Muromonab-CD3 is a mouse monoclonal antibody to CD3, often referred to as OKT3, which is used to treat acute cellular rejection after solid organ transplantation. Muromonab has been linked to mild and transient serum enzyme elevations during therapy, but has not been linked to cases of clinically apparent liver injury. Muromonab is a potent immunosuppressive agent and may result in reactivation of hepatitis B in susceptible patients.
Muromonab (mue” roe moe’ nab) is a mouse monoclonal immunoglobulin G2 antibody to CD3, a cell surface receptor found on T cells. Engagement of the receptor leads to T cell activation, but without secondary signals the binding results in blockage and T cell apoptosis. Infusions of muromonab lead to depletion of T cells and decrease in T cell activity which is the major cause of acute cellular rejection. Muromonab was approved for use in treating acute rejection after renal transplantation in 1997 and its indications were later broadened to include rejection after heart and liver transplantation. Muromonab was the first monoclonal antibody approved for use in humans and is still used commonly to treat acute rejection. Muromonab is used off label to prevent cellular rejection, given as induction therapy before and/or early after transplantation. The name “muromonab” represents a shortened form of “murine monoclonal antibody” and was assigned before the official WHO nomenclature for monoclonal antibodies was introduced. Muromonab-CD3 is available in liquid solution in 5 mL ampules of 5 mg under the brand name Orthoclone OKT3. The usual regimen in adults is 5 mg intravenously each day for 10 to 14 days. The pediatric dose (<30 kg) is 2.5 mg daily. Adverse events are common during muromonab therapy, but many are due to the underlying condition and other complications of organ transplantation. Muromonab is a mouse monoclonal antibody and hypersensitivity reactions and development of inactivating antibodies occur not infrequently. Furthermore, the initial engagement of CD3 receptors can result in a transient, acute release of proinflammatory cytokines (cytokine release syndrome) with symptoms of high fever, weakness, dyspnea, nausea, chest pain and diarrhea arising within the first two days of starting therapy. Less common, but potentially severe adverse reactions after muromonab therapy include bacterial and opportunistic infections, reactivation of viral infections (EBV, HSV, CMV, HBV, RSV, among others), acute thromboses, and malignancies, particularly EBV-associated lymphoproliferative disorders.
When given as a part of induction therapy for solid organ transplantation, muromonab has been linked to a low rate of transient serum enzyme elevations, which is similar to that which can occur with standard therapy. The serum enzyme elevations are generally mild-to-moderate and resolve spontaneously. Muromonab induction therapy has not been linked to instances of clinically apparent liver injury. Administration of muromonab as treatment of acute cellular rejection is commonly associated with acute infusion reactions, but has not been convincingly linked to acute liver injury.
Muromonab is a potent immunosuppressive agent and may be capable of causing reactivation of chronic hepatitis B. However, when used in prevention of organ rejection, it has not been linked to cases of reactivation, perhaps because patients at risk are routinely given prophylaxis and the role of muromonab versus other rejection medications (cyclosporine, tacrolimus, corticosteroids) is not clear.
REPRESENTATIVE TRADE NAMES
Muromonab-CD3 – Orthoclone OKT3®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 18 June 2015
Reuben A. Hepatotoxicity of immunosuppressive drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2011, pp. 569-91. (Review of hepatotoxicity of immunosuppressive agents mentions muromonab and problems of reactivation of hepatitis).
Chabner BA, Barnes J, Neal J, Olson E, Mujagiv H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-53. (Textbook of pharmacology and therapeutics).
A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. Ortho Multicenter Transplant Study Group. N Engl J Med 1985; 313: 337-42. PubMed Citation (Among 123 patients with acute rejection after renal transplantation, 94% of muromonab [OKT3] vs 75% of high dose methylprednisolone recipients had reversal of the acute rejection; adverse events included acute infusion reactions [fever, chills, tremor, dyspnea, chest tightness, wheezing and nausea], no mention of ALT elevations).
Richards JM, Vogelzang NJ, Bluestone JA. Neurotoxicity after treatment with muromonab-CD3. N Engl J Med 1990; 323: 487-8. PubMed Citation (Among 13 patients treated with muromonab for refractory solid tumors, 11 developed signs of neurotoxicity, some with culture negative cerebral spinal fluid pleocytosis, all resolving rapidly with symptomatic therapy).
Swinnen LJ, Costanzo-Nordin MR, Fisher SG, O'Sullivan EJ, Johnson MR, Heroux AL, Dizikes GJ, et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med 1990; 323: 1723-8. PubMed Citation (Retrospective analysis found that 9 of 79 [9%] heart transplant recipients treated with muromonab vs 1 of 75 who did not receive muromonab developed posttransplant lymphoproliferative disorder).
Claesson K, Tufveson G, Wahlberg J. Treatment with poly- and monoclonal antilymphocyte antibodies: assessment of efficacy and safety in transplantation. Transplant Proc 1992; 24: 314. PubMed Citation (Among 145 patients undergoing organ transplantation, graft survival and adverse events were similar in those who received antibody therapy of rejection and those who did not; no mention of ALT elevations or hepatotoxicity).
Norman DJ, Kahana L, Stuart FP Jr, Thistlethwaite JR Jr, Shield CF 3rd, Monaco A, Dehlinger J, et al. A randomized clinical trial of induction therapy with OKT3 in kidney transplantation. Transplantation 1993; 55: 44-50. PubMed Citation (Among 215 patients undergoing renal transplantation, use of muromonab as induction therapy was associated with fewer rejection episodes [51% vs 66%] and marginally improved graft-, but similar patient-survival; adverse events were more common with muromonab than conventional therapy, but were largely due to early infusion reactions [with fever, tachycardia, nausea and hypotension] and viral infections [herpes, CMV]; no mention of ALT elevations or hepatotoxicity).
van Gelder T, Balk AH, Jonkman FA, Zietse R, Zondervan P, Hesse CJ, Vaessen LM, et al. A randomized trial comparing safety and efficacy of OKT3 and a monoclonal anti-interleukin-2 receptor antibody (BT563) in the prevention of acute rejection after heart transplantation. Transplantation 1996; 62: 51-5. PubMed Citation (Among 60 patients undergoing heart transplantation randomized to receive either muromonab or a mouse monoclonal antibody to the IL2 receptor, infusion reactions were more common, and acute rejection episodes were delayed, but similar in frequency among the muromonab recipients; no mention of ALT elevations or hepatotoxicity).
New monoclonal antibodies to prevent transplant rejection. Med Lett Drugs Ther 1998; 40 (1036): 93-4. PubMed Citation (Concise review of the efficacy and safety of basiliximab and daclizumab, two monoclonal antibodies to the IL2 receptor, shortly after their approval for use in transplantation in the US; mentions that muromonab has been used for many years for treatment of transplant rejection and is used with some success to prevent rejection; no mention of ALT elevations or hepatotoxicity).
Midtvedt K, Fauchald P, Lien B, Hartmann A, Albrechtsen D, Bjerkely BL, Leivestad T, et al. Individualized T cell monitored administration of ATG versus OKT3 in steroid-resistant kidney graft rejection. Clin Transplant 2003; 17: 69-74. PubMed Citation (Among 55 patients undergoing renal transplantation treated with variable doses of either ATG or muromonab based upon T cell counts, rejection rates were similar as were adverse events; no mention of ALT elevations or hepatotoxicity).
Sellers MT, McGuire BM, Haustein SV, Bynon JS, Hunt SL, Eckhoff DE. Two-dose daclizumab induction therapy in 209 liver transplants: a single-center analysis. Transplantation 2004; 78: 1212-7. PubMed Citation (Among 352 liver transplant recipients, the 209 who received daclizumab induction therapy had lower rates of acute rejection [25% vs 39%] and hepatitis C recurrent rates were similar; no mention of hepatotoxicity).
Morris JA, Hanson JE, Steffen BJ, Chu AH, Chi-Burris KS, Gotz VP, Gordon RD. Daclizumab is associated with decreased rejection and improved patient survival in renal transplant recipients. Clin Transplant 2005; 19: 340-5. PubMed Citation (Analysis of SRTR database on renal transplant recipients receiving daclizumab [n=8203] or no induction treatment [n=25368] in the US between 1998 and 2003 found lower reported rates of rejection [13% vs 17% after 3 years] and improved patient and graft survival, with no excess mortality from malignancy or opportunistic infections).
Chin C, Pittson S, Luikart H, Bernstein D, Robbins R, Reitz B, Oyer P, et al. Induction therapy for pediatric and adult heart transplantation: comparison between OKT3 and daclizumab. Transplantation 2005; 80: 477-81. PubMed Citation (Comparison of daclizumab [n=40] to muromonab [n=40] as induction therapy to prevent rejection after heart transplantation found no difference in rates of rejection, but higher rates of adverse events with muromonab including infections [33%], anaphylaxis [10%], and single cases of rejection death and acute renal failure [2%]; no mention of ALT elevations or hepatotoxicity).
Rodríguez-Lambert JL, Crespo-Leiro MG, Almenar L, Roig E,
Gómez-Sánchez MA, Lage E, et al. A randomized multicenter comparison of basiliximab and muromonab (OKT3) in heart transplantation: SIMCOR study. Transplantation 2006; 81: 1542-8. PubMed Citation (Among 99 patients undergoing heart transplantation given therapy to prevent rejection with either basiliximab or muromonab, side effects were more common with muromonab and included fever [26%], pulmonary edema [10%], hypotension [8%], headache [4%], diarrhea, flushing, itching, confusion syndrome, nausea and vomiting; no mention of ALT elevations or hepatotoxicity).
Cai J, Terasaki PI. Induction immunosuppression improves long-term graft and patient outcome in organ transplantation: an analysis of United Network for Organ Sharing registry data. Transplantation 2010; 90: 1511-5. PubMed Citation (Since 2003, most solid organ transplant recipients have received induction therapy, and analyses of the UNOS registry for this period shows highest rates of patient and graft survival with alemtuzumab [89% 5 year patient survival] as compared to antithymocyte globulin [89%], basiliximab [84%], daclizumab [77%], steroids [75%] or no induction [71%]).
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