Immunotherapy: Immunosuppressives, Immunomodulators, Immunologicals
Summary: Basic and Clinical Pharmacology: Katzung
Lecturer: Dr. Angeline D. Alabastro
Transcriptionist: Deputy Jonathan
Date of lecture: July 27, 2010
Normal immune response
-protect the host from invading pathogens and to eliminate diseases and recognize self from
non-self
* Natural or Non adaptive immune system
-act as 1st line of defense against antigenic insult and includes physical (skin), biochemical
(complement, lysozyme, interferon), and cellular components (neutrophils, macrophages,
monocytes)
* Adaptive Immune response
-respond to a variety of antigens, each in a specific manner
Abnormal immune response
Hypersensitivity
– antibody mediated or cell mediated.
– Occurs in 2 phases: sensitization phase(occurs upon initial encounter with an antigen;
effector phase (involves immunologic memory and results in tissue pathology upon a
subsequent encounter with an antigen)
A. Immediate hypersensitivity
1. Type I – results from cross linking of membrane bound IgE on blood basophils or tissue
mast by antigen.
- cross linking causes cells to degranulate, releasing substances such as histamine,
leukotrienes and eosinophil chemotactic factor which induces anaphylaxis, asthma, hay
fever, or urticaria in affected individuals.
2. Type II – results from the formation of antigen-antibody complexes between foreign
antigen and IgM or IgG immunoglobulins. e.g blood transfusion reaction
3. Type III – due to the presence of elevated levels of antigen – antibody complexes that
deposit on basement membrane in tissues and vessels.
B. Type IV: Delayed-Type Hypersensitivity
- cell mediated and responses occur 2-3 days after exposure to the sensitizing antigen.
- caused by antigen-specific DTH TH1 cells and induces a local inflammatory response that
causes tissue damage characterized by the influx of antigen non specific inflammatory
cells especially macrophages.
Autoimmunity
- body mounts an immune response against itself due to failure to distinguish self tissues
and cells from foreign (non self) antigens.
- Activation of self reactive T and B lymphocytes that generate cell mediated or humoral
responses directed against self antigens.
Immunodeficiency Diseases
- results from inadequate function in the immune system
 X linked agammaglobulinemia – disease affecting males that is characterized by
failure of immature B- luymphocytes to mature into antibody producing plasma cells.
 DiGeorge’s syndrome – failure of the thymus to develop, resulting in diminished T cell
responses while the humoral response is unaffected.
 SCID (severe combined immunodeficiency disease) - deficiency in Adenosine
deaminase.
Immunosuppressive agent
GLUCOCORTICOIDS
- “lympholytic properties”, reduces the size and lymphoid content of the lymph nodes and
spleen.
- Interfere with the cell cycle of activated lymphoid cells.
- Its immunosuppressive and anti-inflammatory properties account for their beneficial
effects in diseases like idiopathic thrombocytopenic purpura and rheumatoid arthritis.
- 1st line immunosuppressive therapy for both solid organ and hematopoietic stem cell
transplant recipients.
I-5A
IMMUNOPHILIN LIGANDS
1. Cyclosporine
- immunosuppressive agent with efficacy in human organ transplantation and tx of graft vs.
host disease after hematopoietic stem cell transplantation.
- Peptide antibiotic, acts at an early stage in the antigen receptor- induced differentiation of
T cells and blocks their activation.
- Binds to cyclophilin: forms a complex that inhibits the cytoplasmic phosphatase,
calcineurin, which is necessary for the activation of a T cell specific transcription factor.
- Given IV or orally; incompletely absorbed; metabolized by P450 3A in the liver.
- Toxicities: nephro, HPN, hyperglycemia, liver dysfunction, hyperkalemia, altered mental
status, seizures, hirsutism.
- Tx in autoimmune disorders such as uveitis, rheumatoid arthritis, psoriasis and asthma
2. Tacrolimus ( FK 506 )
- microlide antibiotic produced by Streptomyces tsukubaensis.
- Bind to FK-binding protein: forms a complex that inhibit calcineurin which is necessary
for the activation of the T cell specific transcription factor NF-AT
- Standard prophylactic agent ( in combination with methotrexate or mycophenolate
mofetil) for graft versus host disease.
- Given orally or IV; half life is 9 to 12 hours; metabolized by P450 enzymes n the liver.
- Toxicities: nephro, neuro, hyperglycemia, HPN, hyperkalemia, GI complaints
3. Sirolimus
- derived from Streptomyces hygroscopicus
- blocks the response of T cell to cytokines
- potent inhibitor of B cell proliferation and immunoglobulin production
- available only as oral drug; substrate for both P450 3A and P-glycoprotein
- Everolimus: derivative of sirolimus; proliferation signal inhibitor that maybe of benefit in
decreasing rejection in cardiac transplantation
- Toxicities: myelosuppression, hepato, diarrhea, hypertriglyceridemia, headache.
MYCOPHENOLATE MOFETIL
- isolated from the mold Penicillium glaucum
- inhibits T and B lymphocyte responses, including mitogen and mixed lymphocyte
responses by inhibition of de novo synthesis of purine
- Mycophenolic acid: active immunosuppressive moiety
- Used in solid organ transplant px for refractory rejection.
- Used to treat steroid refractory graft vs. host disease in hematopoietic stem cell
transplant px.
- Available in both oral and IV forms.
- Toxicities: GI disturbances ( nausea, vomiting, diarrhea, abdominal pain) headache,
HPN, reversible myelosuppression
THALIDOMIDE
- sedative drug
- inhibits angiogenesis; has anti and immunomodulatory effects.
- Inhibits TNF-α, reduce phagocytosis by neutrophils, increases production of IL-10, alters
adhesion molecule expression and enhances cell mediated immunity via interactions
with T cells.
- Currently used in the tx of multiple myeloma at initial diagnosis and for relapsed-
refractory diseases.
- Toxicity: teratogenic
- ADR: peripheral neuropathy, constipation, rash, fatigue, hypothyroidism and increased
risk of deep venous thrombosis.
- Lenalidomide: immunomodulatory derivative of thalidomide (IMiD) that is effective in the
tx of myelodysplastic syndrome with the chromosome 5q31 deletion
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CYTOTOXIC AGENT
1. Azathioprine
- prodrug of mercaptopurine and function as a metabolite
- well absorbed from the GIT and is metabolized primarily to mercaptopurine.
- Produce immunosuppression by interfering with purine nucleic acid metabolism at steps
that are required for the wave of lymphoid cell proliferation that follows antigenic
stimulation
- Used in the management of acute glomerulonephritis and in the renal component of
systemic lupus erythematosus.
- Toxicities: bone marrow suppression usually manifested as leucopenia, skin rashes,
fever, nausea, vomiting and sometimes diarrhea occur.
2. Cyclophosphamide
- alkylating agent
- at a very large doses: induce an apparent specific tolerance to a new antigen if the drug
is administered simultaneously with, or shortly after, the antigen.
- In smaller doses: effective against autoimmune diseases (SLE) and in px with acquired
factor XIII antibodies and bleeding syndromes, autoimmune hemolytic anemia, antibody
induced pure red cell aplasia and Wegener’s granulomatosis.
- ADR: nausea, vomiting, cardiac toxicity, electrolyte disturbances.
3. Leflunomide
- prodrug of an inhibitor of pyrimidine synthesis
- orally active, and active metabolite has a long half life of several weeks
- approved only for rheumatoid arthritis
- Toxicities: elevation of Liver enzymes with some risk of liver damage, renal impairment
and teratogenic effects
4. Hydroxycholoroquine
- antimalarial agent with immunosuppressant properties.
- Suppress intracellular antigen processing and loading of peptides onto MHC class II
molecules by increasing the pH of lyzosomal and endosomal compartments, thereby
decreasing T cell activation
- Tx of rheumatoid arthritis, SLE
- Prevent graft vs. host disease after allogenic stem cell transplantation
5. other cytotoxic agent
- vincristine, methotrexate, cytarabine
- Vinblastine: prevent mast cell degranulation in vitro by binding to microtubule units
within the cell and to prevent the release of histamine and other vasoactive compounds.
- Pentostatin: adenosine deaminase inhibitor primarily used as an antineoplastic agent
for lymphoid malignancies and produces a profound lymphopenia.
IMMUNOSUPPRESSIVE ANTIBODIES
1. antilymphocyte and anti thymocyte antibodies
- acts primarily on the small, long lived peripheral lymphocytes that circulate between the
blood and the lymph.
- With continued administration, “thymus dependent” lymphocytes from lymphoid follicles
are also depleted, as they normally participate in the recirculating pool. As a result of the
destruction or inactivation of T cells, an impairment of delayed hypersensitivity and
cellular immunity occurs while humoral antibody formation remains relatively intact
2. Muromonab-CD3
- directed against the CD3 molecule on the surface of human thymocytes and mature T
cells
- useful in the tx of renal transplant rejection
- in vitro, blocks killing by cytotoxic human T cell and several other T cell function
3. Immune Globulin Intravenous
- in high doses (2g/kg): effective in a variety of conditions ranging from immunoglobulin
deficiencies to auto immune disorders to HIV disease to bone marrow trabsplants
- in px with Kawasaki’s disease: safe and effective in reducing systemic inflammation and
preventing coronary artery aneurysm
- MOA: reduction of T helper cells, increase of suppressor T cells, decreased
spontaneous immunoglobulin reaction, Fc receptor blockade, increased antibody
catabolism, idiopathic-anti-idiopathic interactions with pathologic antibodies.
4. Rho(D) Immune Globulin Micro Dose
- if administered to the mother within 24-72 hours after the birth of an Rh-positive infant,
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). therefore she has no memory B cells that can
activate upon subsequent pregnancies with an Rho(D) positive fetus.
5. Hyperimmune Immunoglobulins
- made from pools of selected human or animal donors with high titers of antibodies
against particular agents of interest such as viruses or toxins
- tx of respiratory syncytial virus, cytomegalovirus, varicella zoster, human herpesvirus 3,
Hepa B virus, rabies, tetanus, digoxin overload.
MONOCLONAL ANTIBODIES
1. Antitumor MAB’s
- Alemtuzumab: humanized IgG1 with a kappa chain that binds to CD52 found on normal
and malignant B and T lymphocytes, Nk cells, monocytes, macrophages and small
population of granulocytes.
:Tx of B cell chronic lymphocytic leukemia in px who have been treated with alkylating agents
and have failed fludarabine therapy.
: deplete leukemic and normal cells by direct antibody dependent lysis.
:px receiving this antibody become neutropenic, anemic, and thrombocytopenic
- Bevacizumab: humanized IgG1 monoclonal antibody that binds to VEGF and inhibits
VEGF from binding to its receptor, especially on endothelial cells.
: Anti angiogenic drug that inhibits the growth of blood vessels in tumors.
:1st line tx of px with metastatic colorectal cancer alone or in combination with 5-FU- based
chemotherapy.
- Cetuximab: human mouse monoclonal antibody that targets epidermal growth factor
receptor(EGFR).
: binding to EGFR inhibits tumor by decrease in kinase activity, matrix metalloproteinase
activity and growth factor production, and increased apoptosis
- Gemtuzumab: humanized IgG4 monoclonal antibody with kappa light chain specific for
CD33, a sialoadhesion protein found on leukemic blsat cells in 80 – 90% of px with acute
myelogenous leukemia.
: Has antiblast activity
: Approved for the tx of 60 years old and older in 1st relapse with CD33 acute myelogenous
leukemia who are not considered candidates for other types of cytotoxic chemotheraphy.
: ADR: severe myelosuppression, neutropenia, hepatotoxicity, various hypersensitivity
reactions.
- Rituximab: chimeric murine-human monoclonal IgG1 (human Fc) that binds to the CD20
molecule on normal and malignant B lymphocytes and is approved for the therapy of px
with relapsed or refractory low grade or follicular, B cell non Hodgkin lymphoma.
: MOA; complement mediated lysis, antibody dependent cytotoxicity, induction of apoptosis in
the malignant lymphoma cells.
- Trastuzumab: recombinant DNA derived, humanized monoclonal antibody that binds to
the extracellular domain of the human epidermal epidermal growth factor receptor HER-
2/neu.
: blocks the natural ligand from binding and down regulates the receptor.
: approved for the tx of metastatic breast cancer in px whose tumor overexpress HER-2/neu.
2. MAB’s used to deliver isotopes to tumor
- Arcitumomab: murine F(ab’)2 fragment from an anti-carcinogenic antigen antibody
labeled with technetium that is used for imaging px with metastatic colorectal carcinoma
to determine the extent of the disease.
- Capromab pendetide: murine monoclonal antibody specific for prostate
- Ibritumomab tiuxetam: anti Cd20 murine monoclonal antibody labeled with isotopic
yttrium or In.
- Approved for use in px with relapse or refractory low grade, follicular, or B cell non
hodgkin’s lymphoma, including px with rituximab-refractory follicular disease.
- Nofetumomab: mouse monoclonal antibody coupled to 99mTc that is used for diagnostic
purposes to determine extent of disease and to stage px with small cell lung cancer.
- Tositumomab: another anti CD20 monoclonal antibody and is complexed with iodine
131.
: Used in 2 step therapy in px with CD20 positive, follicular non hodgkin’s lymphoma whose
disease is refractory to rituximab and standard chemotherapy.
3. MAB’s used as Immunosuppressants and Anti inflammatory Agents
A. Anti-TNF-Alpha MABs
- Adalimumab: completely human IgG1 approved for use in rheumatoid arthritis.
: blocks the interaction of TNF-α with the TNF receptors on cell surfaces.
:reduced levels of C reactive protein, ESR, serum IL-6 and MMP-1 and MMP3.
- Etanercept: dimeric fushion protein composed of human IgG1 constant regions fused to
the TNF receptor.
: approved for adult RA, polyarticular-course juvenile RA, and psoriatic arthritis.
- infliximab: human mouse chimeric IgG1 monoclonal antibody possessing human
constant (Fc) regions and murine variable.
: Currently approved for use in Crohn’s diease, ulcerative colitis, RA, ankylosing spondylitis,
psoriatic arthritis
B. Abatacept
- a recombinant fusion protein composed of the extracellular domain of cytotoxic T-
lymphocyte associated antigen 4 fused to human IgG Fc.
- 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
- for px with RA
C. Alefacept
- consist of CD2-binding portion of leukocyte function associated antigen 3 fused to human
IgG1 Fc region approved for the tx of plaque psoriasis.
- inhibits activation of T cells by binding to cell surface CD2, inhibiting the normal
CD2/LFA-3 interaction.
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D. Basiliximab Cytokine inhibitors
- chimeric mouse human IGg1 that binds to CD25, the IL-2 receptor alpha chain on activated a. Anakinra
lymphocytes. - Recombinant form of the naturally occurring IL-1 receptor antagonist that prevents IL-1
- IL-2 antagonist, blocking IL-2 from binding to activated lymphocytes and is therefore from binding to its receptor, stemming the cascade of cytokines released if IL-1 were to
immunosuppressive. bind to the IL-1R

E. Daclizumab IMMUNOLOGIC REACTION TO DRUGS and DRUG ALLERGY

- humanized IgG1 that binds to the alpha subunit of the IL-2 receptor.
F. Efalizumab
- recombinant humanized anti-CD11a monoclonal antibody approved for the tx of adult px
with severe psoriasis.
- Binding to CD11a inhibits the interaction of LFA-1 on all lymphocytes with intercellular
adhesion molecule-1 thereby inhibiting the adhesion, activation, and migration of
lymphocytes to the skin.
G. Omalizumab
- anti IgE recombinant humanized monoclonal antibody
- approved for the tx of allergic asthma in adult and adolescent px whose symptoms are
refractory to inhaled corticosteroids.
OTHER MAB’s
 Abciximab
- Fab fragment of a murine human monoclonal antibody that binds to the integrin
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.
Type 1 – IgE mediated acute allergic reactions to stings, pollen, and drugs including
anaphylaxis, urticaria, and angioedema. IgE is fixed to tissue mast cells and blood
basophils and after interaction with antigen the cells release potent mediators.
Type 2 – drugs often modify host protein, thereby eliciting antibody responses to the modified
protein. These allergic responses involve IgG or IgM in which the antibody becomes
fixed to a host cell, which is then subject to complement-dependent lysis or to antibody –
dependent cellular cytotoxicity.
Type 3 – drugs may cause serum sickness which involves immune complexes containing IgG
and is a multisystem complement-dependent vasculitis that may also result in urticaria
Type 4 – cell mediated allergy is the mechanism involved in allergic contact dermatitis from
topically applied drugs or induration of the skin at the site of an antigen injected
intradermally.

 Palivizumab
- monoclonal antibody that binds to the fusion protein of respiratory syncytial virus,
preventing infection in susceptible cells in the airways.
- Used in neonates at risk for this viral infection and reduces the frequency of infection and
hospitalization by 50%

Clinical uses of immnosuppressive drugs

 For solid organ and bone marrow transplantation
-prior to transplant px may receive an immunosuppressive regimen, including: anti thymocyte
globulin, muromonab-CD3, daclizumab, basiliximab.

4 types of rejection that occur in solid organ transplant recipient

1. Hyperacute rejection
- due to preformed antibodies against the donor organ such as anti blod group antibodies.
- occurs within hours and cannot be stopped with immunosupressive drugs
-results in rapid necrosis and failure of the transplanted organ.

2. Accelerated rejection
- mediated by both antibodies and T cell, but it also cannot be stopped by immunosuppressive
drugs.

3. Acute rejection
- occurs within days to months and involves mainly cellular immunity. Reversal in possible with
general immunosuppressive drugs such as azathioprine, mycophenolate mofetil,
cyclosporine, tacrolimus, glucocorticoids, cyclophosphamide, methotrextae and
sirolimus

4. Chronic rejection
- occurs months or even years after transplantation.
- characterized by thickening and fibrosis of the vasculature of the transplanted organ, involving
both cellular and humoral immunity.
- tx is same as that of acute rejection

 for autoimmune disorders

- immunosuppressive therapy is utilized in chronic severe asthma, where cyclosporine
is often effective and sirolimus is another alternative.
- Omalizumab, tx for severe asthma

 immunomodulatory therapy

Cytokines
a. interferons
- IFN- α: tx of several neoplasm, including hairy cell leukemia, chronic myelogenous
leukemia, malignat melanoma, kaposi’s sarcoma and for Hepa B and C infection.
- IFN- β: used in relapsing type multiple sclerosis
- IFN- γ: approved for the tx of chronic granulomatous disease and IL-2, for metastatic
renal cell carcinoma and malignant melanoma.
- Toxicities: fever, chills, malaise, myalgias, myelosuppression, headache, and
depression.

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