Belatacept belongs to a new class of immunosuppressive drugs, is a selective T-cell blocker, and includes two replaced aminoacids in the abatacept (L104E and A29Y). This drug markedly increases its activity in vivo by virtue of its great binding ability to CD80 and CD86.22
Belatacept is a human fusion protein that combines a modified extracellular portion of CTLA-4 with the Fc domain of human IgG1. It prevents the stimulation of CD28 antagonizing CD80 and CD86 on APCs, and thus blocks the three signals of the transduction pathway. This latter antagonist effect results in an inability to produce effector cell cytokines, such as IL-2. This interaction inhibits the complete activation of T-cells and promotes anergy and apoptosis ().6
Moreover, belatacept does not act by depleting T-cells, is well-tolerated, and protects patients against the adverse renal, cardiovascular, and metabolic effects encountered with calcineurin inhibitors (CNIs).
Belatacept binds to CD80 (B7-1) and CD86 (B7-2) and blocks costimulation.
Tregs, a CD4+ CD25+ FOXP3+ subset of T-cells, are known to be able to suppress pathological immune response in autoimmune diseases, transplantation, and graft-versushost disease ().23
Bluestone et al investigated the effect of costimulatory blockade on Tregs in kidney transplanted patients receiving belatacept treatment with basiliximab induction. The results show that, unlike CNIs, belatacept has no short- or long-term effects on the number or function of circulating Tregs.24
Great interest was aroused by the finding of a number of Tregs in graft biopsies during acute rejection that exceeded the number found in patients treated with CNIs. This finding suggests that belatacept may both promote Tregs infiltration in renal allografts and facilitate recovery from rejection.24
The pharmacokinetic parameters of belatacept are not influenced by age, sex, ethnicity, or comorbid conditions. Moreover, hemodialysis, diabetes, and hepatic/renal dysfunction do not affect the pharmacokinetics of belatacept, so that dosage adjustments are not required. The expected half-life of belatacept is about 11 days.25
In renal transplanted nonhuman primates, belatacept demonstrated better effectiveness in preventing acute rejection than abatacept.21
Phase II of a multicenter randomized study in renal transplantation compared data from an intensive regimen of belatacept with those from a less intensive regimen of belatacept or of cyclosporin A (CsA).26
The primary objective was to demonstrate the noninferiority of belatacept over CsA in the incidence of acute rejection at 6 months. Secondary endpoints were the incidence of acute rejection (biopsy-confirmed or presumed) at 6 and 12 months and glomerular filtration rate (GFR) at 1, 6, and 12 months. The incidence of acute rejection was similar at 6 months throughout the three groups recruited for the study. No episodes of acute rejection were reported after month 6 in any group. Moreover, the GFR at 12 months was significantly higher in patients receiving the more intensive (MI) and less intensive (LI) belatacept regimens than in those receiving CsA (P
= 0.01 for the comparison between MI belatacept and CsA, P
= 0.04 between LI belatacept and CsA). Finally, chronic allograft nephropathy was lower in belatacept-treated patients.26
This study was extended to 5 years and demonstrated stable renal function and a high level of safety. Interestingly, the CD86 receptor showed significant saturation in both 4 week and 8 week dosing regimens, thus suggesting that CD86 receptor binding by belatacept persists over many years of administration.27
These results correlate with data from Latek et al,28
which found that free CD86 receptor levels in belatacept treated patients were (1) significantly lower than they were prior to treatment and (2) lower than those of volunteers and of patients treated with CsA.
On the basis of these results, Phase III trials were carried out to verify the benefits of the costimulation blockade on kidneys from standard-criteria donors (BENEFIT [Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppressive Trial]) and on kidneys from expanded criteria donors (ECDs) (BENEFIT-EXT [Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression – EXTended criteria donors]).
In the BENEFIT study, at 12 months, both belatacept regimens showed similar patient/graft survival to that found for CsA and GFR was significantly lower in the MI and LI belatacept group than in the CsA group (55% MI, 54% LI, and 78% CsA). Unexpectedly, the incidence of acute rejection was higher in belatacept patients than in the CsA group (22% MI, 17% LI, and 7% CsA). Amost 100% of rejection occurred within the first 6 months and were histologically more severe than in CsA-treated patients.29
Given the complexity of the CD28/B7 pathway, multiple factors are likely involved in the onset of acute rejection in belatacept-treated patients: (1) possible memory-cell resistance to costimulation blockade and the intervention of other costimulatory pathways in T-cell activation;3
(2) higher B7 occupation by belatacept interfering with inhibitory signals through CTLA-4;31
and (3) possible inhibition of Tregs through the abrogation of CD28 signals and the inhibition of CTLA-4 function.32
The use of the ECDs procedure is perceived as increasingly acceptable and attractive because it enables transplantation to be performed in patients who otherwise would not qualify to receive a donated kidney.
The BENEFIT-EXT trial is a recently published study that aims to underline the superiority of belatacept’s effectiveness compared with that of CsA in patients receiving ECD kidneys.33
The co-primary endpoints at 12 months were composite patient/graft survival and a renal impairment endpoint. Patient/graft survival with MI and LI belatacept was similar to CsA (86% MI, 89% LI, and 85% CsA) at 12 months. Secondary end points included GFR, cardiovascular profile, and metabolic profile, all of which showed better trends in belatecept than in CsA treated patients.
The incidence of acute rejection was similar across groups (18% MI, 18% LI, and 14% CsA). The authors conclude that belatacept provides better renal function and similar immunosuppressive efficacy in comparison with CsA, that it improves cardiovascular risk profile, and that tolerance is high. There were no clinically meaningful differences in efficacy or safety between the MI and LI regimen.
In an analysis of the respective BENEFIT and BENEFIT-EXT datasets, Vanrenterghem et al compared belatacept-based regimens with CsA at month 12. Both the given studies show that belatacept-based regimens had a better cardiovascular and metabolic risk profile, along with lower blood pressure and serum lipids levels and less new onset diabetes after transplant than the CsA-based regimen.34
Analogously comparing performance at 24 months, Larsen et al reported similarity in terms of graft function, but greater renal benefits for belatacept-treated patients than for CsA-treated patients. There were few new acute rejection episodes in either study at 12 and 24 months.35
Finally, in a 36-month study by Florman et al, belatacept demonstrated better renal function and comparable patient/graft survival when compared with CsA, regardless of standard criteria donors or ECD donor type throughout the 3-year period. As of month 24, new cases of acute rejection were infrequent.36
In conclusion, both the BENEFIT and BENEFIT-EXT trials showed that belatacept offers a more positive cardiovascular and metabolic profile, with lower incidence of new-onset diabetes after transplant than do currently used immunosuppressants, and that it might also prevent CNI-associated nephrotoxicity.