Potential of daclizumab in solid organ transplantation.
The central role that the cytokine interleukin-2 (IL-2) and its receptor (IL-2R) play in the induction of the immune response has been recognised for some time. IL-2R consists of 3 chains (alpha, beta and gamma). The alpha-chain (T cell activation antigen or CD25) is expressed only after T-lymphocyte activation. Therefore a monoclonal antibody targeting the alpha-chain can result in selective immunosuppression. The first generation anti-IL-2Ralpha monoclonal antibodies consisted of mouse and rat antibodies that were promising but not totally effective in clinical studies. The immunogenicity, short half-life and inability to recruit host effector functions such as antibody-dependent cell-mediated cytotoxicity associated with the rodent monoclonal antibodies limit their clinical use. Chimerisation or humanisation of these monoclonal antibodies resulted in antibodies with a predominantly human framework that retained the antigen specificity of the original rodent monoclonal antibodies. A fully humanised anti-IL-2R monoclonal antibody, daclizumab, and a chimeric anti-IL-2R monoclonal antibody, basiliximab, have undergone successful phase III pivotal trials in which they were well tolerated and effective in the immunoprophylaxis of patients undergoing renal transplantation. Daclizumab 1 mg/kg every other week for a total of 5 doses in patients administered standard triple immunosuppression who had received grafts from cadaver or living related donors saturated the IL-2Ralpha on circulating lymphocytes for at least 3 months after transplantation. The efficacy and safety of intravenous daclizumab 1 mg/kg prior to transplantation and again at 2, 4, 6 and 8 weeks postoperatively, in conjunction with standard dual or triple immunosuppression, were further assessed in 2 phase III clinical trials. In both trials, biopsy-proven rejection was significantly reduced 6 months after the transplantation. The half-life of daclizumab was 20 days. The addition of daclizumab did not increase the incidence of adverse events, infectious complications or malignancies. Basiliximab 20mg was administered on the day of and on day 4 after transplantation, in conjunction with standard dual immunosuppression, in 2 phase III trials involving cadaver and/or living related transplants. The incidence of biopsy-proven acute rejection at 6 months was significantly reduced with basiliximab. The half-life of basiliximab was 7 days. The drug was not associated with increased risks of adverse events, infectious complications or malignancies. In an ongoing study, patients receiving a maintenance immunosuppression regimen of prednisone, cyclosporin and mycophenolate mofetil were administered daclizumab or placebo. Biopsy-proven rejection was lower in the group receiving daclizumab, and coadministration with mycophenolate mofetil was well tolerated with no pharmacokinetic interactions.
Vincenti
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Transplant Service, Moffitt Hospital, University of California, San Francisco, CA 94143-0116, USA. ROSBUD@ITSA.UCSF.EDU