Muromonab CD3

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Abstract
The murine monoclonal antibody muromonab CD3 (0KT3) is directed against the CD3 antigen on peripheral human T cells and effectively blocks all T cell function. Prophylaxis with muromonab CD3 (5mg intravenously once daily for 10 to 14 days) as induction therapy together with corticosteroids, azathioprine and delayed cyclosporin (sequential therapy) optimises early graft function by delaying the potentially nephrotoxic and hepatotoxic effects of cyclosporin until graft function is established. Although clinical data are limited (by inconsistencies in trial design and trial size), prophylactic muromonab CD3-based sequential therapy is significantly more effective than standard triple therapy in the prophylaxis of allograft rejection in renal and hepatic, but not cardiac, transplant recipients. Benefits are particularly notable in patients with delayed graft function. No significant between-treatment differences in patient survival have been observed. The overall efficacy of muromonab CD3- and polyclonal-based prophylactic regimens appears to be similar, although results vary between investigators and confirmation is needed. An anti-interleukin-2 monoclonal antibody-based prophylactic regimen improved graft and patient survival compared with muromonab CD3-based prophylaxis in hepatic transplant recipients. Antimuromonab CD3 antibodies may develop; however, muromonab CD3 may be successfully reused in patients with low titres. Preliminary pharmacoeconomic data suggest that mean drug costs are greater with quadruple immunosuppressive regimens containing muromonab CD3, antithymocyte globulin (ATG) or antilymphocyte globulin (ALG) than with triple therapy. Drug costs with prophylactic muromonab CD3-based regimens were similar or greater than those with polyclonal—based protocols. The first doses of muromonab CD3 are associated with the ‘cytokine-release syndrome’. More severe first-dose events include aseptic meningitis, intragraft thromboses, seizures and potentially fatal pulmonary oedema. The incidence and/or severity of cytomegalovirus infection with prophylactic muromonab CD3-based immunosuppression is similar to or greater than that with triple therapy and ATG- or ALG-based regimens. However, the risk of infection and also the observed increase in lymphoproliferative disorders appears to be related to the degree of immunosuppression rather than to the drug itself. Thus, sequential muromonab CD3-based therapy is more effective than standard triple therapy (in renal and hepatic transplant recipients) and appears to be similar to that of poly clonal-based regimens in the prophylaxis of transplant rejection. Although the routine use of prophylactic muromonab CD3 in low-risk patients with primary graft function does not appear to be justified, prophylactic muromonab CD3-based therapy has a role in patients at high risk of rejection. Muromonab CD3 (OKT3), a murine monoclonal antibody directed against the CD3 antigen (linked to the T cell antigen receptor; TCR) on mature peripheral human T cells, effectively blocks all T cell function. The mechanism of action includes antigenic modulation of the CD3/TCR complex with subsequent opsonisation and removal of circulating T cells; other mechanisms are proposed. Cytokine release associated with an acute phase reaction occurs after the first doses of muromonab CD3. This is manifest as first-dose adverse events (see ‘Tolerability’ summary). A biphasic reversible haemodynamic response and biphasic activation of coagulation and fibrinolysis, both of which coincide with cytokine release and/or complement activation, occur after initiation of muromonab CD3. Evidence suggests that intraoperative administration of the first muromonab CD3 dose is associated with fewer cardiovascular and pulmonary disturbances than administration in the immediate postoperative period. High antimuromonab CD3 antibody titres (≥ 1:1000) were detected in 5.8 % of >12 000 serum samples from patients who received muromonab CD3 for the treatment or prevention of transplant rejection. IgG but not IgM antibodies are able to reduce the activity of muromonab CD3. Administration of concomitant immunosuppressants such as corticosteroids and azathioprine reduces the likelihood of antimuromonab CD3 antibody formation. Muromonab CD3 is a pure standardised product for which pharmacokinetic data are limited. Plasma muromonab CD3 concentrations vary according to the muromonab CD3 ‘antibody status’, transplanted organ and age. Muromonab CD3 plasma concentrations were 996 μg/L after 1 hour and 104 μ/L at 24 hours in renal transplant recipients receiving 5mg once daily for 10 to 14 days. Mean trough steady-state serum concentrations range from 500 to 1000 μg/L after 2 to 4 days; approximately 1000 μg/L is required to block cytotoxic T cell function in vitro. Steady-state serum muromonab CD3 concentrations are achieved earlier with prophylactic administration than administration for the treatment of rejection. There is evidence of drug accumulation after repeated doses. Muromonab CD3 plasma elimination half-lives of approximately 18 hours (following administration for treatment of rejection) and 36 hours (prophylactic administration) have been reported. There are 2 main reasons for using muromonab CD3 as induction therapy in sequential immunosuppressive regimens (including azathioprine, methylprednisolone/prednisone and delayed cyclosporin): to optimise early graft function by delaying the administration of potentially nephrotoxic and hepatotoxic cyclosporin until graft function is established; and to reduce and delay the occurrence of rejection episodes. Data from clinical trials of muromonab CD3-based prophylaxis are limited by trial size and inconsistencies in design. However, compared with triple therapy, prophylactic muromonab CD3-based sequential therapy was significantly more effective as assessed by severity and/or incidence of rejection episodes and time to first rejection episode in renal transplant recipients and by incidence and/or severity of early acute rejection episodes and time to first rejection in hepatic transplant recipients. Benefits appeared to be maintained for up to 3 years in renal transplant recipients and were particularly marked in patients with delayed graft function. In those with delayed renal graft function, overall graft survival was significantly greater with niuromonab CD3-based induction therapy than with triple therapy. Three-year graft survival in renal transplant recipients was signify icantly greater with sequential muromonab CD3-based therapy (delayed cyclosporin) than with cyclosporin-based therapy not containing muromonab CD3; in high-risk patients, sequential therapy was also associated with significantly greater 3-year graft survival rates than simultaneous muromonab CD3 and cyclosporin administration. Muromonab CD3-based prophylaxis appeared to be similar to triple therapy in terms of rejection incidence, time to first rejection episode and graft survival in cardiac transplant recipients. There were no significant between-treatment differences in patient survival for any type of transplant. In renal transplant recipients, significantly more of those receiving muromonab CD3-based prophylaxis required postoperative dialysis than those receiving triple therapy; in hepatic transplant recipients, muromonab CD3 improved or maintained renal function in the early postoperative period. Data on the relative effects of muromonab CD3-based and polyclonal-based prophylactic regimens are conflicting. In renal transplant recipients, some investigators show muromonab CD3- and antilymphocyte globulin (ALG)- or antithymocyte globulin (ATG)-based prophylaxis to be similar in terms of rejection incidence and/or time to first rejection, while others show ALG or ATG to be superior. The incidence of rejection episodes with muromonab CD3-based induction therapy in dual renal-pancreas transplant recipients is either similar to or lower than that with ALG- or ATG-based induction. Similarly, in cardiac transplant recipients, some studies show a longer time to first rejection episode and/or a lower incidence of rejection with muromonab CD3-based prophylaxis; others show no differences or a lower incidence of rejection or a longer time to first rejection episode with ATG-based therapy. Rejection episodes were fewer with ATG than with muromonab CD3 in the 1 available study in hepatic transplant recipients. Generally, no between-treatment differences were apparent in patient and graft survival or the incidence of delayed graft function. However, an anti-interleukin-2 monoclonal antibody-based prophylactic regimen improved graft and patient survival compared with muromonab CD3-based prophylaxis in hepatic transplant recipients. Several noncomparative trials have shown early rejection in children and adolescents undergoing renal, hepatic or cardiac transplantation to be effectively reduced by prophylactic muromonab CD3 administered as part of a sequential immunosuppressive protocol. Although rejection incidence during the first 14 days was lower with muromonab CD3-based prophylaxis than with standard triple therapy in hepatic transplant recipients, no overall reduction was observed. Further comparative trials are needed to determine the relative benefits of prophylactic muromonab CD3 in this patient group. Although muromonab CD3 reuse following prophylactic use is not recommended in patients with anti-idiotypic antibody titres ≥1: 1000, successful retreatment may occur in patients with lower titres. In theory, potential cost savings with prophylactic muromonab CD3 because of reduced rejection incidence compared with triple therapy may be offset by the increased incidence of infections and adverse events, but this has not been addressed in formal pharmacoeconomic assessments. Preliminary data from cost-minimisation studies suggest that mean first-year drug costs are greater with quadruple immunosuppressive regimens containing muromonab CD3, ATG or ALG than with triple therapy, and hospital costs with prophylactic muromonab CD3-based regimens were similar to or greater than those with polyclonal-based protocols. The first doses of muromonab CD3 are associated with flu-like ‘cytokine-release syndrome’ symptoms (e.g. fever, chills, gastrointestinal disturbance), which occur within 45 to 60 minutes and last for 2 to 48 hours. More severe but rare first-dose effects include aseptic meningitis, intragraft thromboses, seizures and potentially fatal pulmonary oedema. The incidence and severity of initial adverse events with muromonab CD3-based prophylaxis are similar to or greater than those associated with polyclonal antilymphocyte-based regimens. Cytomegalovirus (CMV), herpes simplex virus and bacterial infections are the primary cause of morbidity and mortality in muromonab CD3 recipients. However, the risk of infection appears to be related to the degree of immunosuppression rather than to the drug itself. The risk of CMV infection is increased by high doses (total doses >75mg) and repeated exposure to muromonab CD3. The incidence and/or severity of CMV infection with prophylactic muromonab CD3-based immunosuppression is similar to or greater than that with triple therapy and ATG- or ALG-based regimens. The overall incidence of bacterial and fungal infections with these treatment options is largely similar. Muromonab CD3-based immunosuppression has been associated with an increased risk of neoplasia, mainly lymphoproliferative disorders. However, this is most probably a direct result of the degree of immunosuppression; Epstein-Barr virus infection has also been implicated. The risk of lymphoproliferative disease may be increased by the use of high muromonab CD3 doses (total dose >75mg), long durations of administration, multiple courses and early retreatment. While some investigators report the incidence of neoplasia to be similar with muromonab CD3 and polyclonal preparations, others report a trend towards a greater incidence with muromonab CD3. Other clinically significant pulmonary, cardiovascular or neurological events are uncommon. Adverse events with muromonab CD3 may be prevented or minimised by the intraoperative administration of the first dose of muromonab CD3, pretreatment with a corticosteroid, administration of an antipyretic and antihistamine, prophylactic use of an antimicrobial(s) and correction of increased temperature and fluid overload before prophylaxis initiation. Induction therapy with muromonab CD3 together with azathioprine, methylpred-nisolone/prednisone and delayed cyclosporin therapy is the most accepted muromonab CD3-based regimen for allograft rejection prophylaxis. Although the optimal dosage of muromonab CD3 has not been established, the currently recommended adult dosage is 5mg administered intravenously once daily for 10 to 14 days, irrespective of the organ transplanted. A dosage of 2.5 mg/day has usually been used in children although higher doses may be needed. The dosage should be adjusted according to the presence of clinical signs of rejection in addition to antimuromonab CD3 antibodies, plasma muromonab CD3 concentrations and CD3+ cell levels. Patients should be closely monitored during administration of the first few doses. Intraoperative administration of the first dose and the use of preventative measures improve the tolerability of muromonab CD3. Evidence suggests that procoagulant activity is increased with the concomitant administration of muromonab CD3 and high-dose corticosteroids, and indomethacin may increase the risk of encephalopathy and volatile anaesthetic agents or drugs that decrease cardiac contractility increase the risk of developing cardiovascular problems when administered with muromonab CD3.