Drug
Description
Mechanism of action
Use in induction
Use in rejection
Use in maintenance
Adverse effects
Polyclonal antithymocyte globulin [rabbit] (Thymoglobulin®)
Polyclonal IgG from rabbits immunized with human thymocytes
Blocks various T cell, non-T cell, and MHC membrane proteins leading to prolonged depletion
X
X
Cytokine release syndrome, thrombocytopenia, leukopenia, reactivation and development of viral disease
Alemtuzumab (Campath®)
Humanized monoclonal antibody against CD52
Binds to CD52 on B cells, T cells, macrophages, natural killer cells, and granulocytes and triggers antibody-dependent lysis
X
Neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, headache, and dizziness
Basiliximab (Simulect®)
Chimeric monoclonal antibody against CD25
Binds to the alpha subunit of the IL-2 receptor on the surface of activated T cells and acts as a receptor antagonist
X
Headache, hypertension, peripheral edema
Belatacept (Nulojix®)
Fusion protein which binds to CD80 and CD86 receptors on APCs
Binds to CD80 and CD86, blocking CD28 interaction between APCs and T cells needed to activate T lymphocytes
X
Infusion reactions, peripheral edema, hyper- or hypotension, headache, electrolyte abnormalities, diarrhea, and abdominal pain
Use for Immunosuppressive Therapy in Kidney Transplantation: Large doses of GC are used in many transplant centers perioperatively and immediately postoperatively, consisting one intraoperative dose of 5–10 mg/kg of intravenous methylprednisolone, followed with a transition to 1 mg/kg/day of oral prednisone. This is subsequently reduced to physiological doses or approximately 5 mg/day of prednisone by 1 year or less.
To minimize toxicity and reduce overall immunosuppression, strategies aimed at minimizing or avoiding GC in kidney transplantation have been increasingly applied in the past decade [27–32]. More selective immunosuppressive agents and antibody induction therapy enabled the use of GC to be further minimized via several different strategies: very low-dose maintenance (reducing the prednisone dose to 20 mg/day on postoperative days 3–5 with tapering to 5 mg/day by 1 month or 2), complete withdrawal early after transplantation (several weeks to months) or at a later time (after 1 year), and complete avoidance. However, GC withdrawal following kidney transplantation still remains a controversial issue, and the general policy is to individualize therapy based on a careful assessment of the risk–benefit ratio, such as immunological risk of rejection (prior transplants, high PRA) and risk of side effects (recipients with obesity, diabetes, cardiovascular disease).
When acute cellular rejection (ACR) occurs, pulse methylprednisolone (3–5 mg/kg intravenously daily for 3–5 days) is the first-line therapy for management of active episodes, either alone or in combination with other immunosuppressive agents. After a steroid pulse, oral steroids are tapered rapidly to the same dosage the patient had been taking prior to the episode. The expected reversal rate for the first episode of ACR is approximately 60 % with steroid therapy [33]. If rejection resists steroid treatment, administration of antilymphocyte antibodies could be used as second-line therapy [34–36].
Antimetabolites
Antimetabolites function by inhibition of purine metabolism. Purine (adenine and guanine) synthesis may occur by de novo or salvage pathways. Whereas some cells have the ability to synthesize purines via both pathways, lymphocytes lack the salvage pathway. Thus, by blocking de novo purine synthesis, lymphocyte proliferation, expansion, and activation are inhibited or decreased.
Antimetabolites are used routinely in the management of organ transplant recipients. The rationale, discovery, and development of azathioprine in the 1950s led to the 1988 Nobel Prize in medicine for Gertrude Elion and George Hitchings.
Azathioprine
Mechanism of Action and Structure: Azathioprine was originally described as a therapy for childhood acute leukemia [37]. However, with the advent of kidney transplantation, early observations demonstrated the drug’s ability to prolong renal allograft survival [38].
Azathioprine blocks de novo purine synthesis in addition to blocking co-stimulation of T cells. A structural analog of mercaptopurine, azathioprine is metabolized through multiple steps yielding biologically active metabolites. One of these metabolites, 6-thio-GTP inserts into T cell DNA and prevents DNA replication [39]. Metabolites of azathioprine have also been shown to inhibit Rac-1 activity by binding GTPases [37, 39, 40]. Rac1 inhibition then sets in motion a cascade culminating with mitochondrial-driven T cell apoptosis [39]. More recently, data have suggested that 6-thio-GTP may also inhibit CD28, an important co-stimulation signaling mediator required for T cell activation [37].
Dosage: Azathioprine is typically given orally at 3–5 mg/kg/day immediately following transplantation. With time dosing may be decreased to 1–3 mg/kg/day. The agent is given as a once- or twice-per-day oral pill. In some cases, azathioprine may be given prior to transplantation.
Mycophenolate Mofetil
Mechanism of Action and Structure: Like azathioprine, mycophenolate mofetil also acts as a purine metabolism inhibitor. The agent is a prodrug which is rapidly broken down to mycophenolic acid which subsequently inhibits inosine monophosphate dehydrogenase (IMPDH). IMPDH is the first of two enzymes required for metabolism of inosine monophosphate to guanine monophosphate in the pathway of de novo purine synthesis. Thus, the result of adding mycophenolic acid to lymphocyte populations is inhibition of DNA replication via decreased availability of nucleotides [41, 42].
Dosage: CellCept is available in oral and IV forms. The oral forms are typically given twice daily and are available as 250 and 500 mg pills. Additionally, an oral suspension is also available. The maximum adult dose is 3 g/24 h. Mycophenolate is also available IV and should be reconstituted with D5W. Myfortic is given twice daily at a dose of 720 mg, for a total daily dose of 1,440 mg. The drug is available in either 180 or 360 mg dosages. Myfortic is an enteric-coated formulation which decreases gastrointestinal symptoms (see caveats in “Side Effects” below).
Administration: While both drugs (CellCept and Myfortic) may be used for rejection prevention, CellCept is FDA approved for heart, kidney, and liver rejection prophylaxis, whereas Myfortic is only FDA approved for kidney rejection prophylaxis. Neither drug has been approved for the treatment of rejection [43].
Antimetabolites are primarily used as a maintenance immunosuppressive administered starting at the time of transplantation and are not considered induction therapies. These agents are typically given in conjunction with calcineurin inhibitors and corticosteroids in what is classically referred to as “triple therapy.” Medication adherence is critically important. In a quantitative analysis of drug adherence patterns, missed doses of azathioprine were clearly linked to development of rejection, graft failure, and death [44].
A 1997 pooled analysis of three multinational phase III studies demonstrated that rejection rates for patients taking mycophenolate mofetil were approximately one-half that of patients taking azathioprine [45]. Based on these data, many centers switched patients from azathioprine to mycophenolate mofetil. Although there was a small improvement in graft survival in the mycophenolate mofetil arm, the difference was not statistically significant. In the analysis of the follow-up study to the Mycophenolate Steroids Sparing (MYSS) study, authors demonstrated similar long-term outcomes for patients receiving either azathioprine or mycophenolate, if the patient was also receiving a cyclosporine microemulsion, a newer form of this calcineurin inhibitor [46, 47]. It should be noted that most centers use tacrolimus instead of cyclosporine and most registry data over the last decade support the widespread practice that tacrolimus plus mycophenolate derivatives is the most efficacious regimen for maintenance immunosuppression.
Side Effects: Antimetabolite therapies for transplantation are generally well tolerated clinically. They are known to cause GI upset, bone marrow suppression, and hepatotoxicity. As for other classes of immunosuppressives, antimetabolite therapies are also associated with the development of infection and malignancy. GI upset (diarrhea in particular) is well documented in some patients that receive antimetabolites and may lead to decreased dosing in a large percentage of cases [48]. Some data have shown that higher doses may be achieved with fewer GI symptoms, and avoidance of missed doses, if patients switch to enteric-coated mycophenolate [49]. The antimetabolites may also lead to bone marrow suppression, so monitoring of cell counts is always required.
Calcineurin Inhibitors
Tacrolimus and cyclosporine are the two drugs in this class utilized in renal transplantation management.
Mechanism of Action: Tacrolimus and cyclosporine exert their immunosuppressive action through inhibition of calcineurin–calmodulin activation. Tacrolimus and cyclosporine bind to intracellular targets called immunophilins. Cyclosporine binds to cyclophilin, and tacrolimus binds to FK-binding protein (FKBP). The calcium-sensitive phosphatase calcineurin, also called protein phosphatase 2B, is implicated in eukaryotic activation, including lymphocyte activation, heart–valve morphogenesis, angiogenesis, and neural and muscle development. Calcineurin is dependent on calcium and calmodulin for activation. When the cell surface receptors of T cells are stimulated, there is an influx of calcium into the cell cytoplasm that binds to calmodulin (calcium-modulating protein). Calmodulin is a messenger protein expressed in all cells. The calcium–calmodulin complex activates the phosphatase activity of calcineurin, which then cleaves a phosphate group from the regulatory domain of NFAT (nuclear factor of activated T cells) in the cytoplasm. The dephosphorylated NFAT is then translocated into the nucleus where it acts as a transcription factor for various immunologically important genes. By inhibiting calcineurin, the transcription of genes, such as IL-2, needed for T cell proliferation and differentiation is suppressed.
Tacrolimus
Also known as FK-506 or fujimycin, tacrolimus was isolated in 1984 from a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis. Common trade names in the USA are Prograf and Protopic with several other generic versions now available.
Pharmacokinetics: Tacrolimus is rapidly absorbed from the small intestine [50] and has a bioavailability ranging from 7 to 27 % in adult kidney transplant patients. Tacrolimus is metabolized solely in the liver and the metabolites are primarily excreted in the bile. The elimination half-life of tacrolimus is approximately 8.5 h and is prolonged in hepatic dysfunction [51]. Tacrolimus has its greatest bioavailability in a fasting state and presence of food decreases absorption [52]. Absorption also seems to vary with ethnicity. The mean tacrolimus exposure after a single oral dose in healthy Latin American and African American subjects was 18 and 39 % less than in Caucasians [53]. This may arise from differences in intestinal CYP3A or P-glycoprotein activities. Tacrolimus is lipophilic and after absorption in the intestine undergoes extensive distribution in the body including placenta and breast milk [54]. In the blood, most of it is bound to RBCs and to plasma proteins, namely, α-acid glycoprotein and albumin [55]. Presystemic metabolism by cytochrome P450 (CYP) 3A4 isoenzymes and P-glycoprotein occurs in the intestinal mucosa [5]. P-glycoprotein lowers the intracellular levels of tacrolimus by pumping drug back into the intestinal lumen for further metabolism by CYP3A4. Thereafter, CYP3A4 (and to a lesser extent CYP3A5) isoenzymes in the liver provide extensive metabolism [55]. There are at least 15 metabolites, the major metabolite being 13-O-demethyl-tacrolimus. The terminal half-life of tacrolimus in kidney transplant recipients is approximately 8.7 h. Biliary excretion and fecal elimination are responsible for the major clearance of metabolites, whereas renal excretion plays only a small role (feces 92.4 %, urine 2.3 %, <1 % unchanged) [56].
Use for Induction and Maintenance: Two popular regimens currently exist. The older standard regimen uses high doses of calcineurin inhibitors, steroids, and antimetabolites; and the other uses low doses of the aforementioned immunosuppressive agents with antilymphocyte antibodies. The latter is found to be superior to the regimen using high-dose conventional immunosuppressives [57–59] to prevent allograft rejection and is generally used by most centers. Tacrolimus is generally ineffective to treat acute rejection, although some uncontrolled series and case reports suggest that very high doses may sometimes be effective.
Tacrolimus is available in oral form as capsules and 5 mg/mL IV solution in the USA. Oral formulations are preferred over intravenous. When switching from IV to PO, the first dose of oral therapy should be given 8–12 h after discontinuing the IV infusion. African American patients may require larger doses to maintain trough concentration. Due to its potential for nephrotoxicity, consideration should be given to dosing tacrolimus at the lower end of the therapeutic dosing range in patients having preexisting renal impairment.
In liver dysfunction, there are reduced clearance and prolonged half-life so patients with severe hepatic impairment may require lower doses of tacrolimus. Close monitoring of blood concentrations is warranted.
Monitoring of whole blood trough concentrations is required to assist in the clinical evaluation of toxicity, efficacy, and failure. In conjunction with mycophenolate, goal tacrolimus trough levels for the first year are typically in the 4–11 ng/mL range, with individual programs adopting slightly different goals and protocols according to the assay used to measure serum levels, the type of induction immunosuppression used, and the immunological risk of the recipient.
Side Effects: The most common adverse reactions (≥30 %) are infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, myocardial hypertrophy, and pure red cell aplasia.
Other side effects are anaphylaxis with intravenous formulations, posttransplant insulin-dependent diabetes mellitus, alopecia, and risk of malignancy. Nephrotoxicity was reported in approximately 52 % of kidney transplantation patients on tacrolimus in the USA. Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering tacrolimus with drugs that may be associated with renal dysfunction.
Concurrent use with strong CYP3A4 inhibitors (e.g., grapefruit juice, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) or inducers (e.g., rifampin, rifabutin) is not recommended without close monitoring of tacrolimus trough concentrations. Exposure to mycophenolic acid may be higher with concurrent tacrolimus or in patients changing therapy from cyclosporine to tacrolimus.
Cyclosporine
Cyclosporine (CyA) is a cyclic polypeptide immunosuppressant produced by the fungus Beauveria nivea.
Pharmacokinetics: The absorption of cyclosporine from the gut is incomplete and variable. Due to its lipophilic nature, cyclosporine is largely distributed extravascularly. Compared to an intravenous infusion, the absolute bioavailability of the oral solution is approximately 30 %. In plasma, approximately 90 % is bound to proteins, primarily lipoproteins. Approximately 33–47 % is in plasma, 4–9 % in lymphocytes, 5–12 % in granulocytes, and 41–58 % in erythrocytes. At high concentrations, the uptake by leucocytes and erythrocytes becomes saturated. The disposition of cyclosporine from blood is biphasic with a terminal half-life of approximately 19 h (range: 10–27 h). Elimination is primarily biliary with only 6 % of the dose excreted in the urine. Peak concentrations (C max) in blood and plasma are achieved at about 3.5 h. C max and area under the plasma or blood concentration/time curve (AUC) increase with the administered dose; for blood, the relationship is curvilinear (parabolic) between 0 and 1,400 mg. As determined by a specific assay, C max is approximately 1.0 ng/mL/mg of dose for plasma and 1.4–2.7 ng/mL/mg of dose for blood (for low to high doses).
Cyclosporine is extensively metabolized but there is no major metabolic pathway. Only 0.1 % of the dose is excreted in the urine as unchanged drug. About 15 metabolites are characterized in human urine.
Use for Induction and Maintenance: Cyclosporine has modified (Neoral®) and non-modified formulations (Sandimmune®) which are not bioequivalent. The modified preparation has better bioavailability and, in general, has completely supplanted the non-modified form. Both oral and intravenous formulations are available. Dosing is between 10 and 14 mg/kg/day.
Plasma concentrations should be monitored closely and adjusted as necessary, until desired trough level is obtained. The blood levels are very assay specific. Whole blood 24-h trough levels of 100–200 ng/mL as determined by high-pressure liquid chromatography (HPLC) are often targeted, but therapeutic trough level depends on the type of assay used and is best if referred to the specific institutional protocol. Cyclosporine is not used for the treatment of acute rejection.
Side Effects: Apart from risk of infections and malignancies for all immunosuppressants, common side effects are hirsutism, gingival hyperplasia, hypertension, posttransplant diabetes mellitus, and renal dysfunction. Less common are GI distress, tremors, paresthesias, muscle cramps, hypomagnesemia, seizures, leucopenia, headache, and acne.
mTOR Inhibitors
Rapamycin
Structure and Function: The 23-member macrolide rapamycin (also called sirolimus) is the prototypic example of the mTOR inhibitor (mTORi) family of drugs. Initial tests with rapamycin showed it inhibited proliferation in multiple cell types and led to the discovery of the mammalian target of rapamycin (mTOR). Examinations of mTOR revealed it to be a serine/threonine kinase vital to many aspects of cellular growth and metabolism and marked mTOR as a new target for immunosuppression. Like the CNI family member tacrolimus, sirolimus, and other mTORi, such as everolimus, function requires binding to the protein chaperone FKBP12. The sirolimus/FKBP12 protein complex then interrupts the binding of mTOR to the regulatory-associated protein of TOR (raptor) preventing formation of the mTOR complex-1 (mTORC1), one of the two signaling complexes that require mTOR incorporation. Overall, currently available pharmacologic mTORi (sirolimus and everolimus) demonstrate general suppression of cell proliferation induced by exposure to growth factors [60–64].
Mechanisms of Action: mTORC1 is a component of the phosphoinositide 3-kinase (PI3K) signaling pathway activated by receptor recognition of growth factors, cytokines, and Toll-like receptor ligands. By blocking mTORC1 activity, mTORi drugs prevent activation of multiple proteins involved in regulating the cell cycle, including the P70 ribosomal protein S6 protein kinase 1 (S6K1), eukaryotic initiation factor 4E binding protein 1 (eIF1A), and multiple cyclin-dependent kinases (CDK). Inhibition of these proteins is associated with a severe reduction in protein synthesis and cell cycle arrest in the G1 phase. While mTOR acts a ubiquitous cellular signaling component, increased cellular metabolic demands associated with immune cell activation result in a preferential reliance on mTOR activation for immune cell survival and function. As a consequence mTORi have been shown to effectively inhibit clonal expansion of T cells and modulate T cell trafficking resulting in sequestration of T cells within lymphoid tissue [65]. Further, exposure to mTORi during antigenic stimulation of T cells results in hyporesponsiveness to subsequent stimulation [66, 67]. The mTORi-mediated induction of hyporesponsiveness has also been linked to increased induction and/or survival of FOXP3+ regulatory T cells [68–75]. These findings suggest that mTORi lower the ratio of effector to suppressive T cells.
In addition to T cells, studies have demonstrated that inhibition of mTOR signaling can negatively impact B cell activity [76]. Inhibition of mTOR also decreases the number of circulating neutrophils and inhibits neutrophil GM-CSF-associated tissue migration [77]. For antigen-presenting cells (APC) such as DC and monocytes/macrophages, the effects of mTOR inhibitors are more complex. Studies suggest that mTOR inhibition can block GM-CSF, IL-1, and IL-4 induced DC maturation and subsequent activation of T cells. However, treatment with mTORi has also been shown to increase DC and monocyte production of inflammatory cytokines, including TNF-α, IL-6, IL-12, and IL-23, while blocking production of the anti-inflammatory cytokine IL-10 [78]. Indeed, mTORi treatment has been reported to inhibit the immunosuppressive effects of corticosteroids on these cell types [79]. As such, mTORi can have both anti- and proinflammatory effects on DCs and monocytes [80, 81].
Finally, parenchymal cell involvement in inflammation is modulated by treatment with mTORi [82–84]. Specifically, mTORi treatment decreases the responsiveness of fibroblasts to wound-associated growth factors, preventing cell replacement and wound closure during tissue remodeling [85, 86]. This inhibition reduces VEGF production at the wound site and subsequent vascular tissue recovery [87] and is associated with delayed wound healing.
Overall, mTORi has significant immunosuppressive effects on lymphocyte-mediated acute graft rejection [75, 88] but may increase the chances of long-term graft loss [89–91].
Use for Induction, Maintenance, and Rejection Therapy: While mTOR inhibitors exhibit significant immunosuppressive capabilities, they are typically not utilized as induction therapeutics because of their interference with wound healing. mTORi are used in immunosuppression maintenance, often in combination with drugs targeted to alternate pathways of immunosuppression, such as mycophenolate mofetil [92, 93]. While multiple combinations of immunosuppressive drugs have been examined [94–99], as yet a combination with clearly superior safety and/or efficacy remains undefined. Several studies have examined the use of mTORi as a total or eventual replacement for CNI during maintenance immunosuppression in order to limit CNI-associated nephrotoxicity [99–102]; however, success has been limited by increased rejection and undesirable drug interactions.
Dosing and Levels: The current manufacturer of sirolimus suggests administration of sirolimus in conjunction with cyclosporine and corticosteroids. Dosing depends on the relative risk of immunological complications within an individual patient. For high-risk patients, initial suggested dosing includes a loading dose of 15 mg followed by daily maintenance doses of 5 mg. For lower-risk patients, suggested dosing includes a 6 mg loading dose followed by daily 2 mg doses. For both groups, blood trough levels of sirolimus should be determined 5–7 days after the initial administration and adjusted to give 3–7 ng/mL concentrations for the first year of treatment.
For everolimus, which has a much shorter half-life, the manufacturer suggests administration of 0.75 mg twice daily as maintenance therapy. Blood trough levels of everolimus should be determined 4–5 days after the initial administration and adjusted to give 3–8 ng/mL concentrations.
Side Effects: The effects of mTORi on parenchymal cells result in delayed wound healing and increased incidence of lymphoceles [103]. Additionally, the use of mTORi is also associated with anemia [104], leukopenia, and thrombocytopenia [94]. Further, sirolimus is associated with proteinuria [105, 106], increased incidence of posttransplant pneumonitis [107], and gastrointestinal tract ulcer and inflammation. In addition, sirolimus treatment is associated with enhanced nephrotoxicity of cyclosporine [108, 109]. In contrast, there is also evidence that sirolimus decreases the incidence and growth of tumors.
Treatment with sirolimus also results in dose-dependent hyperlipidemia, possibly contributing to cardiovascular morbidity [96]. Additionally, mTORi treatment increases incidence of reduced insulin sensitivity and disruption of beta cell function resulting in an increased incidence of posttransplant diabetes [110, 111].
The use of mTORi has been associated with increased incidence of bacterial, viral, protozoal, and fungal infections. However, there have also been suggestions that mTORi can ameliorate transplant immunosuppression-associated development of posttransplant lymphoproliferative disease (PTLD) [112, 113] and CMV infections [114].
Depleting Antibodies
Antithymocyte Globulins
Polyclonal antibodies are derived by immunizing animals with human thymocytes and then collecting the resultant IgG from the serum. Two preparations are available commercially: rabbit-derived antithymocyte globulin (ATG-R, Thymoglobulin®) and horse-derived thymoglobulin (Atgam®).
Mechanism of Action: Polyclonal preparations include a wide variety of antibodies and specificities including T cell molecules (i.e., CD2, CD3, CD4, CD8, TCR, CD28, CD40, CD80, CD86, CD154), non-T cell molecules (i.e., CD16, CD20), and class I and class II major histocompatibility complex (MHC) molecules [115–117]. It is uncertain which of these specificities leads to the therapeutic effect of lymphocyte depletion. Potential mechanisms include Fc-receptor-mediated complement-dependent lysis and opsonization and phagocytosis by macrophages. The extensive T cell depletion can persist for months after administration. These agents also likely have other mechanisms of immunosuppressive action such as receptor blockade or activation-induced anergy or cell death.
Use: Antithymocyte preparations are used for both induction and rejection therapy. The rabbit-derived preparation is favored over the horse-derived product because of improved tolerance and efficacy when used for either indication [34, 118, 119].
Dosage: Though rabbit-derived antithymocyte globulin is not labeled for induction therapy, it is commonly used for this purpose in clinical practice. The course of therapy is usually 1.5–2.5 mg/kg/day for 3–10 days for a total dose of 6–15 mg/kg [119]. When treating an acute rejection episode, the duration of treatment can vary from 7 to 14 days [117]. Polyclonal preparation administration is generally through a large-caliber central vein to prevent thrombophlebitis but can also be administered peripherally when diluted and formulated with heparin, hydrocortisone, or bicarbonate solutions [120].
Adverse Effects: Most common antithymocyte acute side effects are due to transient cytokine release as a result of cell surface receptor cross-linking [117]. Chills, fevers, urticaria, rash, and headache are common but can be ameliorated by premedication with corticosteroids, antihistamines, and antipyretics. Pulmonary edema and severe hypertension or hypotension can also occur and range from mild to life-threatening. However, this risk is minimized with repeated dosing as the number of target cells decreases. Additionally, because of their long-lasting immunosuppressive effects, polyclonal antibodies are associated with an increased risk of reactivation and development of viral disease caused by herpes simplex virus, CMV, Epstein–Barr virus (EBV), and varicella. Hematologic complications are also common and may warrant dose reductions to counter leukopenia and thrombocytopenia.
Alemtuzumab
Mechanism of Action: Alemtuzumab (Campath®) is a humanized monoclonal antibody directed against the surface glycoprotein CD52 [121]. Alemtuzumab binds to CD52 present on various cells (i.e., B cells, T cells, macrophages, natural killer cells, granulocytes) and triggers an antibody-dependent lysis. Alemtuzumab’s depletional effect can last for up to 1 year.
Use: Although labeled for use in the treatment of B cell chronic lymphocytic leukemia, alemtuzumab is commonly used for induction immunosuppression therapy but not acute rejection in renal transplant recipients [122, 123].
Dosage: Despite a lack of consensus on the dosing of alemtuzumab, common regimens include doses of 20–30 mg on the day of transplantation and then again on postoperative day 1 or 4 [124–126]. A single 30 mg intraoperative dose is a common regimen in clinical practice.
Muromonab-CD3
Muromonab-CD3 (Orthoclone®) was the first biological agent marketed for use in clinical medicine and thus has significant historical significance and figures prominently in older literature from the 1980s through the end of the 1990s. It was primarily utilized for the treatment of ACR in renal transplantation. Muromonab is a murine monoclonal antibody that binds to the CD3 cell surface antigen of T cells [127, 128]. Once the drugs bind, the antibody mediates both activation-induced cell death and complement-dependent cell lysis and leads to T cell depletion from the peripheral circulation. This agent was particularly noted for inducing an intense cytokine syndrome. Muromonab is entirely mouse derived and can lead to significant adverse effects including the development of an antibody response directed against the drug upon administration. This agent has been discontinued from the market secondary to its severe side effect profile and declining use in clinical practice.
Nondepleting Antibodies
Basiliximab
Mechanism of Action: Basiliximab (Simulect®) is a chimeric monoclonal antibody (70 % human and 30 % murine components) that binds to the alpha subunit of the IL-2 receptor on the surface of activated T lymphocytes (i.e., CD25) and acts as a receptor antagonist [129].
Use: Basiliximab is labeled for induction therapy in renal transplant recipients [129]. Since CD25 primarily has a role in naïve T cell early activation, basiliximab does not have a role in the treatment of rejection [130].
Dosage: Basiliximab is given as a 20 mg IV dose intraoperatively (2 h before renal transplantation) followed by a second 20 mg dose on posttransplantation day 4 [131]. Administration of both doses of basiliximab leads to complete saturation of the CD25 receptor for 5–8 weeks [129, 131].
Adverse Effects: Basiliximab is well tolerated and no cytokine release occurs since it does not mediate T cell activation [129]. There is no increase in infectious complications or delayed wound healing, while the risk of PTLD is similar as when no induction is employed [132]. There is a theoretical concern that this agent may inhibit or deplete suppressive regulatory T cells since they express very high levels of CD25; however, this has not been observed in clinical practice.
Daclizumab
Daclizumab (Zenapax®) is a monoclonal antibody (90 % human and 10 % murine components) that was used for induction therapy in renal transplant recipients [133]. Its mechanism of action and side effect profile are similar to basiliximab. However, daclizumab has a longer and more cumbersome dosing regimen in comparison to basiliximab. Daclizumab was withdrawn for the market secondary to high production costs and low demand.
Belatacept
Belatacept (Nulojix®) is the newest addition to the available options for maintenance immunosuppression therapy. Its unique mechanism of action, route of administration, and limited adverse effect profile make it a viable option in preventing kidney transplant rejection.
Mechanism of Action: Belatacept is not an antibody, but rather a fusion protein of the extracellular domain of CTLA4 with the Fc portion of IgG. This agent binds to CD80 and CD86 receptors on APC, therefore blocking the required CD28-mediated interaction between APCs and T cells needed to activate T lymphocytes [134, 135]. Overall, belatacept acts as a T cell co-stimulation blocker. The saturation of CD80 and CD86 receptors is concentration dependent.
Use: Belatacept is approved for prevention of kidney transplant rejection in combination with basiliximab induction, mycophenolate, and corticosteroids [134].
Dosage: Belatacept is the only intermittent intravenous maintenance therapy for solid organ transplantation [134]. Belatacept infusions are required more frequently during the immediate posttransplant period (i.e., initial phase) but then taper to monthly infusions after 4 months (i.e., maintenance phase). The initial phase consists of 10 mg/kg/dose on the day of transplant and then followed with a dose on day 5 (~96 h after first dose), at the end of week 2, week 4, week 8, and week 12. The maintenance phase consists of 5 mg/kg/dose every 4 weeks (±3 days) beginning at week 16 posttransplant. Belatacept is dosed based on actual body weight with the dose rounded to the nearest 12.5 mg to match the marketed disposable syringe sizes.
Adverse Effects: An increased incidence of PTLD has been associated with the use of belatacept in clinical trials [134, 136–139]. Belatacept is contraindicated in EBV seronegative patients since this population was found to have particularly high PTLD risk. Infusion-related reactions are rare and usually present as mild to moderate. Other potential side effects include peripheral edema, hyper- or hypotension, headache, electrolyte abnormalities (e.g., hypokalemia, hyperkalemia, hypophosphatemia, hypocalcemia), diarrhea, and abdominal pain. Based on clinical trial data, it does not appear that belatacept poses a higher risk of infection (e.g., urinary tract infections, CMV, upper respiratory infections) in comparison to cyclosporine maintenance immunosuppression.
Though long-term data is needed to establish belatacept’s role in maintenance immunosuppression therapy, its use may help avoid some of the side effects seen with calcineurin inhibitors (i.e., nephrotoxicity, neurotoxicity, metabolic disorders) as well as drug–drug interactions. Belatacept’s dosing may improve patient compliance while the absence of drug monitoring may reduce the burden on both patients and clinicians.
Biological agents are valuable in induction, maintenance, and rescue therapies in renal transplant patients. In clinical practice, it is always crucial to evaluate the potential risk versus benefits of these agents and tailor immunosuppressive therapy to each patient.
Eculizumab
Mechanism of Action and Structure: Complement is required for antibody-mediated tissue damage during rejection. This antibody-initiated process is mediated by the classical pathway of complement activation. The development of the membrane attack complex (MAC) is a crucial step of the classical pathway of complement activation. The MAC consists of C5, 6, 7, 8, and 9. Eculizumab is a humanized monoclonal antibody which contains human constant regions and murine variable regions and is FDA approved for the treatment of paroxysmal nocturnal hemoglobinuria. This agent binds to and prevents cleavage of C5 subsequently inhibiting MAC formation [140, 141].
Dosages: Eculizumab is only available as an IV infusion and dosing likely varies between programs. In one trial of eculizumab for renal transplantation in patients with a history of catastrophic antiphospholipid syndrome, the drug was given preoperatively at a dose of 1,200 mg, followed by a single 900 mg dose on postoperative day 1. Thereafter, patients receive 900 mg weekly with transition to 1,200 mg biweekly dosing in the maintenance phase [142].
Administration: Like bortezomib, administration of eculizumab is currently considered experimental therapy for prevention of antibody-mediated rejection (AMR) in the sensitized patient. In small case series, the drug has been shown to prevent AMR when compared with highly sensitized patients that received plasma exchange in addition to conventional immunosuppression [140, 143].
Side Effects: Eculizumab has been associated with headache, fever, infection, and sensitization. In a recent phase III study of eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria, investigators observed that 49 % of patients experienced headache within the first week of drug administration. This figure dropped to 15 %, however, during the second week. Nasopharyngitis (32 %) and fever (19 %) were also reported during the first week. In the same study, authors found that 89 patients (92 %) experienced an infection after starting eculizumab; however, nearly 75 % of these were mild in nature and only 23 % were thought to be related to the drug. Only 1 % of patients experienced a severe infection [144]. The development of serious meningococcal infection has been reported following eculizumab therapy [145]. Based on these concerns, the FDA recommends vaccination against meningococcus at least 2 weeks prior to initiation of eculizumab. The development of anti-eculizumab antibodies has been reported in approximately 2 % of drug recipients [144].
Intravenous Immunoglobulin
Mechanism of Action: Intravenous immunoglobulin (IVIG) formulations are derived from human plasma from thousands of donors and have numerous clinical applications [146, 147]. When given as replacement, IVIG confers passive immunity by providing antibodies from the donor pool. However, the mechanisms of the anti-inflammatory and immunomodulatory effects of IVIG are not fully defined. Theories include inhibition of complement activation and complement-mediated inflammation, modification of cell-mediated immune responses, inhibition of deleterious antibody production, and induction of regulatory T cells.
Use: IVIG is approved for immunoglobulin replacement therapy, yet this indication accounts for less than half of its current use [146, 147]. IVIG is used in various treatment regimens including immunodeficiency, autoimmunity, and inflammatory disorders. In solid organ transplantation, IVIG has several applications. Patients who are sensitized to human leukocyte antibodies resulting from pregnancy, previous transplants, or blood transfusions have longer wait times on the transplantation list. IVIG has been used for its immunomodulatory properties in combination with plasmapheresis and rituximab as part of desensitization protocols for this patient population [148]. Additionally, high-dose IVIG is commonly used in AMR treatment in combination with plasmapheresis and rituximab with data supporting the modification of donor-specific antibody levels and improvement of long-term allograft survival [149, 150]. Hypogammaglobulinemia has been linked to increased risk for infection in solid organ transplant patients and may be related with long-term immunosuppression [151–154]. IVIG therapy can provide passive immunity in patients with CMV, parvovirus B19, and BKV.
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