of the
CD2-binding portion of LFA-3 fused to a human IgG1 Fc
approved for the treatment of plaque psoriasis. It
inhibits activation of T cells by binding to cell surface
CD2, inhibiting the normal CD2/LFA-3 interaction.
Treatment of patients with alefacept also results in a dosedependent reduction of the total number of circulating T cells
and the drug discontinued if CD4 lymphocyte levels fall
below 250 cells/μ L.
#Anakinra is a recombinant IL-1 receptor antagonist it is
approved for use in adult rheumatoid arthritis patients who have
failed treatment with one or more DMARDS.
#Basiliximab is a chimeric MAB that binds to CD25, the
IL-2 receptor alpha chain on activated lymphocytes. It
functions as an IL-2 antagonist,and is therefore
immunosuppressive. It is indicated for prophylaxis of
acute organ rejection in renal transplant patients
#Daclizumab is a humanized MAB similar basiliximab,
but the mode of administration differs.
#Efalizumab is humanized anti-CD11a MAB approved
for the treatment of adult patients with severe
psoriasis. Binding of efalizumab to CD11a (the alpha
subunit of LFA-1) inhibits the interaction of LFA-1 on all
lymphocytes with ICAM-1, thereby inhibiting the
adhesion, activation, and migration of lymphocytes into
skin.It is administered by S.C. injection.
#Omalizumab is an anti-IgE humanized MAB that is
approved for the treatment of allergic asthma in adult
and adolescent patients refractory to inhaled steroids.It
blocks the binding of IgE to the high-affinity Fcέ
receptor on basophils and mast cells, which suppresses
IgE-mediated release of type I allergy mediators such
as histamine and leukotrienes.
Other MABs
Abciximab is a Fab fragment of MAB that binds to the
GPIIb/IIIa receptor on activated platelets and inhibits
fibrinogen, von Willebrand factor, and other adhesion
molecules from binding to activated platelets, thus
preventing their aggregation.
Palivizumabis a MAB that binds to the fusion protein of
respiratory syncytial virus, preventing infection in
susceptible cells in the airways. It is used in neonates
at risk for this viral infection.
Immunostimulatory Cytokines
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Interleukins
IL-2 (enhance antitumor actions of cytotoxic T cells and
NK cells)
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Colony Stimulating Factors
G-CSF (Filgrastim)(Neupogen®)
treat neutropenia
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GM-CSF (Sargramostim)(Leukine®)
myeloid recovery after bone marrow transplant
_
Interferon Alpha (Roferon®, Intron®) (prod. by
leukocytes)
(antiviral, antiproliferative)
malignant melanoma, renal cell carcinoma, hairy cell
leukemia, Kaposi’s sarcoma
_
Interferon Beta (Avonex®, Rebif®) (prod. by
fibroblasts)
(antiviral, antiproliferative)
relapsing type MS
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Interferon Gamma (Actimmunex®)(prod. by
lymphocytes)
(stimulates NK cells and macrophages)
chronic granulomatous disease
Other Hematopoetic Growth Factors
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Erythropoietin alpha (Epoetin alpha) (Procrit®)
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Produced by recombinant DNA technology
Stimulates division and differention of erythroid
progenitor cells
Used for anemia due to renal failure or cancer
chemotherapy
Adverse effects include hypertension, headache,
hypersensitivity reactions are rare
Darbopoetin alpha (Aranesp®)
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Recombinant long-acting erythropoetin (3X epoetin)
Other Immunostimulants
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Thymic Hormones
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Synthetic Stimulants
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Improve primary immune deficiency in children
Levamisole stimulates phagocytosis and T cell
production of cytokines
Adjuvants of bacterial origin
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BCG is viable strain of Mycobacterium bovis that
enhances macrophage activity
BCG used for bladder cancer and melanomas
References
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-Clinical Immunology: Principles and Practice. Robert Rich et
al. Second Edition.
-Rheumatology Secrets. Sterling West. Second Edition.
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-Review of Immunology. Andrew Lichtman. 2005
-Genomic and non genomic effects of glucocorticoids. Stah and
Buttgereit. Nature Clinical Practice. 2008 Vol4 no10; 525-533
-Therapeutic vaccination for chronic diseases: a new class of
drugs in sight. Bachman and Dyer. Nature reviews. 2004 vol3
-Inflammatory resolution: new opportunities for drug discovery.
Derek Gilroy et al. Nature reviews. 2004 vol3.
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response. Ruslan Medzhitov. Nature 2007 vol449/18.
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System. Abul Abbas. 2nd edition.