Potential of daclizumab in solid organ transplantation

The central role that the cytokine interleukin-2 (IL-2) and its receptor (I L-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-ch ain (T cell activation antigen or CD25) is expressed only after T-lymphocyt e activation. Therefore a monoclonal antibody targeting the alpha-chain can result in selective immunosuppression. The first generation anti-IL-2R alp ha monoclonal antibodies consisted of mouse and rat antibodies that were pr omising but not totally effective in clinical studies. The immunogenicity, short half-life and inability to recruit host effector functions such as an tibody-dependent cell-mediated cytotoxicity associated with the rodent mono clonal antibodies limit their clinical use. Chimerisation or humanisation of-these monoclonal antibodies resulted in an tibodies with a predominantly human framework that retained the antigen spe cificity of the original rodent monoclonal antibodies. A fully humanised an ti-IL-2R monoclonal antibody, daclizumab, and a chimeric anti-IL-2R monoclo nal antibody, basiliximab, have undergone successful phase III pivotal tria ls 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 admi nistered standard triple immunosuppression who had received grafts from cad aver or living related donors saturated the IL-2R alpha on circulating lymp hocytes for at least 3 months after transplantation. The efficacy and safet y of intravenous daclizumab I mg/kg prior to transplantation and again at 2 , 4, 6 and 8 weeks postoperatively, in conjunction with standard dual or tr iple immunosuppression, were further assessed in 2 phase III clinical trial s. In both trials, biopsy-proven rejection was significantly reduced 6 mont hs after the transplantation. The half life of daclizumab was 20 days. The addition of daclizumab did not increase the incidence of adverse events, in fectious complications or malignancies. In an ongoing Study, patients receiving a maintenance immunosuppression reg imen of prednisone, cyclosporin and mycophenolate mofetil were administered daclizumab or placebo. Biopsy-proven rejection was lower in the group rece iving daclizumab, and coadministration with mycophenolate mofetil was well tolerated with no pharmacokinetic interactions.