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

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