Immune Modifiers

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Chapter 17 Immune Modifiers

Systemic Steroids

Description

Steroids as used in this section refers to glucocorticoids that are administered systemically. Inhaled, topically administered, and injected steroids are described in other sections.

Prototype and Common Drugs

image Prototype: prednisone
image Others: cortisone, hydrocortisone, methylprednisolone, dexamethasone, triamcinolone

MOA (Mechanism of Action)

image Cortisol is the endogenous glucocorticoid and is synthesized from cholesterol. The hypothalamus secretes corticotropin-releasing hormone (CRH), which stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH), which acts on the adrenal glands to produce cortisol.
image Cortisol acts in the nucleus of the cell; therefore it must first diffuse through the cell membrane. It is bound in the cytoplasm with heat shock protein and other proteins and transported into the nucleus.
image Steroid receptors located in the nucleus are called glucocorticoid receptor elements. They regulate transcription of DNA by acting on promoters, which are specific DNA sites where RNA polymerase binds and starts transcription.
image Steroids exert their actions in a broad range of tissues, and therefore there are many effects of glucocorticoids:

image Catabolism

• Increased serum glucose: increased gluconeogenesis, increased lipolysis, decreased uptake of glucose into tissues, and direct inhibition of insulin via cortisone (breakdown of cortisol)
• Mobilization of calcium from bones
• Increased breakdown of muscle to liberate amino acids

image Inflammatory effects

• Increased blood neutrophil counts: increased marrow release and decreased tissue margination
• Decreasing numbers of other white blood cells: lymphocytes, eosinophils, macrophages
• Reduced function of lymphocytes and macrophages
• Reduced function of phospholipase A2, resulting in reduced mediators of inflammation: prostaglandins and leukotrienes

image Antimitotic effects (decreased cell division)
image Water retention (because of mineralocorticoid effect)

Pharmacokinetics

image Cortisol is largely bound to corticosteroid-binding globulin (CBG); it is also bound to albumin but with only low affinity (Table 17-1).

TABLE 17-1 Steroid Potencies

image

Indications

image Inflammatory states:

image Autoimmune disorders

• Lupus, rheumatoid arthritis (RA), Crohn’s disease, and many others

image Asthma
image Allergic responses, including anaphylaxis

image Cancer treatment

image As one component of chemotherapy for some tumors
image In brain tumors that are associated with swelling of the brain and increased intracranial pressure from edema secondary to the tumor

image Transplant medicine

image Prevention of rejection
image Graft-versus-host disease (GVHD)

image Steroid deficient states

image Addison’s disease
image Adrenal suppression (which is caused by previous steroid administration)
image Adrenal insufficiency during severe illness

image Maturation of fetal lungs (if preterm delivery is anticipated)
image Pneumocystis pneumonia co-treatment

Contraindication

image Active serious infection

Side Effects

image Hyperglycemia and steroid induced diabetes
image Weight gain and severe swelling, particularly in the face; caused, in part, by the mineralocorticoid effects
image Psychiatric symptoms including depression, mania, and psychosis; other types of cognitive dysfunction can also occur, including euphoria, insomnia, mental confusion
image Gastric and duodenal bleeding secondary to inflammation or ulceration
image Infections resulting from immunosuppression
image Skin effects: thin skin, violaceous striae (stretch marks), acne
image Eyes: cataracts and glaucoma
image Muscular effects: muscle wasting, myopathy
image Adipose distribution: buffalo hump, central obesity
image Skeletal effects:

image Adults and children: Osteoporosis may occur.
image Children: Short stature results from interference with growth plates.
image Avascular necrosis (AVN) of the hips: The femoral head loses its blood supply, resulting in a devastating destruction of bone and joint. The lack of blood supply means that healing cannot occur and could necessitate joint replacement.

image Cushing’s syndrome is a collection of signs from endogenous overproduction of cortisol. A cushingoid appearance can be produced from iatrogenic exogenous steroid:

image Moon facies, buffalo hump (cervical fat pad), central obesity, supraclavicular fat collection, acne

image Adrenal suppression: Because of negative feedback loops, exogenous glucocorticoids will suppress CRH and ACTH. Rapidly terminating exogenous glucocorticoids after prolonged exposure will result in hypoadrenalism. Steroids must therefore be tapered (administration of smaller and smaller doses) before being stopped if they have been administered for more than about 1 or 2 weeks.

Important Notes

image The baseline secretion of cortisol in the body is 10 to 20 mg. In periods of stress (illness, trauma, inflammation, infection), the secretion increases.
image Glucocorticoids must be differentiated from mineralocorticoids; the prototype mineralocorticoid is aldosterone, also a steroid, which acts primarily on the kidney to regulate water and electrolyte homeostasis.
image One significant side effect of glucocorticoids is an increased white blood count (driven by an increase in neutrophils). Increased neutrophil counts are more commonly caused by infection; because steroids increase the risk of infection, it is sometimes clinically difficult to differentiate whether the increased white count is the result of a new infection (which would make the steroids relatively contraindicated) or the result of a direct effect of the steroid. The rise in white cell count can be quite dramatic when caused by steroid effect alone.
image Steroids and nonsteroidal antiinflammatory drugs (NSAIDs) are commonly coadministered for inflammatory conditions that result in pain (e.g., RA). The risk of gastrointestinal (GI) bleeding with steroids or NSAIDs alone is 2 times and 4 times (respectively) higher than baseline, but when these agents are taken together, the risk is 12 times higher than baseline.
image Because of the long list of side effects, steroids are not ideal for long-term high-dose administration. In diseases in which prolonged and substantial immunosuppression is required, steroid-sparing immunosuppressants are administered so that doses of steroids can be reduced or the steroids can be completely discontinued.

Advanced

image Prophylactic antibiotics against Pneumocystis pneumonia (also called Pneumocystis jiroveci pneumonia or Pneumocystis carinii pneumonia [PCP]) are administrated to patients on long-term moderate- to high-dose steroids because of the risk of acquiring this infection when immunosuppressed. Human immunodeficiency virus (HIV) infection is the most common risk factor for PCP
image In addition to being a risk factor for PCP, steroids are also coadministered to patients being treated for PCP because the antibiotic-mediated destruction of the pathogen generates a strong inflammatory response in the lungs, making the respiratory condition much worse. Steroids blunt this response.

Evidence

The range of diseases treated with systemic steroids is too large to be summarized, but some of the more common uses of systemic steroids are presented here.

image Systemic steroids and adult asthma: A systematic review in 2009 concluded that the available studies were frequently underpowered. However, some general conclusions and recommendations were made: steroids administered in the emergency department reduce hospitalizations; steroids accelerate improvements in lung function; there was no benefit in using doses larger than 50 to 100 mg prednisone equivalent; and no benefit was seen when steroids were administered for longer than 5 to 10 days total.
image Systemic steroids and RA: A Cochrane review in 2007 (15 studies, N = 1414 patients) examined radiological progression of disease and concluded that the proportion of benefit gained by glucocorticoids in reducing the progression of erosions from an average of all the studies over 1 year was 67.2% (confidence interval [CI] 48.9%, 85.4%) and over 2 years was 61.3% (CI 46.5%, 76.1%). Furthermore, this benefit was achieved in patients who were (mostly) already receiving disease-modifying antirheumatic drug (DMARD) treatment. It therefore represents a gain over and above any benefits from DMARDs alone.

FYI

image Memory tip: the effects of elevated cortisol in starvation would predict the metabolic effects: releasing and making available carbohydrate, fats, and proteins from body stores to be used by the body.

Introduction to Monoclonal Antibodies

Monoclonal antibodies (mAbs) belong to a broad category of agents (often called simply biologics) with a very large number of effects and clinical indications. The common denominator among all these drugs is the use of engineered proteins that are antibodies. There are two main categories of biologic drugs: mAbs and dimeric fusion proteins.

mAbs are produced by the body’s immune system (by B lymphocytes) for the function of recognizing, binding, and subsequently destroying infectious agents that display foreign antigens. By creating antibodies that target antigens that are part of a disease process, the disease process can potentially be inhibited or completely destroyed.

To produce large quantities of an antibody, an animal first needs to be exposed to an antigen so that the B cells are able to produce the specific antibody. Second, a method of collecting the antibody-producing cell and enabling it to produce massive quantities is required. This is accomplished by fusing two cells together into a hybridoma. Antibody-producing cells (which have a limited life span) are then fused with cells that have an unlimited life span (a cancer cell, specifically a B-lymphoma cancer cell called a myeloma), which creates cells that can indefinitely produce antibodies. In a batch of these cells, there are many different cells, giving rise to many different clones of future generations (polyclonal). The isolation and growth of single cells that produce the desired antibody results in a monoclonal production of antibodies. These monoclonal hybridomas can be grown in cultures or in mice.

Newer technologies are enabling the animal (usually mouse) portion of the antibody to be less and less, so that the resulting antibody is mostly human and therefore not destroyed by the patient’s own immune system for being a foreign antibody by human antimurine antibodies (HAMAs). Chimeric (human-mouse combination) antibodies contain fewer mouse regions than full mouse antibodies. Humanization involves replacing most of the mouse antibody with equivalent human regions while keeping only the variable, antigen-specific regions intact. Humanized mAbs have more human regions than chimeric mAbs do. Finally, fully human mAbs that contain no mouse regions are now being created (Figure 17-1).

image

Figure 17-1

Fusion Proteins

Fusion proteins are antibodies but are engineered differently than mAbs. The antigen portion is fused to the Fc fragment. The dimeric molecule can then bind to the specific cell surface binding protein and allow the activity of the Fc portion of the antibody to be directed to the cell. For example, etanercept is a combination of tumor necrosis factor (TNF) receptor bound to the antibody Fc fragment. The drug binds TNF, and the Fc fragment results in inactivation and removal of circulating TNF.

Use of Monoclonal Antibodies

The list of uses for mAbs is growing, but the major categories are as follows:

image Cancer: Cancer cells express unique antigens that can be directly targeted for destruction. Furthermore, there are growth factors that stimulate cancer cell growth that can also be inhibited.
image Immunosuppressants:

image Inflammatory diseases: Autoimmune diseases in which the immune system attacks self tissues and cells, such as lupus and RA, have been treated with mAbs that target specific components of the immune system such as TNF and many of the interleukins (ILs) in an attempt to blunt the immune response.
image Transplant rejection: Organs that are transplanted in a host patient are foreign tissue and therefore will be attacked by the host; mAbs are being used to inhibit the process of rejection.

image Infection treatment: By binding specific functional proteins expressed on bacteria or viruses, the infectious agent can be suppressed or controlled.

Conjugating or combining other molecules can provide special functions to the mAb. For example, attaching radioactive isotopes can deliver radiation to provide highly localized radiation to kill tumor cells. An example is ibritumomab, which is a CD20 mAb bound to radioactive yttrium. Conjugating toxins is another approach to delivering highly targeted cytotoxicity. An example is gemtuzumab ozogamicin; the antibody-bound toxin calicheamicin dimethyl hydrazide is cleaved from the antibody inside the cell and binds to DNA, producing apoptosis.

Naming Monoclonal Antibodies

image mAbs have multiple different targets (but only one each). mAbs are derived from different sources.
image The convention for naming mAbs is as follows: target-source-mab.

Targets

image Disease processes or tissues: immune = lim, ILs = kin, viral = vir, bacterial = bac, infectious lesions = les, cardiovascular = cir, fungal = fung, neurologic = ner, musculoskeletal = mul, bone = os, toxin as target = toxa
image Tumors: any tumor = tu(m), prostate = pro, colon = col, melanoma = mel, mammary = mar, testis = got, ovary = gov

Sources

image Human = u, mouse = mo, humanized = zu, chimera = xi

Examples

image Abciximab: ci + xi + mab = circulatory, from chimeric source

image IIb/IIIa blocker on platelets; for antiplatelet therapy

image Trastuzumab: tu + zu + mab = tumor, from humanized source

image Human epidermal growth factor target; for breast cancer
image Trastuzumab is the first mAb to be approved for the treatment of a solid tumor.

image Infliximab: li + xi + mab = immune, from chimera

image TNF-α blocker; antiinflammatory

Notes

Clinical uses for each mAb are changing and thus are not specifically listed for each drug. For drugs with which there is considerable clinical experience, separate sections will discuss further details.

Table 17-2 will not be fully inclusive by the time it is published because of the rapid growth of this area of medicine. Some drugs listed may not yet be approved for use.

Table 17-2 Monoclonal Antibodies

Name Type Target
Rituximab Chimeric CD20 on B lymphocytes
Ocrelizumab Humanized CD20 on B lymphocytes
Ofatumumab Human CD20 on B lymphocytes
Tositumomab Mouse
CD20, bound to 131I

Ibritumomab Mouse
CD20, bound to 90Y or 111In

Epratuzumab Humanized CD22 on B lymphocytes Alemtuzumab Humanized CD52 on B and T lymphocytes Muromonab Mouse CD3 on T lymphocytes Efalizumab Humanized CD11a on T lymphocytes Inolimomab Mouse CD25 (IL-2) on T lymphocytes Basiliximab Chimeric CD25 (IL-2) on T lymphocytes Daclizumab Humanized CD25 (IL-2) on T lymphocytes Gemtuzumab Humanized CD33 on hematopoietic cells Bevacizumab Humanized Vascular-endothelial growth factor (VEGF) Ranibizumab Humanized Vascular-endothelial growth factor (VEGF) Cetuximab Chimeric Epidermal growth factor receptor (EGFR) Satumomab Mouse Tumor-associated glycoprotein TAG-72 Capromab Mouse PSA (prostate), bound to 111In Omalizumab Humanized IgE (increased in asthma) Eculizumab Humanized C5 (complement) Palivizumab Humanized Fusion protein of RSV Trastuzumab Humanized HER2 (EGF) Infliximab Chimeric TNF-α Adalimumab Human TNF-α Certolizumab pegol Humanized TNF-α, bound to polyethylene glycol Denosumab Human Receptor activator for nuclear factor κ B ligand (RANKL) in bone

EGF, epidermal growth factor; HER2, human epidermal growth factor receptor 2; 131I, iodine-131; IgE, immunoglobulin E; IL, interleukin; 111In, indium-111; PSA, prostate-specific antigen; TNF, tumor necrosis factor; 90Y, yttrium-90.

B-Cell Biologics

Description

B-cell biologics specifically target B-cell lymphocytes for either destruction or suppression.

Prototypes and common drugs

mAbs (-tu-mab refers to tumor)

CD20 Target

image Prototype: rituximab
image Others: bound to radioactive ligands: tositumomab, ibritumomab

CD22 Target

image Prototype: epratuzumab

MOA (Mechanism of Action)

image Drugs that target B cells cause either destruction of the cells or interference with their ability to mount an immune response.
image As a B cell–depleting agent (destruction of B cells):

image CD20 is implicated in antibody-dependent cytotoxicity, complement-dependent cytotoxicity, and induction of apoptosis of B lymphocytes.
image Through this process, CD20 blockade therapy results in depletion of mature B cells in the blood.
image CD20 is located on 90% of B-cell neoplasms and therefore is effective at depleting these (abnormal) cell lines.

image Accelerated destruction by other anticancer drugs has also been observed when used in combination with CD20 therapy.
image As an immunomodulator (inhibitor of B cells):

image B-cell depletion (through the cytotoxic actions described previously) is an effective method of blunting a pathologic inflammatory response.
image B cells play a pivotal role in the development and progression of many autoimmune diseases. B cells must go through a series of steps before they become immunologically active, and many of these steps require cytokine binding and stimulation. Therefore blocking these cytokines can result in inhibition of the following B cell functions:

• Maturation and differentiation
• Memory induction (TNF)
• Activation
• Proliferation

image Bound to radioactive ligands: When bound to radioactive ligands, the mAb delivers targeted radiotherapy to the target cells and destroys the cells through close contact with the radioactive ligand.
image CD20 is expressed only on B cells and is present on all stages of B-cell differentiation except the very first and very last stages.

image CD20 regulates early steps in the activation process for B-cell cycle initiation and differentiation.

image Rituximab is a chimeric mAb, and most CD20 therapy clinical experience and publications are currently based on rituximab.

Pharmacokinetics

image The half-life of rituximab can be variable when treating tumor. The drug will become bound and removed from circulation when a high number of CD20 receptors are present, effectively decreasing the drug concentration and half-life. Therefore at the start of cancer therapy the half-life is around 75 hours, whereas at the end of therapy it can be as long as 200 hours.
image Rituximab is usually administered every 2 weeks by intravenous infusion.

Indications

image Tumors of B-cell lineage (through actions that destroy the cells):

image Multiple myeloma
image Lymphocytic leukemias: acute (ALL) and chronic (CLL)
image B-cell lymphomas

image Inflammatory autoimmune diseases (inhibiting or depleting B cells will potentially reduce inflammation and the disease process):

image RA
image Systemic lupus erythematosus (SLE)
image Some types of vasculitis such as Wegener’s vasculitis
image Many other inflammatory diseases are being treated in clinical trials.

image Transplant medicine (inhibiting or depleting B cells will potentially reduce a response against either the transplant or the host):

image Preventing and treating organ rejection
image Treating GVHD

Contraindications

image Active infection: These drugs are immunosuppressants and therefore would inhibit the body’s ability to fight off an infection.
image Latent infection: An example would be viral hepatitis (hepatitis B or C).

Side Effects

Early

image Infusion reactions:

image Common and mild: hypotension, hypertension, chills, rash, scratchy sensation in the throat, and bronchospasm
image Mucocutaneous reactions
image Rare and severe: hypoxia, acute respiratory distress syndrome (ARDS), myocardial infarction, shock, death
image Infusion reactions are most common during the first infusion and can be reduced by slowing down the infusion and pretreating with intravenous steroids.

Late

image Immunosuppression resulting in infections: Patients should be monitored closely for infection, particularly when treated with other immunosuppressive agents.
image Progressive multifocal leukoencephalopathy (PML) is destruction of white brain matter in a patchy distribution, believed to be caused by reactivation of the JC virus, a polyomavirus, through the process of immunosuppression. This is a rare event.

Important Notes

image CD20 antigen is not expressed by either plasma cells or B-lymphoid stem cells; therefore rituximab does not reduce total immunoglobulin (Ig) serum concentrations.
image After a four-dose course of rituximab therapy, B-lymphocyte counts recover in 9 to 12 months.

Advanced

image B cell–depleting and B cell–nondepleting strategies have both been used for treatment of autoimmune diseases.
image Future therapies:

image BAFF (B-cell activating factor), also called BlyS (B-lymphocyte stimulator), prolongs the survival of B cells, stimulates maturation, and promotes survival of autoreactive B. Anti-BAFF antibodies (belimumab) or BAFF receptor fusion proteins (briobacept) are being investigated for treating RA and SLE.
image Similarly, another receptor called APRIL (a proliferation-inducing ligand) is being targeted by a fusion protein (atacicept) that binds BAFF and APRIL. It is still under investigation.

Evidence

image The diseases being treated with B cell–targeting drugs are too numerous to list, and a summary of the current evidence is beyond the scope of this text.

FYI

image Rituximab was the first mAb used for treating cancer.
image Epratuzumab, a B cell CD22 (not CD20)–targeting drug is currently being investigated in a number of phase 3 trials for treatment of lupus and lymphoma but is not yet approved in North America.
image Ocrelizumab and ofatumumab are humanized and human mAbs respectively that target CD20 but are not yet approved. Rituximab is a chimeric mAb.

T-Cell Biologics

Description

T-cell biologics specifically target T-cell lymphocytes for either destruction or suppression.

Prototype and Common Drugs

mAbs (-li–mab, -li- refers to the immune system)

CD3 Target

image Prototype: OKT3 (an early murine mAb)
image Others: Teplizumab, otelixizumab, and visilizumab

CD25 Target (IL-2 receptor)

image Prototype: daclizumab
image Others: basiliximab, inolimomab

CD11a Target (lymphocyte function–associated antigen 1 [LFA-1])

image Prototype: efalizumab

Fusion Proteins (-cept)

LFA-3 Target

image Prototype: alefacept

CD28 Target (cytotoxic T-lymphocyte antigen [CTLA4])

image Prototype: abatacept

MOA (Mechanism of Action)

image The roles and activities of T cells are extremely diverse and complicated. Their contributions to disease are currently incompletely understood, and this section is a very simplified explanation of a very complicated system. This area of medicine is changing quickly, as is the understanding of these disease processes.

CD3

image CD3 is the defining marker for T cells. Therefore, all T cells express CD3. As a result, drugs that target CD3 have the potential to influence all subtypes of T cells and are therefore nonspecific. They will influence proinflammatory as well as antiinflammatory T cells and also target activated and nonactivated T cells.
image A strong inflammatory reaction, cytokine-release syndrome, often occurs with the first dose of OKT3. It can be severe, resulting in a range of signs and symptoms from fever to tachycardia to meningitis (noninfectious) and adult respiratory distress syndrome (ARDS). This reaction occurs because of a massive synchronized T-cell activation.

image Newer modified CD3 inhibitors have been designed to be nonactivating, thus reducing the probability of this syndrome.

image CD3 targeting drugs also induce selective apoptosis of activated T cells after binding to CD3.

Transplant Medicine

image CD3 inhibition has been used to prevent acute graft rejection.

Autoimmune Diseases

image Newer CD3 inhibitors are currently in clinical trials for diseases such as psoriatic arthritis (arthritis associated with psoriasis) and type I diabetes.

CD25 (IL-2 Receptor)

image CD25 is the IL-2 receptor. There are many roles of IL-2.

Autoimmune Diseases

image Increased CD25 (IL-2 receptor) expression has been demonstrated in many autoimmune diseases. Suppression or antagonism of IL-2 has resulted in reduced inflammation in many of these diseases.
image Important source of apparent conflict:

image Regulatory T cells (Treg) are very important in the control of self-tolerance. They play a vital role in preventing the immune system from attacking a person’s own tissues and cells. They express CD25 and require IL-2 for their growth and survival; however, they suppress the immune system.
image Autoreactive T cells are defined as T cells that attack self antigens (those that are present in the body), and these attacks are a major contributor to autoimmune diseases.
image Treg cells suppress the autoreactive T cells. Abnormal (low) Treg levels and function are associated with many autoimmune diseases.
image Treatment with CD25 inhibition seems clearly beneficial, so the benefits from overall T cell immune suppression must outweigh any specific effects on suppressing Treg function.

Cancer

image Very few normal (nonactivated) cells express CD25; however, many lymphocyte malignancies express this receptor. Targeting this receptor in certain cancers with a lymphocyte lineage will deplete those cells.

Transplant Medicine

image Solid organ transplant rejection is associated with an elevated CD25 level that is linked to the activation of T cells. Inhibiting CD25 therefore blunts the immune response to transplanted organs.
image Bone marrow and stem cell transplants result in foreign white blood cells being introduced into the patient. These cells can mount an immune response against the patient, a condition called graft-versus-host disease (GVHD). This process can be suppressed by inhibition of CD25.

CD28 (CTLA-4)

Autoimmune Diseases

image T cells require two signals to activate them: the antigen and a second costimulator. Costimulatory molecules are antigen independent; the costimulation does not require the binding of antigen. CTLA-4 is a costimulator that regulates the immune response. It is up-regulated in activated T cells.
image CTLA-4 inhibition:

image Interrupts the costimulatory signal, preventing and potentially reversing T-cell activation. In fact, exposure of T cells to antigen in the absence of costimulation inhibits responses to future exposure to antigen.
image Increases the number of Treg cells.

Cancer Therapy

image CTLA-4 inhibition does not deplete T cells or other leukocytes and is therefore not useful for cancer treatment.

Transplant Medicine

image Prevention of binding of the costimulator on first exposure to a new antigen (the transplanted organ) blunts the immune response against the organ and is therefore effective.

CD11a (LFA-1)

image CD11a is important for interactions between the integrin LFA-1 and cell adhesion molecule intercellular adhesion molecule 1 (ICAM-1). Integrins are proteins that facilitate the attachment of cells to other cells or to extracellular matrices. Once attached, the cell can transmigrate from the blood into the tissue, across the endothelial barrier.
image In addition to adherence, integrins also communicate signals to the inside of the lymphocyte.
image Efalizumab inhibits tight lymphocyte adhesion to inflamed endothelium; inhibiting this adhesion results in reduced lymphocyte entry into the site of inflammation and thus reduces the inflammatory response locally.
image It is currently being used to treat psoriasis.

Cancer Therapy

image LFA-1 inhibition does not deplete T cells or other leukocytes and is therefore not useful for cancer treatment.

LFA-3

image LFA-3, like LFA-1, is involved with cellular adhesion. LFA-3 is located on antigen-presenting cells (APCs).

Pharmacokinetics

image These drugs are administered by intravenous infusions over 30 minutes to a few hours.

Indications

image Tumors of T-cell lymphocyte lineage (through actions that destroy the cells)
image Inflammatory autoimmune diseases (inhibiting inflammatory cells such as T cells will potentially reduce inflammation and the disease process):

image Rheumatoid arthritis (RA)
image Systemic lupus erythematosis (SLE)
image Some types of vasculitis such as Wegener’s vasculitis
image Many others inflammatory diseases are being treated in clinical trials.

image Transplant medicine

image Preventing and treating rejection
image Preventing and treating GVHD

Contraindication

image Active infection is a contraindication to immunosuppressive therapies.

Side Effects

image With all classes of drugs, the risk of immunosuppression leading to infection is an ever-present side effect.
image Infusion reactions: Nausea, vomiting, diarrhea, hypotension, shortness of breath, and headache, to name a few, can all occur.

CD3

image With OKT3 only, cytokine release syndrome: a massive inflammatory response caused by binding to the T cells combined with Fc receptor cross-linking.

image The syndrome is attributed to increased serum levels of cytokines, particularly the production of TNF.
image Symptoms usually are worst with the first dose; frequency and severity decrease with subsequent doses.
image Signs and symptoms include the following:

• Common: fever, chills, rigor, headache, tremor, nausea, vomiting, diarrhea, abdominal pain, malaise, muscle and joint pain, and generalized weakness
• Less common: skin reactions, aseptic meningitis, and cardiorespiratory effects:

image Potentially fatal: severe cardiac and/or respiratory dysfunction, namely ARDS, circulatory shock, arrhythmias, and cardiac arrest

Evidence

Abatacept and Rheumatoid Arthritis

image A Cochrane review in 2009 (seven studies, 2908 patients) found that patients treated with abatacept, compared with placebo, were more likely (relative risk [RR] 2.21) to achieve clinical benefit as measured by the ACR50, an index of pain, disability, and number of affected joints. The number needed to treat (NNT) was 5. The risk of side effects was low (RR 1.05) compared with placebo, and the harms were assessed to be not significant except for increased infections assessed at 12 months.

FYI

image CD4+ T cells are depleted in acquired immunodeficiency syndrome (AIDS); drugs that target CD4 exist but are currently not in clinical practice.

Mixed Biologics

Description

Mixed biologics target B- and T-cell lymphocytes or their cytokine mediators for either destruction or suppression.

Prototype

mAbs (-tu-mab refers to tumor and -li-mab to the immune system)

CD52 (CAMPATH-1) Target

image Prototype: alemtuzumab

IL-6 Receptor Target

image Prototype: tocilizumab

MOA (Mechanism of Action)

CD52 (CAMPATH-1)

image Alemtuzumab is a humanized mAb against CD52.
image CD52 is present on both B- and T-cell lymphocytes, normal neutrophils, and most B- and T-cell lymphomas.
image CD52 is not expressed on CD34+ lymphocytes (which is a marker for hematopoietic progenitor cells), so hematopoietic progenitor cells are not targeted with CD52 therapy. This is important because targeting very early stem cells will result in destruction of multiple cell lines, which would be undesirable.
image CD52 targeted by mAbs induces tumor cell death through the following:

image Antibody-dependent cellular cytotoxicity
image Complement-dependent cytotoxicity

image This results in extensive lympholysis (destruction of lymphocytes) by inducing apoptosis and produces prolonged T- and B-cell depletion
image Through the depletion of T- and B-cell lymphocytes, CD52 targeted therapy has become clinically useful for the treatment of:

image Lymphomas and leukemias, especially CLL because of its ability to destroy these cells
image Transplant medicine (GVHD) and autoimmune disorders because of its ability to suppress B- and T-cell function, thus acting as an immunosuppressant

IL-6 Receptor

image Tocilizumab is a humanize1d mAb.
image Overproduction of IL-6 is thought to play an important role in the pathogenesis of some autoimmune diseases such as RA. IL-6 is elevated in patients with RA, and IL-6 levels correlate with disease severity
image Tocilizumab binds selectively and competitively to both soluble (in the blood) and cell surface IL-6 receptors, blocking IL-6 signal transduction.
image Blockage of IL-6 does not destroy lymphocytes, and therefore IL-6 does not deplete cell lines and is not used in cancer treatment.

Pharmacokinetics

image Tocilizumab is administered intravenously every 4 weeks.

Indications

Alemtuzumab

image Leukemia and lymphoma
image Transplant medicine

image Prevention and treatment of rejection
image Prevention and treatment of GVHD

Tocilizumab

image RA

Contraindications

image Active infections: Immunosuppression results in a decreased ability to fight off infection.
image An existing immunodeficiency would result in an increased risk of new infection.

Side Effects

Alemtuzumab

image Acute infusion reactions and the depletion of hematopoietic cells and T cells may occur. Patients also may develop severe pancytopenia and death.
image Opportunistic infections are a serious side effect.

Tocilizumab

image Nasopharyngitis
image Elevated cholesterol (reversible)
image Elevated liver enzymes (mild and not associated with detectable liver damage)
image Neutropenia
image Infections

Important Notes

image Nomenclature (-li- or -tu-) designation does not restrict the use of a drug to that class of therapy. Many drugs are used to treat both autoimmune diseases and hematologic cancers because of the roles that lymphocytes play in both.

Evidence

image Beyond scope

Tumor Necrosis Factor (TNF)–α Inhibitors

Description

image TNF-α is an important inflammatory cytokine.

Prototype and Common Drugs

mAbs (-li–mab; -li- refers to the immune system)

image Prototype: infliximab
image Others: adalimumab, certolizumab, golimumab

Fusion Protein (-cept)

image Prototype: etanercept

MOA (Mechanism of Action)

image TNF-α is mostly produced by macrophages but is also produced by other inflammatory cells. It binds to TNF receptors (called TNFRs), which are present on many different cells of the immune system.
image It promotes inflammation and is believed to play important roles in both inflammatory reactions to infections and also, when present in abnormally high levels, in the pathogenesis of autoimmune diseases. It has been called the master regulator of the immune system.
image The inflammatory cascades are very complicated. TNF-α is believed to exert its proinflammatory actions by promoting:

image The acute phase response, which occurs early in the inflammatory response and is mediated in part by the release of other proinflammatory cytokines, including IL-1, IL-6, and IL-8, resulting in fever, loss of appetite, vasodilation, and tachycardia
image Increased expression of endothelial adhesion molecules, which results in increased migration of leukocytes into target organs
image Apoptosis

image In summary, through inhibition of TNF-α, the inflammatory response is blunted.
image mAbs bind TNF-α receptors. In contrast, the fusion protein etanercept is a circulating TNF receptor that binds TNF (the ligand itself, not the receptor).

Pharmacokinetics

image Drugs are administered by injection, usually every 2 to 4 weeks.
image The half-lives of these drugs are in the range of 5 to 14 days. The elimination half-life of certolizumab (a PEGylated mAb) is the longest, because of the polyethylene glycol (PEG) portion, which decreases renal elimination.

Indications

image Autoimmune diseases:

image Rheumatoid arthritis (RA)
image Crohn’s disease and ulcerative colitis (inflammatory conditions of the digestive tract)
image Psoriasis (inflammatory disease of the dermis)
image Ankylosing spondylitis

Contraindications

image Latent TB: TB can be reactivated if the immune system is suppressed.
image Patients who are immunocompromised: Combination with additional immunosuppression increases the risk of infection.
image Active infection: The immune system must remain intact to fight the current infection before treatment with an immunosuppressant begins.

Side Effects

image Injection site irritation
image Acute inflammatory reaction: Because of the ability of TNF to influence the immune system, extensive inflammatory reactions can occur within 24 hours (usually within 6 hours) after administration. They are characterized by fever, hypotension, tachycardia, itching, chest pain, and shortness of breath. These reactions are relatively common (10% of the time), but only rarely are they severe enough to discontinue treatment.
image Delayed inflammatory reaction: Signs and symptoms that occur within 2 weeks after the injection are probably mediated by antibodies to the drug. Symptoms of these reactions include fever, rash, urticaria (itching), myalgia (muscle pain), arthralgia (joint pain), jaw tightness, and edema.
image Infection: Because of the immune suppression, common bacterial and also opportunistic infections are more common in patients receiving TNF suppression:

image Bacterial sepsis (widespread inflammatory response caused by bacterial infection in the blood)
image Fungal infections
image Latent TB (previous TB can be reactivated); patients must be screened for previous TB infections before starting anti-TNF therapy
image Herpes zoster

image Severe but rare side effects include heart failure, liver failure, and demyelinating disorders of the central nervous system (CNS).
image Cancer: Another function of the immune system is to provide surveillance of early cancer cells and to destroy them early. A blunted immune system therefore can increase the potential for development of cancer.

Important Notes

image Anti-TNF therapy for RA is considered a biologic DMARD, which, as previously noted, stands for disease-modifying antirheumatic drug. DMARDs slow the progression of joint destruction. Use of DMARDs is in contrast to “symptom-only” therapy, which would include analgesics (such as acetaminophen or NSAIDs), in that symptom-only therapy does not slow the progression of the disease.
image Antibodies to the antibody (ATA) can occur. In this situation, the patient’s immune system recognizes the mAb as a foreign antigen and generates antibodies against it, thus neutralizing it. This reaction is less common with mAb types that are more similar to human antibodies: human (3%) < humanized < chimeric (10%).

Advanced

image TNF is active when three monomers bind together into a trimeric unit and bind to two different receptors: TNFR1 and TNFR2. These receptors are also called p55 and p75, respectively.
image In contrast to infliximab and adalimumab, certolizumab does not contain an Fc portion and therefore does not induce complement activation, antibody-dependent cellular cytotoxicity, or apoptosis. Remember that the Fab portion is the antigen-specific region and the Fc region is important for determining the type of response that occurs after the Fab portion binds to the antigen.

image The Fc portion is replaced by polyethylene glycol (PEG), which is conjugated to the Fab portion. The PEG portion results in a longer half-life and also eliminates any immune function that would have been activated by the Fc portion of the antibody.

Evidence

Rheumatoid Arthritis

Monotherapy versus Methotrexate, and Monotherapy versus Combination Therapy

image A 2008 systematic review of DMARD therapy for RA concluded that anti-TNF monotherapy was similar in efficacy to treatment with methotrexate alone, whereas the combination of an anti-TNF agent with methotrexate reduced disease activity more and slowed radiographic progression to a greater extent than did anti-TNF monotherapy or methotrexate alone. These findings were similar to those of a Cochrane review in 2009 that examined all biologic DMARDs in the treatment of RA.

Infliximab (with or without Methotrexate) versus Placebo (Plus Methotrexate)

image A Cochrane review in 2002 (two trials, 529 patients) found that after 6 months, response rates were significantly improved with all infliximab doses compared with controls. The NNT with infliximab to achieve an American College of Rheumatology (ACR) 20, 50, or 70 response (these are different measures of response based on disability, pain, and number of affected joints) in patients with refractory RA under specialist care ranged from 2.94 to 3.33 for ACR 20, up to 5.88 to 12.5 for ACR 70. Withdrawals because of adverse events and withdrawals for other reasons were not statistically significantly different in patients receiving infliximab than in controls.

Crohn’s Disease

Infliximab versus Placebo

image A 2004 Cochrane review (four studies) found one randomized controlled trial (RCT) (N = 108) that provided evidence that infliximab was more effective than placebo in inducing remission of Crohn’s disease (RR 8.1). The four studies were too heterogeneous for results to be combined.

Ulcerative Colitis

Infliximab versus Placebo or Steroid

image A 2006 Cochrane review showed that in the population of patients with refractory ulcerative colitis, infliximab was more effective in inducing clinical remission than placebo (RR 3.22); it also showed that there was no statistical difference between steroid and infliximab for the same endpoint.

FYI

image TNF-α was initially called cachexin and was described in 1975 for its ability to lyse tumors in animal models (giving rise to the name tumor necrosis factor).
image Cachectic is a term used to describe someone who has lost a lot of weight with considerable muscle atrophy, generally because of an advanced disease process.
image TNF-β (note this is beta, not alpha) is also called lymphotoxin and is produced by CD8+ T cells.

Antimetabolites

Description

image Antimetabolites are purine or pyrimidine analogues. This section deals with antimetabolites that are used primarily as immunosuppressants; see also the section on antimetabolites used for cancer therapy.

Prototypes

image Azathioprine
image Mycophenolate (mycophenolate mofetil [MMF])

MOA (Mechanism of Action)

image Purines and pyrimidines are the two types of bases used in DNA and RNA. Purines are guanine (G) and adenine (A); pyrimidines are cytosine (C), thymine (T), and uracil (U). Uracil (U) is found only in RNA, whereas thymine (T) is only in DNA. The bases are all attached to a single phosphate group, making them monophosphates.
image Inosine monophosphate (IMP), the precursor to guanine monophosphate (GMP), is converted by IMP dehydrogenase.
image Mycophenolate is hydrolyzed to mycophenolic acid (MPA), which inhibits IMP dehydrogenase and thereby prevents GMP production. GMP is a required base for both DNA and RNA, and without it, DNA and RNA synthesis is reduced (Figure 17-2).
image Azathioprine is converted to mercaptopurine (itself a drug), which is then metabolized through more steps to 6-thio-GTP; 6-thio-GTP can be incorporated into DNA and RNA, but because it is not a normal base, it halts further DNA and RNA synthesis. It is called a fraudulent nucleoside.
image Regardless of the exact mechanism of action on DNA and RNA:

image Reduced DNA synthesis results in reduced proliferation of cells. As a general rule, rapidly dividing cells are more sensitive to drugs that influence cell division. These include the following:

• Hematologic precursor cells in the bone marrow; lymphocyte suppression is the primary mechanism by which these drugs are immunosuppressants
• GI tract mucosal cells
• Cancer cells

image Reduced RNA synthesis results in reduced protein transcription and thus reduced functional activity of cells.

• For example, antibody-producing cells (B lymphocytes) would produce less antibody.

image Two features of antimetabolites that make them a little more specific to inhibiting the immune system include:

image Both T and B lymphocytes depend on de novo (they must produce their own) synthesis of purines, whereas other cell types are able to use salvage pathways to obtain their DNA and RNA building blocks. Therefore lymphocytes are more susceptible to antimetabolites than are these other cell lines.
image Mycophenolate reversibly inhibits the type II isoform of IMP dehydrogenase, which is preferentially expressed by activated lymphocytes.

image The similarities between mercaptopurine (the azathioprine metabolite) and the purines guanine and adenine are easily seen (Figure 17-3).
image

Figure 17-2

image

Figure 17-3

Pharmacokinetics

Azathioprine

image Azathioprine is metabolized quickly (half-life of 10 minutes) but has many active metabolites; therefore blood level measurements of the parent drug do not provide useful information.
image Azathioprine is metabolized by the liver to mercaptopurine; mercaptopurine metabolism occurs via a couple different enzymes, one of which is xanthine oxidase, an enzyme that is important in the disease gout; allopurinol, a xanthine oxidase inhibitor used to treat gout, results in dramatically increased levels of active metabolites. This is an important drug interaction.

image Another important enzyme that metabolizes mercaptopurine is thiopurine methyltransferase (TPMT); the TPMT activity rate is very important because TPMT catalyzes a reaction to produce an inactive metabolite and is therefore felt to be a strong predictor for myelosuppression and hepatotoxicity. Patients with low TPMT activity develop higher levels of 6-thio-GTP and are therefore more susceptible to acute bone marrow suppression and liver damage. TPMT activity is genetically determined, and tests for TPMT activity levels are available.

image Timing of efficacy: It can take a couple of months before azathioprine exerts its effects. This is thought to be related to the long time required to generate intracellular levels of 6-thio-GTP.
image Because these drugs are frequently used in patients with kidney transplants and the transplanted kidney function is often less than the level of function of a normal kidney, it is critical to know how these drugs are metabolized and eliminated

image Azathioprine: Although renal clearance is not the primary mode of elimination, the dose should be decreased in patients who are anuric (complete absence of renal function).

Mycophenolate

image As with azathioprine, the half-life of the parent compound is only minutes, because of conversion to active and inactive metabolites.

Side Effects

image Most side effects are related to systems that require high cell turnover:

image GI: mucositis, diarrhea, vomiting
image Bone marrow: leukopenia, thrombocytopenia, anemia
image Alopecia: hair loss caused by hair follicle suppression

image Immunosuppression-related effects include the following:

image Infections
image Cancer risk from decreased tumor surveillance by the immune system
image Dermatitis: many different inflammatory skin diseases

image Other effects:

image Hepatic dysfunction: indicated by elevated liver laboratory test results and possibly jaundice

Indications

image Prevention of cell division:

image Cancer

image Decreased lymphocyte T-cell division:

image Prevention and treatment of transplant organ rejection
image Treatment of autoimmune diseases such as the following:

• RA
• Inflammatory bowel disease
• Psoriasis
• Lupus (especially for lupus nephritis)

Contraindications

image Mycophenolate is contraindicated in pregnancy, whereas azathioprine is not.
image An active, severe infection is a contraindication.

Important Notes

image In treatment of autoimmune diseases, steroids are generally the first-line immunosuppressants employed because they act quickly; however, there are many side effects related to prolonged steroid use, and therefore nonsteroid immunosuppressants are generally preferred for long-term immunosuppression. Antimetabolites are used therefore for long-term “steroid-sparing” immunosuppression.
image Antimetabolites exert their immunosuppressant effects over a period of weeks, which is a slower onset than that of steroids, which become effective in about a day.

Advanced

image Azathioprine is converted to mercaptopurine; however, azathioprine is felt to be a more effective immunosuppressant than mercaptopurine because of increased intracellular uptake. Intracellular levels of the metabolite 6-thio-GTP need to be high for the drugs to be effective, and azathioprine appears to be taken up specifically by lymphocytes.
image Another mechanism recently suggested for the immunosuppressive effect of azathioprine involves 6-thio-GTP leading to activation of a mitochondrial pathway of apoptosis in lymphocytes.

Evidence

Azathioprine Plus Steroid versus Steroid Alone for Treatment of Lupus Nephritis

image A Cochrane review in 2004 (3 studies, 78 patients) demonstrated that azathioprine plus steroids reduced the risk of all-cause mortality compared with steroids alone (RR 0.60) but did not alter renal outcomes. Neither therapy was associated with increased risk of major infection.

FYI

image The two drugs in this class are structurally different but do have some common features (the side-by-side rings) (Figure 17-4).
image One of the other pyrimidine antimetabolites (flucytosine) is an antifungal drug.
image When all three hematologic cell lines (white cells, red cells, and platelets) are decreased, the condition is called pancytopenia.
image

Figure 17-4

Calcineurin Inhibitors

Description

Calcineurin inhibitors are immunosuppressants.

Prototype and common drugs

image Prototype: cyclosporine
image Others: tacrolimus (FK506), pimecrolimus

MOA (Mechanism of Action)

image These drugs act on T cells (a type of lymphocyte). T cells are involved in cell-mediated immunity (as opposed to humoral immunity, which is mediated by B lymphocytes).
image Calcineurin is a protein phosphatase responsible for the transcription of IL-2, an important immune system cytokine. Calcineurin inhibitors stop the production of IL-2.
image IL-2 enables the activation of inactive T cells. It also plays a role in proliferation and differentiation of T cells (resulting in immunologic memory).
image A protein called nuclear factor of activated T cells (NFAT) binds T cell DNA and stimulates production of IL-2. NFAT is activated through dephosphorylation by calcineurin (Figure 17-5).
image Therefore, calcineurin is an enzyme in T cells that results in transcription of IL-2.
image Through the inhibition of IL-2 production and thus T cell activation, proliferation, and differentiation, calcineurin inhibitors are immunosuppressants.
image Calcineurin inhibitors are not very effective at blunting the activity of T cells that have already been activated. They are more effective at preventing the immune response before it starts. For example, if acute rejection of a transplanted organ has already started, other immunosuppressants are required for effective treatment.
image

Figure 17-5

Pharmacokinetics

image Cyclosporine has a narrow therapeutic index. Levels must be frequently measured to help reduce the probability of side effects.
image Cyclosporine is extensively metabolized by the liver and secreted in the bile. Only 6% is secreted in the urine. Dose adjustment is required in liver failure but not in kidney failure.

image When cyclosporine is administered to liver transplant patients, there is an important consideration if the transplanted liver is not functioning at 100%, and cyclosporine toxicity could result.

image Drugs that inhibit CYP3A will result in increased cyclosporine levels.
image Drugs that induce CYP3A will result in decreased cyclosporine levels.

Indications

image To prevent or suppress organ rejection in solid organ transplant recipients, most commonly the kidney
image To suppress inflammation in inflammatory diseases, but not as a first-line drug:

image Psoriasis
image RA

Side Effects

Consequences of Immunosuppression

image Increased risk of infections, especially opportunistic infections

image Fungal
image Viral: Epstein-Barr virus (EBV), cytomegalovirus (CMV)
image Atypical bacterial: Nocardia, Listeria, mycobacterial

image Increased risk of neoplasm: Cancer is often detected and eradicated by the immune system in its very early stages.

Other

image Nephrotoxicity: Kidney damage is a common problem with administration of cyclosporine. This is the most important side effect. It is possibly mediated through renal arteriolar vasoconstriction. Renal damage often limits administration of cyclosporine.
image Hypertension: The exact mechanism is unknown, but cyclosporine has been shown to increase sympathetic nervous system activity, which would result in increased blood pressure.
image CNS problems: Tremors and headaches may occur, usually seen with larger doses.
image Tacrolimus only: Hyperglycemia (diabetes) may occur as a result of pancreatic beta cell inhibition.

Less Common

Cyclosporine Only

image Hirsutism or hypertrichosis (hair growth): a cosmetic problem
image Gum hyperplasia

Tacrolimus Only

image Alopecia (paradoxically, the opposite of hypertrichosis)

Important Notes

image In patients with kidney transplants (a population of patients who regularly receive calcineurin inhibitors), it can be diagnostically difficult to determine if declining renal function is a result of rejection (which would be managed by increasing the dose or adding immunosuppressive drugs) or of toxicity of the immunosuppressive drugs (which would be managed by lowering the dose or stopping the drugs).

Advanced

image Less common side effects include the following:

image Haemolytic uremic syndrome is characterized by microangiopathic anemia, thrombocytopenia, and acute renal failure. Simply thought of, it is a process whereby platelets are consumed into intravascular aggregates, causing a meshwork of clots that lyse red blood cells and the floating intracellular debris plugs up the glomeruli and tubules, resulting in kidney failure.
image Posterior reversible encephalopathy syndrome is an uncommon side effect with cyclosporine that is also seen with eclampsia and in the setting of severe hypertension (two conditions of extreme vasoconstriction). On brain imaging studies, there is widespread edema that predominates in the parietal and occipital regions (posterior regions). There is also clinical evidence of neurotoxicity (dysfunction).

image Cyclosporine versus tacrolimus side effects:

image Tacrolimus seems to induce less nephrotoxicity and less hypertension.
image Cyclosporine seems to induce less neurotoxicity.

Evidence

Cyclosporine versus Tacrolimus in Kidney Transplants

image A Cochrane review in 2005 (20 studies, 4102 patients) found that kidney transplant loss at 6 months was significantly reduced (RR 0.56) in patients treated with tacrolimus. This effect was persistent for up to 3 years.

FYI

image Nomenclature caution:

image Do not confuse cyclosporine with another immunosuppressant, cyclophosphamide.
image Sirolimus and everolimus are immunosuppressives and also function to inhibit T cells, but they do not bind to calcineurin and therefore are not calcineurin inhibitors. Note the similarity of nomenclature to tacrolimus.

image Tacrolimus is in the same chemical family as macrolide antibiotics, but it is never used as an antibiotic.
image The IL-2 receptor is also called CD25. CD stands for cluster of differentiation and reflects a nomenclature system for defining cell surface markers on white blood cells (and now for other cells, too). There are more than 300 different CDs. The number gives no indication of the function or structure of the CD, and there is an enormous range of CDs. CD4 and CD8 are probably the most widely recognized CDs.
image Cyclosporine is not water soluble and requires bile production to be intact for oral administration. In patients with liver transplant who might have impaired bile production, the absorption of cyclosporine would be unpredictable. It was modified into a microemulsion in the 1990s, which solved this problem.

Target of Rapamycin (mTOR) Inhibitors

Description

mTOR inhibitors are immunosuppressant and antineoplastic agents and are classified as proliferation signal inhibitors.

Prototype and common drugs

image Prototype: sirolimus (also called rapamycin)
image Others: temsirolimus, everolimus

MOA (Mechanism of Action)

image mTOR (mammalian target of rapamycin) is a serine-threonine protein kinase activated by several growth factors after receptor binding.
image Sirolimus binds a protein called FKBP 12 (FKBP stands for FK506 binding protein) in the cytoplasm. The drug-protein complex then binds and inhibits mTOR (Figure 17-6).
image Inhibition of mTOR blocks cell-cycle progression at the G1 → S phase transition.
image mTOR regulates important functions of the cell, including proliferation, angiogenesis (blood vessel formation), cell survival, protein synthesis, and transcription. It is recognized as a key point in many cellular functions.
image Through this mechanism, mTOR inhibitors:

image Impede vascular endothelial cell stimulation by vascular endothelial growth factor (VEGF)
image Reduce abnormally increased proliferation of endothelial and vascular smooth muscle cells, which is an important component of chronic rejection
image Block the action of IL-2 and alter the activation of T and B lymphocytes
image Alter the growth and proliferation of cancerous lymphocytes

image All functions of mTOR are not yet fully elucidated, and mTOR could be involved in a wider variety of biologic effects.
image

Figure 17-6

Pharmacokinetics

image Sirolimus and everolimus are administered orally, whereas temsirolimus is administered intravenously.
image Half-lives are 43 hours for everolimus and 60 hours for sirolimus.
image Metabolism is by CYP3A4, and transport is by P-glycoprotein. Temsirolimus is metabolized to sirolimus.
image Drug interaction: Cyclosporine, another antirejection drug used in renal transplants, increases the levels of sirolimus and everolimus; when used together with sirolimus or everolimus, drug levels must be measured.

Indications

image To prevent transplant rejection
image Drug-eluting stents: to reduce endothelial overgrowth of coronary (and other vascular) stents
image Treatment of renal cell carcinoma

Contraindications

image None

Side Effects

image Antiproliferative side effects (reduced proliferation of cells that normally proliferate quickly):

image Mucositis and aphthous ulceration (oral canker sores) may occur.
image Anemia, thrombocytopenia, and neutropenia: Inhibitors of mTOR should be stopped if the platelet count falls below 75 or the absolute neutrophil count (ANC) falls below 1.0.

image Interstitial pneumonitis
image Infection (resulting from immunosuppression)
image Metabolic effects: hyperglycemia, hyperlipidemia

Important Notes

image Sirolimus is not nephrotoxic, a very significant advantage over calcineurin inhibitors, especially when being used in the setting of renal transplant, when every effort is made to protect the new transplanted kidney. Calcineurin inhibitors, which are also used in renal transplant patients, are nephrotoxic.

Advanced

image Sirolimus first binds FKBP (FK506 binding protein), the protein that FK506 (tacrolimus) binds to. However, the drug-protein complex when bound to sirolimus acts differently than when bound to tacrolimus. Therefore the two drugs act on the same protein in the body but in a different way.
image Among rapamycin, cyclosporine, and tacrolimus (immunosuppressants for transplant rejection), rapamycin has the strongest antiangiogenic activity.

image It may be useful for the prevention of secondary tumors (lymphomas and squamous carcinomas) in the transplant population.
image Chronic use of cyclosporine or tacrolimus is a risk factor for secondary tumor development, as these agents suppress the tumor surveillance function of the immune system.

image Drug interaction: Although sirolimus is not nephrotoxic alone, coadministration with a calcineurin inhibitor (another drug used for renal transplants) results in greater kidney damage than with a calcineurin inhibitor alone. Therefore there is some interaction with calcineurin inhibitors that potentiates the renal damage induced by the calcineurin inhibitor, and the two drugs should not be coadministered.

FYI

image Important nomenclature:

image Tacrolimus is not an mTOR inhibitor. It is a calcineurin inhibitor, and although it is also an immunosuppressant used for prevention of organ rejection, these drugs belong to two different classes of drug, despite the similarity of their names.
image Sirolimus is produced by the bacterium Streptomyces hygroscopicus, which was isolated from Rapa Nui (Easter Island).

image Sirolimus is classified as a macrolide (antibiotic). However, it was initially developed as an antifungal and does have antifungal properties. It is important to note that when an infection is being treated, a strong immune system is desirable; sirolimus is an immunosuppressive and therefore is used clinically in a way, ironically, that is the polar opposite of the use for which it was originally designed.
image Sirolimus is a large cyclic molecule (as are macrolides), and the difference between sirolimus and everolimus is a single hydroxyl (-OH) group.
image Sirolimus is being investigated as:

image An antiangiogenic agent for cancer therapy, specifically renal cell carcinoma
image Therapy for psoriasis

Activated Protein C

Description

Activated protein C is part of the coagulation cascade but is used as an antiinflammatory.

Prototype

image Drotrecogin alfa (also called activated protein C or APC)

MOA (Mechanism of Action)

image The inflammatory system and coagulation system are tightly linked:

image Activation of each system activates the other; thus inflammation causes coagulation and coagulation causes inflammation.

image Therefore, selectively inhibiting the coagulation cascade has the potential to inhibit the inflammatory response, and this is the basis for using activated protein C in severe inflammatory states known as severe sepsis or septic shock.
image Protein C is a natural anticoagulant that is a vitamin K–dependant protein synthesized by the liver. It becomes activated and works in conjunction with protein S to inhibit coagulation by:

image Inactivating factors Va and VIIIa
image Inhibiting release of plasminogen activator inhibitor 1 (plasminogen is converted to plasmin, which lyses clots; inhibition of an inhibitor of this process will therefore increase its activity)
image Inhibiting activation of thrombin-activatable fibrinolysis inhibitor (TAFI) (Figure 17-7)

image In addition to its anticoagulant properties, activated protein C has also been shown to demonstrate the following antiinflammatory effects:

image Blocks the accumulation of leukocytes at sites of inflammation
image Modulates endothelial cell function

image Low levels of protein C are present in more than 85% of patients with severe sepsis, and therefore the ability of naturally occurring protein C to exert its antiinflammatory effects in these patients is reduced and could potentially be enhanced by supplementation of activated protein C.
image

Figure 17-7

Pharmacokinetics

image Activated protein C is metabolized by plasma proteases: 80% is eliminated within 13 minutes, and 98% is cleared within 2 hours. This is important because patients with septic shock sometimes require surgery, and activated protein C needs to be discontinued 2 hours before surgery. Furthermore, if bleeding occurs while a patient is on activated protein C, then the anticoagulant effect can be reversed within 2 hours.
image Activated protein C is administered intravenously as an infusion, usually for 96 hours.

Indications

image Severe sepsis or septic shock in selected (very sick) patients

image Specifically, patients with an APACHE score (measure of severity of acute illness) greater than 25

Contraindications

image Active bleeding or very high risk of bleeding (e.g., a recent stroke)

Side Effect

image Bleeding

Important Notes

image Patients who are candidates for activated protein C are very sick and are cared for in a critical care setting. Decisions to administer activated protein C are generally made by physicians specializing in critical care.

Evidence

image In two large RCTs (the PROWESS and ADDRESS studies) comparing activated protein C with placebo, a mortality benefit (absolute risk reduction of 6.1%) was demonstrated in patients who were very sick (APACHE score greater than 25) and treated with activated protein C. However, there was no mortality benefit in patients who were less sick (APACHE score less than 25).

FYI

image APACHE stands for Acute Physiology and Chronic Health Evaluation, and the APACHE scoring system is used to describe severity of illness of patients admitted to the intensive care unit. The score ranges from 0 to 71 and is based on 17 physiologic parameters such as heart rate, white blood count, and Pco2.
image Primitive organisms use coagulation as an immune response; to produce clot around the infection and isolate it from the rest of the circulation. This helps to defend against the advancement of the infection.
image Other primitive organisms without a circulatory system (and thus no need to stop bleeding) still have a coagulation system to help defend against microbial invasion.
image Activation of plasminogen to plasmin (a step that is promoted by activated protein C) results in lysis of clots; tPA, or tissue plasminogen activator, is a thrombolytic drug.

Glatiramoids

Description

Glatiramoids are used in the treatment of multiple sclerosis (MS).

Prototype

image Glatiramer

MOA (Mechanism of Action)

image The key pathophysiologic features of MS include mononuclear cell infiltration, demyelination, and scarring (gliosis) of the central nervous sytem, leading to significant neurologic deficits.
image The actions of glatiramer in the treatment of MS are not well understood and are believed to be mediated by multiple mechanisms, with the common theme of having an immunomodulating effect.
image Glatiramer competes for binding to major histocompatibility complex (MHC) class II molecules on APCs.
image Glatiramer also induces specific T-helper 2 (TH2)–type suppressor cells. The TH2 cells may cross the blood-brain barrier and secrete antiinflammatory cytokines and neurotropic factors that suppress surrounding inflammation (commonly referred to as bystander suppression).
image These neurotrophic factors may also facilitate remyelination and provide a protective effect for axons.

Pharmacokinetics

image Glatiramer is administered by subcutaneous injection.
image It is rapidly degraded after injection, leaving only about 10% at the site of injection after only 1 hour. Systemic plasma concentrations are therefore not detectable, nor can any be detected in the feces or urine.

Indications

image MS:

image Relapsing-remitting
image Clinically isolated syndrome (CIS)

Contraindications

image None of major significance

Side Effects

image Local injection site reactions may occur.
image Chest pain has been observed during clinical trials; its mechanism is unknown. The pain is transient and does not appear to be clinically harmful.
image Postinjection reaction: Flushing, palpitations, anxiety, dyspnea, and constriction of the throat may occur. Serious anaphylactic-type reactions are rare.
image Infection: Glatiramer is an immunomodulator and may impair the immune response to infection.

Important Notes

image CIS is characterized by a single demyelinating event, an attack that is suggestive of MS. These attacks include typical MS symptoms, such as sudden loss of vision. CIS is a recognized precursor to development of MS, although not all patients with CIS will go on to develop this disease. This has made it difficult to determine whether CIS patients should be initiated on this very expensive therapy, which includes daily injections, for an indeterminate amount of time.
image The other main agents used to treat MS are the interferons (IFNs) IFN alfa-1a and IFN beta-1b. These agents also have to be injected, and their main side effect is a flulike syndrome.

Advanced

image A new class of drugs has emerged in the fight against MS. The integrin inhibitors prevent the movement of lymphocytes from blood vessels into the brain. α4β1 Integrin is expressed on the surface of activated lymphocytes and acts on a receptor on the luminal surface of vascular endothelium, vascular cell adhesion molecule (VCAM).
image This interaction between α4β1 integrin and VCAM results in adherence of the activated lymphocyte to the vascular wall, which induces the lymphocyte to secrete proteases that enable the lymphocyte to transmigrate across the vascular endothelium and gain access to tissue.
image Natalizumab binds to α4β1 integrin, thus interfering with the interaction between it and VCAM, resulting in the inhibition of lymphocyte adherence and preventing transmigration of activated lymphocytes into tissue.
image The theory is that by preventing activated lymphocytes from gaining access to the CNS, natalizumab could reduce neuroinflammation and therefore modify the disease course.
image Natalizumab is reserved for advanced MS because of concerns over toxicity caused by an opportunistic infection of the CNS called progressive multifocal leukoencephalopathy.

FYI

image Protiramer, the second glatiramoid, is currently being evaluated in clinical trials for treatment of MS.
image A random sequence of amino acids is often referred to as a polymer by biochemists, in the same way that a polymer in chemistry is a sequence of molecules. Glatiramer is actually a polypeptide consisting of a random sequence of four amino acids: glutamate, lysine, alanine, and tyrosine, hence the name glatiramer.

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