Administration of daclizumab in addition to dual immunosuppression therapy significantly reduced biopsy-proven acute rejection after renal transplantation, improved patient survival, and did not add to the toxicity of the immunosuppressive regimen.
Daclizumab, a humanized monoclonal IgG1 directed against the chain of the interleukin-2 receptor (IL-2R), is a competitive inhibitor of IL-2 on activated lymphocytes. To test the hypothesis that specific inhibition of activated lymphocytes in patients with ongoing acute graft-versus-host disease (GVHD) might ameliorate the process, we treated 43 patients with advanced or steroid-refractory GVHD with daclizumab. The first cohort of 24 patients was treated with daclizumab 1 mg/kg on days 1, 8, 15, 22, and 29. On day 43, the complete response (CR) rate was 29% (95% confidence interval [CI], 13%-51%). Survival on day 120 was 29% (95% CI, 13%-51%). A second cohort of 19 patients was treated with daclizumab 1 mg/kg on days 1, 4, 8, 15, and 22. For these patients, the CR rate on day 43 was 47% (95% CI, 24%-71%), and survival on day 120 was 53% (95% CI, 29%-76%). There were no infusion-related reactions and no serious side effects related to daclizumab. Following treatment, there was a reduction in serum concentrations of soluble IL-2R and peripheral blood CD3 + 25+ lymphocytes, but these changes were not predictive of response. Daclizumab has substantial activity for the treatment of acute GVHD, and the second regimen evaluated is recommended for a controlled study. (Blood, 2000; 95:83-89)
The efficacy of murine monoclonal anti-interleukin 2 alpha chain receptor (Tac) antibodies is limited by a short half-life and the development of antibodies to the heterologous protein. The safety, pharmacokinetics-dynamics, and immunosuppressive effect of a humanized anti-Tac antibody (HAT) was evaluated in 12 renal transplant recipients. Ten patients received living related transplants (three HLA-identical matches and seven one-haplotype or zero-haplotype matches) and two patients received cadaver organs. The patients were divided into four HAT treatment arms: 0.5 mg/kg/week (n=4), 1 mg/kg/week (n=2), 0.5 mg/kg every other week (n=3), and 1 mg/kg every other week (n=3). The first dose of HAT was given within 12 hr before transplantation, and four additional doses were given after transplantation. Patients were also placed on cyclosporine, steroids, and azathioprine. Only one patient, a recipient of a cadaver kidney in the lowest HAT treatment arm, had a reversible rejection episode. The 10 recipients of living related transplants were compared with 17 historical controls treated with an identical immunosuppressive regimen except for HAT. Whereas none of the HAT-treated living related donor recipients had a rejection episode, 6 of 17 (41%) of the historical controls had a rejection episode in the first year after transplantation. There were no first-dose reactions after HAT therapy or other subsequent side effects. None of the patients experienced opportunistic infections or malignancies. One patient developed low-titer anti-HAT antibodies, although the patient maintained high serum HAT concentrations throughout the study. Immune monitoring showed that there were no changes in the percentage or absolute counts of CD3 cells or T-cell subsets after HAT therapy. However, there was a significant decrease in the number of circulating lymphocytes that expressed free Tac. The overall harmonic mean half-life of HAT was 273 hr. The results of this study indicate that HAT given at 1 mg/kg every other week for a total of five doses may provide therapeutic HAT concentration levels and result in good saturation of Tac receptors for at least 12 weeks after transplantation. In summary, HAT is safe and is well tolerated by patients. Its long half-life and lack of immunization could make it a very useful immunosuppressive drug.
Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological disease that results from an interaction of retroviral infection and immune activation. In this study, five doses (1 mg/kg) of humanized anti-Tac antibody were administered to 9 HAM/TSP patients at weeks 0, 2, 6, 10, and 14. Preliminary immunological studies on HAM/TSP patients treated with humanized anti-Tac indicate that there is a selective down-regulation of activated T cells and a decrease in the HTLV-I viral load in peripheral blood lymphocytes, most likely through the selective removal of HTLV-I-infected, activated CD4+ lymphocytes.
A single HuM291 dose rapidly depleted circulating T cells in a dose-dependent manner and was associated with only mild to moderate symptoms of cytokine release.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.