Pharmacology notes

Interleukin-2 receptor-blocking monoclonal antibodies: evaluation of 2 new agents

wo mouse/human monoclonal antibodies have been introduced to the market with approval for use in the prevention of acute renal transplant rejection. The following is a review of these agents and an analysis of their potential usefulness in antirejection regimens.

BACKGROUND

The development of immunosuppressive agents with less toxicity and more specificity has led researchers to explore the role of interleukin-2 (IL-2) in the immunosuppression cascade. The IL-2 receptor is composed of at least 3 subunits. One subunit, the a chain, named the Tac antigen, is predominantly expressed on activated T cells. Interleukin-2 facilitates the proliferation of alloantigen-activated T-cell clones by interacting with the IL-2 receptor, a critical step in the process of allograft rejection. For this reason, monoclonal antibody development was directed at this portion of the receptor and was called anti-Tac. Agents such as cyclosporine and tacrolimus target different sites along the immunosuppression cascade. It is thought that the IL-2 receptor-blocking monoclonal antibody will produce a synergistic effect when given in addition to current 3-drug regimens (i.e., cyclosporine or tacrolimus plus steroids plus azathioprine or mycophenolate mofetil) (1–3).

Muromonab-CD3 (Orthoclone OKT3, Ortho Biotech, Inc., Raritan, N.J.) was the first monoclonal anti–T-cell preparation used to produce immunosuppression. This product, developed with murine hybridoma techniques, has been used in both the prevention and the treatment of acute rejection after renal and liver transplantation (4). Typically, transplant centers reserve the use of muromonab-CD3 for situations in which 1) induction of immunosuppression using cyclosporine or tacrolimus as the primary immunosuppressive agent is contraindicated due to poor renal function, or 2) it is used as rescue therapy in steroid-resistant rejection. Both indications are suitable for kidney or liver transplant recipients.

The use of murine anti-Tac monoclonal antibodies has been limited, however, for several reasons. Eighty percent of recipients develop antibodies to the mouse immunoglobulin, rendering muromonab-CD3 ineffective with repeat exposure. Side effects, including the risk of anaphylaxis, are high with this product (5). Theoretically, these problems could be resolved with a more humanized product. Another disadvantage of muromonab-CD3 is its short half-life. Daily administration is required, increasing costs associated with drug acquisition, premedication, nursing labor, and lengthened hospital stays.

BASILIXIMAB

Basiliximab (Simulect, Novartis Pharmaceuticals Corporation, East Hanover, N.J.) is a chimeric IgG1 mouse/human monoclonal antibody that binds to the chain of the IL-2 receptor, thus blocking IL-2–mediated activation of T lymphocytes. The half-life of this product is approximately 7 days. The frequency and types of side effects seen with basiliximab in the clinical trials did not differ from those observed in the placebo group.

Two small studies assessed the pharmacodynamic and pharmacokinetic properties of the drug in renal transplantation (5, 6). In a larger, multicenter (European/Canadian) trial designed to assess the effects of prophylactic treatment with basiliximab, 376 patients were randomly assigned to receive either 2 doses of basiliximab (n = 190) or placebo (n = 186). Both groups received cyclosporine microemulsion (Neoral, Novartis Pharmaceuticals Corporation, East Hanover, N.J.) and steroids, according to the institution’s established regimen. All patients received primary renal transplantation from a donor with at least 1 human leukocyte antigen class I or class II mismatch. Patients in the treatment group were given basiliximab (20 mg) infusion 2 hours prior to transplant. A second infusion of basiliximab (20 mg) was administered on day 4. Patients assigned to the control group received the same regimen with placebo infusions. Rejection was defined as “a rejection episode confirmed by final clinical diagnosis and for which therapy was given.” Confirmation and grading of rejection episodes were determined through biopsy sampling, when technically feasible. Patients who experienced episodes of acute rejection were treated with steroid boluses according to institutional standards. Patients with steroid-resistant rejection were treated with site-specific drug regimens (7).

Data on the rates of rejection, the prevalence of biopsy-confirmed episodes of rejection, the number of steroid-resistant first rejection episodes treated with antibody therapy, as well as graft survival, are presented in Table 1. Noteworthy is the difference in antibody therapy requirements due to episodes of steroid-resistant rejection (basiliximab, n = 19; placebo, n = 43; P < 0.001). Current treatment for this type of rejection with muromonab-CD3 adds an additional $7200 to the cost of therapy. One also should note that, although the incidence of acute rejection was reduced in patients receiving basiliximab, at 12 months differences in overall graft and patient survival rates between the 2 groups were not statistically significant (7).

The acquisition cost for a 20-mg vial of basiliximab at our institution is $1009.70. The cost for the full course of basiliximab therapy, when given according to the trial design and corresponding manufacturer’s recommendations, is $2019.40.

DACLIZUMAB

Daclizumab (Zenapax, Roche Pharmaceuticals, Nutley, N.J.) is a molecularly engineered human anti–IL-2 receptor antibody. The drug has a long half-life of about 20 days. Genetic engineering is thought to have produced a product with high affinity and high specificity for the target receptor. In the clinical trials, there were no differences in side effects between the treatment group and the placebo group (8).

Two major trials have been reported. Results of these trials are compiled in Tables 2 and 3. Trial #1 was a randomized, double-blind, placebo-controlled phase III study that was conducted in Europe, Canada, and Australia. Patients receiving a first cadaveric renal transplant were enrolled in the study, and all patients were treated with cyclosporine and corticosteroids. A total of 5 doses of daclizumab was given (1 mg/kg; maximum, 100 mg per dose) to those randomized to the treatment arm (n = 141). The first dose was administered on the day of transplantation. The 4 remaining doses were then given every 2 weeks. Placebo (n = 134) was given on the same schedule. Primary efficacy was based on biopsy-proven acute rejection that occurred within the first 6 months of transplantation, although some patients were considered to have presumptive rejection if treated for a rejection episode. Secondary efficacy assessment compared patient and graft survival at 6 months and 12 months after transplantation. Time from transplantation to the first episode of rejection and the total number of episodes of acute rejection also were examined in this assessment (9, 10).

The incidence of biopsy-proven rejection, as well as presumptive acute rejection, was lower in the treatment arm. Similarly, the delay to the first episode of rejection was greater for the treatment group. Graft survival rates, however, were not statistically significant between the 2 groups (9, 10).

The second study with daclizumab, trial #2, involved triple-drug therapy regimens (cyclosporine, azathioprine, and prednisone). This was a randomized, double-blind, placebo-controlled, multicenter trial (USA, Canada, Sweden) designed to compare the efficacy of daclizumab with placebo for the prevention of acute rejection in primary renal transplantation. Dosing regimens were consistent with the dual-therapy trial (trial #1), with similar primary and secondary endpoint targets. Results of the study are shown in Table 3 (11).

The results of this study were similar to those of the trial #1 study. Statistically significant differences were seen in the number of episodes of acute rejection and the time between transplantation and that first rejection episode. The difference in graft survival rates for treatment and placebo groups was not significant (11).

Daclizumab is available as a 25-mg/5-mL vial. Its cost at our institution is $344.98. The cost for each dose of daclizumab is $1034.94, and the full course of therapy costs $5174.70 when given according to study design and manufacturer’s recommendations.

SUMMARY

In previous studies, renal transplant recipients who experienced delayed (versus immediate) episodes of acute rejection had a better overall likelihood of graft survival. Impressive data from the clinical studies assessing basiliximab and daclizumab confirm statistically significant reductions in the time from transplantation to the time to the first rejection episode. This was not, however, carried over to the data for graft survival at 12 months for either agent. A noteworthy finding in the basiliximab trials was a reduction in the incidence of steroid-resistant rejection, which could potentially reduce the need for, and subsequent cost of, muromonab-CD3 therapy.

No studies have reported the results of these therapies in other solid organ transplant patient populations or bone marrow transplant recipients. Currently, muromonab-CD3 is the only formulary agent. If either basiliximab or daclizumab is obtained, data will be collected to evaluate parameters similar to those in the trials cited. These data would be available for future formulary decisions for this class of medications.