Rabbit Antithymocyte Globulin (Thymoglobulin®)

Abstract

Rabbit antithymocyte globulin (rATG) [Thymoglobulin®; Thymoglobuline®] is a purified, pasteurized preparation of polyclonal gamma immunoglobulin raised in rabbits against human thymocytes that is indicated for the prevention and/or treatment of renal transplant rejection in several countries worldwide. rATG induction in combination with immunosuppressive therapy is more effective in preventing episodes of acute renal graft rejection in adult renal transplant recipients than immunosuppressive therapy without induction. The efficacy of rATG induction is generally better than that of equine antithymocyte globulin (eATG) induction and generally no different from that of basiliximab or low-dose daclizumab induction in this patient population. However, in high-risk patients, rATG induction was more effective than daclizumab or basiliximab induction in preventing acute renal graft rejection. In the treatment of renal graft rejection in adult renal transplant recipients, rATG was more effective than eATG in terms of the successful response rate, although the agents generally did not differ with regard to most other endpoints. Both induction and treatment with rATG are generally well tolerated, although adverse events, such as fever, leukopenia and thrombocytopenia, appear more common with rATG than with other antibody preparations. The overall incidence of infection associated with rATG induction was generally no different from that seen with eATG or basiliximab induction, although was higher with rATG than with basiliximab in high-risk patients. The incidence of cytomegalovirus (CMV) disease generally did not differ between rATG and eATG induction, and there was no significant difference between rATG and daclizumab induction with regard to the incidence of CMV infections or the proportion of patients who received treatment for a CMV episode or infection. Relative to basiliximab, the incidence of CMV infection was generally higher with rATG, except in high-risk patients. In the treatment of acute renal rejection, the nature and incidence of infections were generally similar with rATG and eATG. The incidence of malignancies is generally low with rATG therapy and generally does not differ from that seen with other agents. Further prospective comparative studies would be beneficial in order to definitively position rATG with respect to other antibody preparations. In the meantime, available clinical data suggest that rATG is an effective and generally well tolerated option for the prevention and treatment of acute renal graft rejection in renal transplant recipients. rATG displays specificity towards a wide variety of surface antigens on both immune system and endothelial cells. The precise mechanism(s) of action underlying its immunosuppressive efficacy is unclear, although T-cell depletion is considered to play a key role. Other mechanisms include lymphocyte surface antigen modulation, transcription factor activation, and interference with processes of immune system cells, such as cytokine production, chemotaxis, endocytosis, stimulation and proliferation. rATG may also induce apoptosis, antibody-dependent lysis or complement-mediated lysis of various immune system cells, and negate leukocyte-endothelial cell adhesion. Treatment with rATG sustained T-cell depletion more effectively than eATG in renal transplant recipients experiencing acute renal rejection. Moreover, rATG induction was at least as effective as eATG induction in depleting lymphocytes, and as expected, was associated with lower lymphocyte levels than basiliximab or daclizumab induction in renal transplant recipients. Serum concentrations of rATG appear to increase during treatment with intravenous rATG, and the serum concentration of total rATG, but not active rATG, is closely related to the cumulative dose. Levels of rATG in serum decline steadily after infusion cessation, with an elimination half-life of 2–3 days after an initial dose of 1.25–1.5mg/kg, although the decline of active rATG levels appears to be more rapid. Among renal transplant patients who received rATG 1.5mg/kg/day for up to 14 days, rATG and active rATG were present at measurable levels in 81% and 12% of patients 90 days after initiation of therapy. Prevention of Acute Renal Transplant Rejection: In two randomized, open-label, multicentre trials in adult renal transplant recipients, rATG induction in combination with tacrolimus-based immunosuppressive therapy was more effective than tacrolimus-based therapy without induction in preventing acute renal graft rejection at 6 or 12 months post-transplantation. In one of these studies, the incidence of biopsy-confirmed acute rejection (BCAR) in recipients of rATG induction with tacrolimus-based therapy did not significantly differ from that seen in recipients of rATG induction with ciclosporin-based therapy. Moreover, the median time to BCAR was >1 week longer with rATG induction therapy than with noninduction therapy, although there were no significant differences between regimens in terms of patient or graft survival. rATG induction was generally more effective than eATG induction in adult renal transplant recipients receiving immunosuppressive therapy in a double-blind, single-centre trial. rATG recipients had a lower incidence of BCAR episodes and greater event-free survival than eATG recipients up to 10 years post-transplantation, and greater graft survival up to 5 years post-transplantation, although there was no significant between-group difference in terms of patient survival. Moreover, in three randomized, open-label, multicentre studies, the efficacy of rATG induction therapy was generally no different from that of basiliximab or low-dose daclizumab in adult renal transplant recipients receiving triple immunosuppressive therapy. There were generally no differences between rATG and these agents in terms of the incidence of BCAR, or patient or graft survival at 6 months or 1 year...