pharmacology REVIEWER immunosuppressive agents

DR. SALVADOR

GLUCOCORTICOIDS

- 1st to have lympholytic property

- reduces the size and lymphoid content of the lymph nodes and spleen
- no toxic effect on proliferating myeloid or erythroid stem cells in the bone marrow
- MOA: interfere with the cell cycle of activated lymphoid cells
- immunologic effects are probably due to their ability to modify cellular functions rather than to direct cytotoxicity
- cellular immunity is more affected than humoral immunity
-
CLINICAL INDICATIONS ADVERSE EFFECTS
idiopathic thrombocytopenic purpura and rheumatoid arthritis Adrenal suppression
first-line immunosuppressive therapy for both solid organ and Proximal muscle wasting
hematopoietic stem cell transplant recipients, with variable results Diabetes
asthma GI bleeding
Fluid retention
Serious viral, bacterial and fungal infection

CALCINEURIN INHIBITORS
Cyclosporine
Tacrolimus
CYCLOSPORINE
- Cyclosporine is a peptide antibiotic that appears to act at an early stage in the antigen receptor-induced differentiation of T cells and blocks their
activation
- binds to cyclophilin
- Cyclosporine and cyclophilin complex inhibits calcineurin (necessary for the activation of a T-cell-specific transcription factor called NF- AT, w/c
is involved in the synthesis of IL- 2
- absorbed drug is primarily metabolized by the P450 3A enzyme system in the liver
-
Clinical indications Adverse Effects
graft-versus-host disease after hematopoietic stem cell transplantation nephrotoxicity, hypertension, hyperglycemia, liver dysfunction,
kidney, pancreas, liver, and heart transplant hyperkalemia, altered mental status, seizures, and hirsutism
ophthalmic solution: dry eye syndrome increased incidence of lymphoma and other cancers due to its release
Inhaled cyclosporine: lung transplantation of TGF-
autoimmune disorders: uveitis, rheumatoid arthritis, psoriasis, and
asthma

TACROLIMUS
- (FK 506) is an immunosuppressant macrolide antibiotic produced by Streptomyces tsukubaensis.
- binds to the immunophilin FK-binding protein (FKBP) blocking calcineurin
- tacrolimus is 10100 times more potent than cyclosporine
-
Clinical Indications Adverse Effects
preventing rejection in solid-organ transplant patients even after failure nephrotoxicity, neurotoxicity, hyperglycemia, hypertension,
of standard rejection therapy hyperkalemia, and gastrointestinal complaints.
considered a standard prophylactic agent (usually in combination with
methotrexate or mycophenolate mofetil) for graft-versus-host disease.
Tacrolimus ointment: atopic dermatitis and psoriasis
pharmacology REVIEWER immunosuppressive agents
DR. SALVADOR

MAMMALIAN TARGET OF RAPAMYCIN (mTOR) INHIBITORS

Sirolimus and its analogs everolimus and temsirolimus
SIROLIMUS
- immunosuppressant macrolide antibiotic produced by Streptomyces hygroscopicus
- binds the circulating immunophilin FK506- binding protein 12, resulting in an active complex that inhibits mTOR
- available only as an ORAL drug
Clinical Indications Adverse Effects
prophylaxis and as therapy for steroid-refractory acute and chronic profound myelosuppression (especially thrombocytopenia),
graft-versus-host disease in hematopoietic stem cell transplant hepatotoxicity, diarrhea, hypertriglyceridemia, pneumonitis, and
recipients headache.

MYCOPHENOLATE MOFETIL
semisynthetic derivative of mycophenolic acid, isolated from the mold Penicillium glaucus.
inhibits T- and B-lymphocyte responses, including mitogen and mixed lymphocyte responses, probably by inhibition of de novo synthesis of purines.
Clinical Manifestations Adverse Effects
first-line drug for preventing or reducing chronic allograft vasculopathy Toxicities include gastrointestinal disturbances (nausea and vomiting,
in cardiac transplant recipients diarrhea, abdominal pain) headache, hypertension, and reversible
used as prophylaxis for and treatment of both acute and chronic graft- myelosuppression (primarily neutropenia).
versus-host diseases in hematopoietic stem cell transplant patients

THALIDOMIDE
sedative drug that was withdrawn from the market in the 1960s because of its disastrous teratogenic effects when used during pregnancy.
inhibits angiogenesis and has anti-inflammatory and immunomodulatory effects.
It inhibits tumor necrosis factor-alpha (TNF-), reduces phagocytosis by neutrophils, increases production of IL-10, alters adhesion molecule
expression, and enhances cell-mediated immunity via interactions with T cells.
Clinical Indications Adverse Effects
Thalidomide is currently used in the treatment of multiple myeloma at The most important toxicity is teratogenesis
initial diagnosis and for relapsed-refractory disease

CYTOTOXIC AGENTS
Azathioprine
Cyclophosphamide
Leflunomide
Hydroxychloroquine
Other cytotoxic agents
AZATHIOPRINE
- prodrug of mercaptopurine and, like mercaptopurine, functions as an antimetabolite
- Xanthine oxidase splits much of the active material to 6-thiouric acid prior to excretion in the urine
- 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
Clinical Indications Adverse Effects
maintaining renal allografts and may be of value in transplantation of The chief toxic effect of azathioprine and mercaptopurine is bone
other tissues. marrow suppression,
Hepatic dysfunction, manifested by very high serum alkaline
phosphatase levels and mild jaundice
pharmacology REVIEWER immunosuppressive agents
DR. SALVADOR
CYCLOPHOSPHAMIDE
- alkylating agent cyclophosphamide is one of the most efficacious immunosuppressive drugs available
- MOA: destroys proliferating lymphoid cells but also appears to alkylate DNA and other molecules in some resting cells.
Clinical Indications Adverse Effects
In smaller doses: autoimmune disorders (including systemic lupus carries considerable risk of pancytopenia and hemorrhagic cystitis
erythematosus) and in patients with acquired factor XIII antibodies and
bleeding syndromes, autoimmune hemolytic anemia, antibody-induced
pure red cell aplasia, and Wegeners granulomatosis.

LEFLUNOMIDE
- inhibitor of pyrimidine synthesis
- orally active, and the active metabolite has a long half-life of several weeks
Clinical Indications Adverse Effects
only for rheumatoid arthritis at present elevation of liver enzymes with some risk of liver damage, renal
impairment, and teratogenic effects.

HYDROXYCHLOROQUINE
- antimalarial agent with immunosuppressant properties.
- It is thought to suppress intracellular antigen processing and loading of peptides onto MHC class II molecules by increasing the pH of lysosomal and
endosomal compartments, thereby decreasing T-cell activation.
Clinical Indications Adverse Effects
only for rheumatoid arthritis at present

OTHER CYTOTOXIC AGENTS

- including vincristine, methotrexate, and cytarabine
Vincristine Pentostatin
useful in idiopathic thrombocytopenic purpura refractory to prednisone. adenosine deaminase inhibitor primarily used as an antineoplastic
agent for lymphoid malignancies, and produces a profound
lymphopenia.

IMMUNOSUPPRESSIVE ANTIBODIES
Antilymphocyte & Antithymocyte Antibodies
- ALG acts primarily on the small, long-lived peripheral lymphocytes that circulate between the blood and lymph
- 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
Clinical Indications Adverse Effects
ALG and ATG are useful for suppressing certain major compartments Local pain and erythema often occur at the injection site (type III
(ie, T cells) of the immune system and play a definite role in the hypersensitivity)
management of solid organ and bone marrow transplantation Complexes of host antibodies with horse ALG may precipitate and
localize in the glomeruli of the kidneys

Muromonab-CD3 (OKT3)
- blocks killing by cytotoxic human T cells and several other T-cell functions
Clinical Indications Adverse Effects
Treatment of acute renal allograft rejection and steroid-resistant acute NONE (as per Katzung)
cardiac and hepatic transplant rejection
pharmacology REVIEWER immunosuppressive agents
DR. SALVADOR
Immune Globulin Intravenous (IGIV)
- An approach of intravenous use of polyclonal human immunoglobulin
- immunoglobulin preparation (usually IgG) is prepared from pools of thousands of healthy donors, and no single, specific antigen is the target of the
therapeutic antibody.
Clinical Indications MOA
safe and effective in Kawasakis disease reduction of T helper cells
systemic lupus erythematosus and refractory idiopathic increase of regulatory T cells
thrombocytopenic purpura. decreased spontaneous immunoglobulin production,
Fc receptor blockade
increased antibody catabolism, and idiotypic-anti-idiotypic interactions
with pathologic antibodies.

Rho(D) Immune Globulin Micro-Dose

- The technique is based on the observation that a primary antibody response to a foreign antigen can be blocked if specific antibody to that antigen
is administered passively at the time of exposure to antigen. 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.
Clinical Indications Adverse Effects
prophylactic treatment to prevent erythroblastosis fetalis infrequent and consist of local discomfort at the injection site or, rarely,
a slight temperature elevation

MONOCLONAL ANTIBODIES (MABs)

Antitumor MABs
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 a small population of granulocytes
Clinical uses: B-cell chronic lymphocytic leukemia
Adverse effects: lymphopenia, neutropenia, anemia, and
thrombocytopenia
Cetuximab
human-mouse chimeric monoclonal antibody that targets epidermal
growth factor receptor (EGFR)
MOA: decreases in kinase activity, matrix metalloproteinase activity,
and growth factor production, and increased apoptosis
Clinical uses: EGFR-positive metastatic colorectal cancer
Adverse effects: lymphopenia, neutropenia, anemia, and
thrombocytopenia
Panitumumab
fully human IgG2 kappa light chain monoclonal antibody
MOA: It inhibits cell growth, induces apoptosis, decreases vascular
growth factor production, and suppresses internalization of the EGFR
Clinical uses: EGFR- expressing metastatic colorectal carcinoma
Trastuzumab
recombinant DNA-derived, humanized monoclonal antibody that binds
to the extracellular domain of the human epidermal growth factor
receptor HER-2/neu
MOA: blocks the natural ligand from binding and down- regulates the
receptor
Clinical uses: HER-2/neu-positive tumors in patients with breast
cancer and patients with metastatic gastric or gastroesophageal
junction ade- nocarcinoma
Bevacizumab
humanized IgG1 monoclonal antibody that binds to vascular endothelial
growth factor (VEGF) and inhibits VEGF from binding to its receptor,
especially on endothelial cells.
Clinical uses: treatment of patients with metastatic colorectal cancer,
non-small cell lung cancer, glioblastoma multiforme
Ofatumumab
human IgG1 monoclonal antibody directed against a different epitope
on CD20 than rituximab
Clinical uses: treatment of patients with chronic lymphocytic leukemia
(CLL) who are refractory to fludarabine and alemtuzumab
Adverse effects: slight risk of hepatitis B virus reactivation
Rituximab
chimeric murine-human monoclonal IgG1 (human Fc) that binds to the
CD20 molecule on normal and malignant B lymphocytes
MOA: complement-mediated lysis, antibody-dependent cellular
cytotoxicity, and induction of apoptosis in the malignant lymphoma cells.
Clinical uses: relapsed or refractory low-grade or follicular B-cell non-
Hodgkins lymphoma and chronic lymphocytic leukemia and treatment
of rheumatoid arthritis
pharmacology REVIEWER
MABs Used to Deliver Isotopes to Tumors
Arcitumomab
murine Fab 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
Ibritumomab tiuxetan
anti-CD20 murine monoclonal antibody labeled with isotopic yttrium
(90Y) or 111In
MABs Used as Immunosuppressants and
Anti-Inflammatory Agents
A. Anti-TNF-Alpha MABs
Adalimumab
completely human IgG1 approved for use in patients with rheumatoid
arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing
spondylitis, Crohns disease, and plaque psoriasis
Etanercept
binds to both TNF- and TNF-
MOA: decreases in kinase activity, matrix metalloproteinase activity,
and growth factor production, and increased apoptosis
Clinical uses: approved for adult rheumatoid arthritis, polyarticular
juvenile idiopathic arthritis, ankylosing spondylitis and psoriatic
arthritis. It may be used in combination with methotrexate in some
patients with arthritis.
Infliximab
human-mouse chimeric IgG1 monoclonal anti- body possessing
human constant (Fc) regions and murine variable regions
MOA: decreases in kinase activity, matrix metalloproteinase activity,
and growth factor production, and increased apoptosis
Clinical uses: Crohns disease, ulcerative colitis, rheumatoid arthritis,
ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis.
B. Abatacept
recombinant fusion protein composed of the extra- cellular domain of
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) fused to hinge,
CH2, and CH3 domains of human IgG1
binds more tightly to CD80/86 than CD28
Clinical uses: rheumatoid arthritis and juvenile idiopathic arthritis.
D. Basiliximab and Daclizumab
chimeric mouse-human IgG1 that binds to CD25, the IL-2 receptor
alpha chain on activated lymphocytes.
MOA: Both agents function as IL-2 antagonists, blocking IL-2 from
binding to activated lymphocytes, and are therefore
immunosuppressive.
immunosuppressive agents
DR. SALVADOR
Capromab pendetide
murine monoclonal antibody specific for prostate specific membrane
antigen. It is coupled to isotopic indium (111In)
Tositumomab
another anti-CD20 monoclonal antibody and is complexed with iodine
131 (131I).
Certolizumab pegol
recombinant humanized Fab fragment that binds to TNF-.
It is coupled to a 40-kDa polyethylene glycol
Clinical uses: treatment of patients with Crohns disease and rheumatoid
arthritis
Golimumab
human IgG monoclonal antibody that also binds to soluble and
membrane-associated TNF-
Clinical uses: treatment of patients with chronic lymphocytic leukemia
(CLL) who are refractory to fludarabine and alemtuzumab
Adverse effects: slight risk of hepatitis B virus reactivation
C. Alefacept
engineered protein consisting of the CD2-binding portion of leukocyte-
function-associated antigen-3 (LFA-3) fused to a human IgG1 Fc region
(hinge, CH2, and CH3).
Clinical uses: treatment of patients with plaque psoriasis
E. Natalizumab
humanized IgG4 monoclonal antibody that binds to the 4-subunit of
41 and 47 integrins expressed on the surfaces of all leukocytes
except neutrophils, and inhibits the 4-mediated adhesion of
leukocytes to their cognate receptor.
Clinical uses: treatment of patients with multiple sclerosis and Crohns
disease
pharmacology REVIEWER immunosuppressive agents
DR. SALVADOR
F. Omalizumab G. Tocilizumab
anti-IgE recombinant humanized monoclonal antibody that is recombinant humanized IgG1 that binds to soluble and membrane-
approved for the treatment of allergic asthma in adult and adolescent associated IL-6 receptors.
patients whose symptoms are refractory to inhaled corticosteroids Clinical uses: rheumatoid arthritis who are refractory to other anti-TNF-
MOA: blocks the binding of IgE to the high-affinity Fc receptor on biologicals.
basophils and mast cells, which suppresses IgE-mediated release of
type I allergy mediators such as histamine and leukotrienes
H. Ustekinumab
is a human IgG1 monoclonal antibody that binds to the p40 subunit
of IL-12 and IL-23 cytokines.
MOA: It blocks IL-12 and IL-23 from binding to their receptors,
therefore inhibiting receptor-mediated signaling in lymphocytes.
Clinical uses: moderate to severe plaque psoriasis.

OTHER MABs
Abciximab
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
Eculizumab
humanized IgG monoclonal antibody that binds the C5 complement
component, inhibiting its cleavage into C5a and C5b thereby inhibiting
the terminal pore-forming lytic activity of complement.
Denosumab
human IgG2 monoclonal antibody specific for human RANKL
- Binding RANKL it inhibits the maturation of osteoclasts, the cells
responsible for bone resorption
postmenopausal women with osteoporosis at high risk for fracture.
Palivizumab
monoclonal antibody that binds to the fusion protein of respiratory
syncytial virus, preventing infection in susceptible cells in the airways

Ranibizumab
recombinant human IgG1 Fab that binds to VEGF-A
prevents new blood vessel formation by blocking VEGF from binding
to its receptor