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Chapter: Pharmaceutical Biotechnology: Fundamentals and Applications : Monoclonal Antibodies in Solid Organ Transplantation

Muromonab - Specific Agents Used In Solid Organ Transplant

Muromonab was the first monoclonal antibody used in solid organ transplantation.

SPECIFIC AGENTS USED IN SOLID ORGAN TRANSPLANT

 

Muromonab

 

Muromonab was the first monoclonal antibody used in solid organ transplantation. Muromonab is a murine monoclonal antibody directed against human CD3 receptor, which is situated on the T-cell antigen receptor of mature T-cells, inducing apoptosis of the target cell (Bodziak, 2003; Wilde, 1996). Cells which display the CD3 receptor include CD2, CD4, and CD8 positivelymphocytes (Ortho Biotech, 2004). Other investigators suggest that muromonab may also induce CD3 com-plex shedding, lymphocyte adhesion molecule expres-sion causing peripheral endothelial adhesion, and cell mediated cytolysis (Wilde, 1996; Ortho Biotech, 2004 Buysmann et al., 1996; Magnussen and Moller, 1994; Wong et al., 1990). Muromonab is approved for the treatment of kidney allograft rejection and steroid resistant rejection in heart transplant recipients (Ortho Biotech, 2004). Muromonab was initially employed as an induction agent for kidney transplant recipients, in conjunction with cyclosporine, azathioprine, and corti-costeroids. Muromonab administration at the time of transplant decreased the rate of acute rejection and prolonged the time to first acute rejection when compared to no induction (Kahana, 1989). Liver recipients with renal dysfunction at the time of transplant who received muromonab induction were able to avoid cyclosporine without an increased incidence of acute rejection and sustain renal function versus those who received cyclosporine (Mills, 1989). Therefore administration of muromonab enabled pre-servation of renal function in the setting of reduced calcineurin inhibitor exposure when compared to those who did not receive muromonab (Wilde, 1996). The use of muromonab as an induction agent is nearly extinct with the introduction of newer agents that have more favorable side effect profiles.

 

 

Today, muromonab is reserved for treatment of refractory rejection. Muromonab is extremely effective at halting most corticosteroid as well as polyclonal antibody resistant rejections. These rejections are treated with 5 mg of muromonab given daily for 7 to 14 days (Ortho Biotech, 2004). The dose and duration of therapy is often dependent on clinical or biopsy resolution of rejection or may be correlated with circulating CD3 cell concentrations in the serum.

 

Most patients who are exposed to muromonab will develop human against mouse antibodies (HAMA) following initial exposure. These IgG anti-bodies may lead to decreased efficacy of subsequent treatment courses, but pre-medication with corticos-teroids or antiproliferative agents during initial ther-apy may reduce their development (Wilde, 1996). Following administration, in vitro data indicate that a serum concentration of 1000 mg/L is required to inhibit cytotoxic T-cell function (Wilde, 1996). In vivo concen-trations near the in vivo threshold immediately (1 hour) following administration, but diminish significantly by 24 hours (Wilde, 1996). Steady-state concentrations of 900 ng/mL can be achieved after three doses, with a plasma elimination half life of 18 hours when used for treatment of rejection and 36 hours when used for induction (Wilde, 1996; Ortho Biotech, 2004).

 

Muromonab administration is associated with significant acute and chronic adverse effects.Immediately following administration, patients will experience a characteristic OKT3 cytokine release syndrome. The etiology of this syndrome is character-ized by the pharmacodynamic interaction the OKT3 molecule has at the CD3 receptor. Muromonab will stimulate the target cell following its interaction with the CD3 receptor prior to inducing cell death. Consequently, CD3 cell stimulation leads to cytokine production and release, which is compounded by acute cellular apoptosis leading to cell lysis and release of the intracellular contents. The cytokine release syndrome associated with muromonab manifests as high fever, chills, rigors, diarrhea, capillary leak and in some cases aseptic meningitis (Wilde, 1996). Capillary leak has been correlated with increased tumor necrosis factor release leading to an initial increase in cardiac output secondary to decreased peripheral vascular resistance, followed by a reduction in right heart filling pressures (pulmonary capillary wedge pressure) which leads to a decrease in stroke volume (Wilde, 1996). Sequelae of this cytokine release syndrome can occur immediately, within 30 to 60 minutes, and last up to 48 hours following administration (Ortho Biotech, 2004). This syndrome appears to be the most severe following the initial dose when the highest innoculum of cells is present in the patient’s serum or when preformed antibodies against the mouse epitope exist. Subsequent doses appear to be better tolerated, though cytokine release syndrome has been reported after five doses, typically when the dose has been increased or the CD3 positive cell population has rebounded from previous dose baseline (Wilde, 1996). Pre-treatment against the effects of this cytokine release is necessary to minimize the host response. Specifically, corticoster-oids are to prevent cellular response to cytokines, non-steroidal anti-inflammatory agents to prevent sequelae of the arachidonic acid cascade, acetaminophen to halt the effects of centrally acting prostaglandins, and diphenhydramine to attenuate the recipient’s response to histamine.

 

 

In addition to immediate adverse effects, the potency of muromonab has been associated with a high incidence of post-transplant lymphoprolifera-tive disease and viral infections. For all patients, the 10-year cumulative incidence of post-transplant lymphoproliferative disease is 1.6% (Opelz, 2004). Review of large transplant databases, revealed that deceased donor kidney transplant recipients who received muromonab for induction or treatment had a cumulative incidence of post-transplant lympho-proliferative disease that was 3 times higher than those who did not received muromonab or other T-cell depleting induction (Opelz, 2004). This ob-servation may be multifactorial. It is well known that post-transplant lymphoproliferative disease may be induced secondary to Epstein-Barr viral B-cell

malignant transformation. Muromonab’s potent in-hibition of T-lymphocytes over a sustained period of time diminishes the immune system’s normal sur-veillance and destruction of malignant cell lines, consequently leading to unopposed transformed B-cell proliferation and subsequent post-transplant lymphoma (Opelz, 2004).

 

Early use and development of muromonab in solid organ transplantation was beneficial for the novel development and use of newer monoclonal agents. The immunodepleting potency of muromo-nab, combined with the significant risk for malig-nancy, has reduced its use in modern transplantation. However, this agent is still a formidable option in the treatment of severe allograft rejection.

 

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Pharmaceutical Biotechnology: Fundamentals and Applications : Monoclonal Antibodies in Solid Organ Transplantation : Muromonab - Specific Agents Used In Solid Organ Transplant |


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