Servicio de Nefrología, Hospital Ramón y Cajal, Universidad de Alcalá, Madrid, Spain
Keywords: basiliximab; daclizumab; monoclonal antibodies
At present, classical induction therapy is inadvisable for low-risk renal transplantation (RT) recipients, given the efficacy of immunosuppressive regimens based on micro-emulsified cyclosporin, tacrolimus, MMF, or sirolimus and the risk of infections and malignancies [1]. The classical induction is more questionable for high immunological risk patients. Monoclonal antibodies against IL-2 receptor (IL-2r) offer the possibility of more selective immunosuppression.
Murine anti-IL-2r antibodies significantly reduce the incidence of early acute rejection without any relevant associated toxicity [2]. However, they stimulate a potent immune response in the human recipient that limits their use at medium or long-term, exhibit a half-life and are inefficient to destroy human cells.
A chimeric anti-IL-2r antibody: basiliximab
Basiliximab is a chimeric monoclonal antibody (murine/human) with human IgG1 constant heavy chain regions and kappa light chain. It specifically binds and blocks CD25 antigen, IL-2r -chain, at the surface of activated T-lymphocytes [3]. This specific basiliximab binding to IL-2r competitively inhibits IL-2 mediated lymphocyte activation, a crucial phase in cellular immune response of allograft rejection.
Three phase II studies are available in primary cadaveric RT recipients treated with basiliximab [35]. They showed (i) absence of adverse reactions attributed to antibody infusion, (ii) absence of anti-basiliximab immunization, (iii) restricted initial distribution volume and slow clearance, with prolonged half-life, (iv) a unique pre-transplant dose being potentially adequate for acute rejection prophylaxis during the first 46 post-transplant weeks, (v) no influence of weight and sex on pharmacokinetic parameters and (vi) the requirement of basiliximab to be administered in association with cyclosporine starting in the the immediate post-transplant period.
Two phase III multicentre, randomized, double-blind placebo-controlled trials have been undertaken in Europe/Canada (n=380) [6] and the US (n=348) [7] with basiliximab induction. Therapy was double cyclosporin-steroids and basiliximab was administered at a dose of 20 mg pre-transplant and 20 mg at day 4. The results were similar in both studies: reduction in the incidence of acute rejection and good patient and graft survivals (Table 1). The incidence of major adverse events attributed to the study drug, namely infections and neoplasia were similar to those observed with placebo.
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Small studies have compared efficacy and safety of classic induction with OKT3 [1114] or ATG [15,16] and two-dose basiliximab. The incidence of acute rejection and survival were similar with all agents, but classic induction was associated with longer hospital stay and more frequent adverse events.
Safety and tolerability of basiliximab are good in paediatric RT patients [17]. However, paediatric recipients receiving basiliximab had significantly increased blood concentrations of cyclosporin, early cyclosporin toxicity, and lower dose requirement within the first 2 weeks compared with controls. The authors suggested that a basiliximab mediated alteration of the cytochrome p450 system caused this systemic drug alteration.
To our knowledge, only one study analysed induction therapy with basiliximab and delayed introduction of tacrolimus [18]. The incidence of acute rejection was lower and graft survival was better than those observed in historical controls with OKT3/ATG. Preliminary results with sirolimus and delayed neoral are also available [19].
Basiliximab is associated with a significant reduction in acute rejection and an excellent safety profile in RT patients with diabetes as shown in the analysis of pooled results from the two phase III trials [6,7] as reported recently [20]. One-year graft survival was better in diabetics treated with basiliximab compared with those receiving placebo (96% vs 86%, P=0.022). No objective evidence supports the need of induction therapy in combined kidney and pancreas transplantation. In case of deciding the convenience of induction, basiliximab is efficacious and safe, and OKT3 does not show superiority [21].
A humanized anti-IL-2r antibody: daclizumab
Daclizumab is a humanized anti-IL-2r antibody built by total gene synthesis using oligonucleotides. Daclizumab is 90% human, retaining original 10% murine compartments in critical hypervariable segments for binding specificity.
Mild late immunogenicity, prolonged terminal half-life and prolonged survival were seen using daclizumab 1 mg/kg/48 h until graft loss in a cardiac transplant model in monkeys [22]. No toxicity was observed. Safety, pharmacokinetics, and immunosuppressive effect was studied in a phase I study in 12 RT recipients, treated with triple therapy cyclosporin/azathioprine/steroids and four different dosages of daclizumab [23]. No first-dose reactions, opportunistic infections, or neoplasias were observed. Five 1 mg/kg doses (every 2 weeks) achieved sufficiently high antibody concentrations to inhibit more than 90% of antigen-induced lymphocyte proliferation during more than 12 weeks, thus considering this dosage adequate for further efficacy trials.
Daclizumab efficacy in preventing acute rejection after RT was analysed in two multicentre, randomized, placebo-controlled phase III trials (Table 1). Recipients received daclizumab or not (1 mg/kg every 2 weeks five doses) in addition to triple therapy cyclosporin, azathioprine, and steroids [24] or double therapy without azathioprine [25]. In the first trial, 15% of patients randomized to receive daclizumab and 20% assigned to placebo did not receive the five scheduled doses, most of them because of post-transplant acute tubular necrosis and induction with anti-lymphocyte antibodies. Although the authors suggested that the beneficial results with daclizumab were not modified by delayed graft function, initial use of anti-lymphocyte preparations or failure to not-complete the five-dose regimen, they did not present any data to confirm this assumption.
Both studies yielded similar 6-month results: reduction in acute rejection and good patient and graft survival (Table 1). Acute rejection grades were not specified, however, and we ignore the percentages of severe acute rejection in both groups. In the first trial, the difference in the percentages of patients requiring anti-lymphocyte preparations to treat acute rejection did not reach statistical significance [24]. In the second trial, the authors underline a better (statistically significant) 1-year patient survival in the patients given daclizumab (99% vs 94%, P<0.01) [25]. Eight patients from the placebo group and only one of the daclizumab group died. Seven of the eight placebo patients died with a functioning graft. This difference in patient survival was parallel to a poor 83% graft survival in placebo group, worse than that obtained in placebo group in the other phase III trial with daclizumab and survivals in placebo groups in basiliximab trials. On the other hand, patient survival was particulary good in the daclizumab group (only one dead in 140 patients in 1 year), better than the survival obtained with any other treatment modality in all clinical RT trials published during the last few years. Consequently, an aggregation of negative factors for patient survival in placebo group and positive factors in the daclizumab group undoubtedly favoured the appearance of a better, more statistically than clinically relevant, patient survival in the daclizumab group.
To avoid nephrotoxicity, a protocol of daclizumab induction (first 2 mg/kg pre-transplant and then four doses every 2 weeks 1 mg/kg), MMF 3 g/day and steroids has been applied in a multicentre, open non-comparative trial including 100 patients [26]. The incidence of biopsy-proven acute rejection was 45%.
Two non-randomized studies compared induction therapy with daclizumab and OKT3. The first included high immunological risk RT recipients [27]. Daclizumab regime consisted of four doses: 2 mg/kg before surgery and then 1 mg/kg at days 7, 14 and 28; OKT3 was given 5 mg/day for 7 days. All patients received cyclosporin, MMF, and steroids. The incidence of acute rejection and its severity was higher with daclizumab, although undesired effects were less frequent.
The most extensive trial giving two doses of daclizumab instead of the more usual by administered five doses, was undertaken in 169 cadaveric RT recipients: the first dose was delivered before surgery and the second dose at hospital discharge [28]. All received cyclosporin/MMF/steroids and were compared with 124 historical controls receiving OKT3 induction for 714 days and the same triple therapy. Daclizumab reduced acute rejection incidence, infection rate, and frequency of readmissions.
Some studies have attempted to assess safety and efficacy of induction therapy with daclizumab in recipients with a theoretically high immunological risk or high risk for delayed graft function [2931]. Small sample size and diversity of daclizumab dosage preclude to draw uniform conclusions.
The problem of dosage
Phase I/II developments of basiliximab and daclizumab looking for safe and efficacious dosage were quite different. Phase II studies with basiliximab explored the dose after which serum antibody concentrations minimized the amount of T lymphocytes with activated IL-2r during the considered critical period of 46 weeks [35]. The studies showed that this dose was 40 mg, and it was decided to divide it in two 20 mg doses (one pre-transplant and the other one at day 4 post-transplant) in order to save 20 mg in case of technical failure during the first days. The protocol was easy to follow, always with the patient being hospitalized and effective during the critical period to prevent acute rejection. Pharmacodynamic data confirmed that adjusting dose for sex and body weight was not necessary. Consequently, all phase III studies and further developments have been undertaken with 40 mg administration in two 20 mg doses, and accumulated safety and efficacy experience with the antibody has been achieved with this dose. This uniformity in the dosage provides reliable comparisons among groups, patient groups and different trials, which would have been impossible if the doses and regimens had been diverse.
On the contrary, the pre-clinical phase with daclizumab was developed with dosage corrected for body weight. Phase I dose-finding study was based on only 12 patients with four different dosages [23]. The critical post-transplant period was considered to last for 12 weeks, thus adopting a dosage covering this period, pre-transplant 1 mg/kg and then four other doses every 2 weeks. Phase III efficacy trials with daclizumab have been developed with these five doses in 2 months protocols, assuring IL-2r saturation during 12 weeks. Extrapolating efficacy results to other protocols with different doses is unfair and unreliable although it may look reasonable. Consequently, the protocol with basiliximab ends at day 4, while the protocol with daclizumab lasts until day 60 post-transplant. The i.v. administration of a given preparation scheduled in 95% of cases to exceed the period of patient hospitalization is cumbersome and inconvenient, and largely impracticable if the benefits are not spectacular. This situation explains why most of the clinical development studies with daclizumab have been undertaken with abbreviated treatment dosages, usually two to three doses, frequently with 2 mg/kg each. No pharmacokinetic, pharmacodynamic, or efficacy studies in human patients are available with these dosages. Therefore, we largely ignore the behaviour of this antibody in this context. After having reviewed the available literature in this field during the last 2 years, it is obvious that there are not two equal studies in terms of daclizumab regimen.
Conclusions
Classical anti-lymphocytic induction therapy is inadvisable for low-risk RT recipients, given the efficacy of current immunosuppressive drug regimens. Monoclonal antibodies against IL-2r offer the possibility of more selective immunosuppression. Induction therapy with basiliximab in two doses or daclizumab in five doses reduces the incidence and severity of acute rejection, with good patient and graft survival and absence of significant adverse events. The use of less than five daclizumab doses is not supported by phase III trials and the evidence for efficacy and safety of such low dosage is soft. Experience with basiliximab in the absence of concomitant anti-calcineurin treatment showed excessive rates of acute rejection. Comparisons with OKT3 or ATG show similar efficacy but a much better safety profile for the new agents. Although cost-effectiveness studies of anti-IL2r antibodies in RT induction treatment are not available yet, the savings in acute rejection episodes probably overcome increased drug costs. The absence of undesirable effects associated with these new preparations reinforce this idea. Randomized large multicentre trials comparing basiliximab and daclizumab are needed.
Notes
Correspondence and offprint requests to: Julio Pascual, Servicio de Nefrología, Hospital Ramón y Cajal, Universidad de Alcalá, Carretera de Colmenar km 9, 100, E-28034 Madrid, Spain.
References