Daclizumab

Abstract

The humanised monoclonal antibody daclizumab is an immunosuppressive agent that reduces acute rejection in renal transplant recipients. It is specific for the a subunit (Tac/CD25) of the interleukin-2 (IL-2) receptor on activated T cells and achieves immunosuppression by competitive antagonism of IL-2-induced T cell proliferation. Daclizumab has advantages over murine antibodies to the IL-2 receptor, including improved effector function, a low potential for immunogenicity and long elimination half-life.

When added to standard cyclosporin-based immunosuppressive therapy with or without azathioprine, daclizumab (1 mg/kg prior to surgery and once every 2 weeks thereafter for a total of 5 doses) significantly reduced the 6-month rate of acute rejection compared with placebo in 2 phase III studies. The mean number of rejection episodes was significantly reduced and the time to first acute rejection significantly increased in daclizumab versus placebo recipients. Patient survival at 1 year after transplantation was significantly higher with daclizumab than placebo in 1 study and showed a trend in favour of the drug in the other study. The 1-year graft survival rate tended to be greater in daclizumab than in placebo recipients in both studies.

In a phase II study, acute rejection rates in patients treated with both daclizumab and mycophenolate mofetil (plus standard cyclosporin-based immunosuppression) were lower than those achieved with mycophenolate mofetil alone.

Preliminary results indicate that daclizumab is also a useful agent in paediatric renal transplant recipients. Further investigation of the efficacy and tolerability of the drug in this patient group is clearly warranted.

Daclizumab does not increase the incidence of adverse events when added to standard cyclosporin-based therapy. The incidence of opportunistic infections, lymphoproliferative disorders and malignancies was not increased above that seen with placebo.

Conclusions: Although the effects of daclizumab on long term graft and patient survival require further investigation, available data indicate that daclizumab is an important advance in renal transplant immunosuppression, reducing acute graft rejection without affecting the tolerability of standard cyclosporin-based immunosuppression.

Pharmacodynamic Properties

Daclizumab is a humanised monoclonal antibody that binds specifically to the a subunit (Tac) of the interleukin-2 (IL-2) receptor present on the surface of activated T lymphocytes. It retains a high affinity for Tac, but has about 3-fold lower affinity than the murine monoclonal antibody from which it was derived.

Saturation of lymphocytes expressing the IL-2 receptor was shown in patients undergoing renal transplantation treated with daclizumab. Receptors remainedsaturated on peripheral blood lymphocytes in daclizumab-treated patients for up to 4 months after transplantation (2 months after the last dose of daclizumab).

Daclizumab antagonises the action of IL-2 at its receptor, thus causing inhibition of IL-2-dependent T lymphocyte proliferation in response to antigen recognition. In vitro studies have shown that daclizumab inhibits human T lymphocyte proliferation to a similar extent to the murine anti-Tac antibody.

Post-transplantation total lymphocyte and lymphocyte subset counts were similar in daclizumab and placebo recipients.

Pharmacokinetic Properties

Available data on the pharmacokinetic properties of daclizumab in renal transplant recipients indicate that a dosage of 1 mg/kg every 14 days for a total of 5 doses can maintain sufficient serum concentrations to provide immunosuppression 3 months after transplantation. Daclizumab has a small volume of distribution (about 5.3L), and systemic clearance is low (estimated at 15.1 ml/h for an 80kg 45-year-old Caucasian male; interindividual variation is about 20% and increases with increasing body weight). The drug has a long terminal elimination half-life (harmonic mean about 480 hours), which is similar to that reported for human immunoglobulin G (IgG).

Clinical Efficacy

Intravenous daclizumab (1 mg/kg within 24 hours before surgery and once every 2 weeks thereafter for a total of 5 doses) reduces the incidence of acute biopsyproven rejection in cadaver kidney transplant recipients.

The acute rejection rate at 6 months (the primary efficacy end-point) was significantly lower in patients treated with daclizumab plus cyclosporin-based double or triple therapy than in those treated with placebo plus cyclosporin-based therapy in 2 large phase III multicentre studies (rejection rates of 22 and 28% with daclizumab versus 35 and 47% with placebo). In addition, the mean number of rejection episodes was significantly lower and the time to acute rejection significantly longer with daclizumab.

The graft survival rate after 1 year was higher in daclizumab recipients in both studies (88 and 95% vs 83 and 90%, respectively), but the difference did not reach statistical significance.

Patient survival after 1 year was significantly higher in daclizumab compared with placebo recipients in 1 study (99 vs 94%), but not in the other (98 vs 96%).

The requirement for additional antilymphocyte therapy to treat rejection was lower with daclizumab than placebo, as was the cumulative dose of corticosteroids; however, only 1 of the phase III studies found these differences to be statistically significant.

In a phase II study, the graft rejection rate at 6 months after transplantation with combined daclizumab plus mycophenolate mofetil and standard immunosuppressive therapy (12%) was lower than that observed historically with standard immunosuppression plus mycophenolate mofetil.

Daclizumab showed promising results in a preliminary study in paediatric renal transplant recipients (median age 10 years). At follow-up (44% followed for ≥1 year and 87% for ≥6 months), only 3 of 54 patients (5%) treated with daclizumab [1mg/kg prior to transplantation and once every 2 weeks thereafter for a total of 5 doses, in addition to standard immunosuppressive therapy (predominantly cyclosporin-based)] experienced an acute rejection episode.

Tolerability

Available data from phase III studies indicate that daclizumab is well tolerated in the majority of patients. The incidence of all adverse events considered to be possibly or probably related to treatment was similar in daclizumab and placebo recipients, as was the incidence of severe events. Gastrointestinal disturbance was the most common event in both treatment groups, but was not considered to be treatment related. Daclizumab did not increase the incidence of opportunistic infections [bacterial, fungal or viral (including cytomegalovirus)] compared with placebo, and lymphoproliferative disorders and malignancies were rare. Specific toxicities related to the infusion of daclizumab such as allergic or anaphylactic reactions were not observed. First-dose adverse events occurred in a similar proportion of daclizumab and placebo recipients.

Daclizumab has a low potential for immunogenicity. Anti-daclizumab antibodies were found in about 10 to 15% of patients treated with the drug; however, their presence did not appear to alter the pharmacological properties or clinical efficacy of daclizumab.

Dosage and Administration

The recommended dosage of daclizumab for immunosuppression in renal transplant recipients is 1 mg/kg administered within 24 hours before surgery and once every 2 weeks thereafter for a total of 5 doses. Daclizumab 1 mg/kg should be diluted in 50ml of sterile 0.9% saline and administered intravenously via a peripheral or central vein over a 15-minute period.

No drug interactions have been observed after administration of daclizumab with standard immunosuppressive regimens.