Belatacept in renal transplantation
Belatacept is a novel agent that prevents CD28 signaling and inhibits T-cell activation by costimulation blockade. It was developed from abatacept (CTLA-4 Ig), the ﬁrst recombinant immunoglobulin fusion protein that contains extracellular portion of CTLA-4, and the Fc domain of IgG. Early studies have shown that belatacept recipients show comparable patient and graft survival, superior renal function and renal biopsy data compared with cyclo-sporine-treated patients. Newer biologic agents such as belatacept offer the promise of real change—due to their lack of mechanism-related toxic effects—and help monitor drug administration, thereby improving compliance. Belatacept is a potential option for maintenance biologic therapy without a calcineurin inhibitor, accompanied by excellent mid-term results with yet unknown long-term safety and efﬁcacy. The increased rate of TCMR and possibly central nervous system post-transplantation lymphoproliferative disorder are worrisome and need to be further elucidated.
Modern day immunosuppression relies heavily on calci-neurin inhibitors (CNI) such as cyclosporine and tacrolimus. Although they have dramatically reduced the rates of acute cellular rejection over the last few decades, these agents have numerous undesirable metabolic and cosmetic side effects. In addition, CNIs acutely decrease renal blood ﬂow and over time cause renal scarring and perhaps functional deterioration. Many agents have been studied with the promise of either minimizing or completely avoiding the use of CNIs. However, with the possible exception of mammalian target of rapamycin (mTOR) inhibitors under some circumstances, no agent has been able to replace these agents reliably. Recent studies with the agent belatacept have shown promise in terms of eliminating CNIs, along with the burden of toxicities that accompany their use.
Belatacept is a human fusion protein that prevents CD28 signaling and inhibits T-cell activation. It was developed from abatacept (CTLA-4 Ig), the ﬁrst recombinant immunoglobulin fusion protein, containing an extracellular portion of CTLA-4 and the Fc domain of IgG. Abatacept provided selective co-stimulation blockade of T-cell activation and binds CD80 and CD86.1 This agent is currently approved by the Food and Drug Administration (FDA) under the trade name Orencia for the treatment of rheumatoid arthritis. CTLA4-Ig was studied in rodents and showed prolonged transplanted organ survival, which led to studies in non-human primate transplant models. These studies showed that CTLA-4 Ig did not completely inhibit B7-mediated responses and did not completely inhibit T-cell activation; thus it was felt that adequate immunosuppression could not be achieved without the use of a CNI.2 A new molecule was developed that would have a higher afﬁnity for B7 ligands, speciﬁcally, CD86. This molecule, ﬁrst termed LEA29Y, was found to have increased afﬁnity for CD86 and CD80 on lympho-cytes. The CTLA-4 portion of belatacept contains two amino acid substitutions from the parent molecule abatacept, and it is felt that this modiﬁcation is responsible for the greater avidity for these receptors.2–4
The pharmacokinetics of belatacept is characterized by a linear and time-invariant model with a clearance of 0.86 L/d, a volume of distribution of 10.3 L, and a terminal half-life of 11 days. Belatacept's concentrations for any given dose were lower with an increase in body weight (either increased clearance or increased volume of distribution, leading to a shorter terminal half-life), thus supporting weight-based dosing. However, clearance is not affected by age, gender, renal or hepatic function, diabetes, or dialysis.5
This complex process of immune allorecognition is triggered by three signals. An alloantigen on the surface of recipient dendritic cells that triggers T cells with cognate T-cell receptors constitutes “signal 1,” transduced through the CD3 complex. Dendritic cells then provide costimulation, or “signal 2,” delivered when CD80 and CD86 on the surface of dendritic cells engage CD28 on T cells. Signals 1 and 2 activate three signal transduction path-ways: the calcium-calcineurin pathway, the RAS-mitogen-activated protein (MAP) kinase pathway, and the nuclear factor κB pathway.6
These pathways then activate tran-scription factors that trigger the expression of many new molecules, including inter-leukin-2 (IL-2), CD154, and CD25. IL-2 and other cytokines (e.g., IL-15) activate the “target of rapamycin” (TOR) pathway to provide “signal 3,” the trigger for cell proliferation, leading to nucleotide syn-thesis, and eventual proliferation and dif-ferentiation of effector T cells. B cells are activated similarly when antigen engages their antigen receptors, usually in lym-phoid follicles or in extrafollicular sites. The ultimate products of this operation are activated T cells, and antibody against the donor.6
Review of the Clinical Trials
A large Phase 2 study was conducted to evaluate the safety and efﬁcacy of belata-cept versus a cyclosporine-based regimen in kidney transplant recipients.7 This multicenter study included 218 patients with low immunologic risk who were randomly assigned to receive one of three regimens for primary immunosuppression; intensive regimen of belatacept, less intensive regimen of belatacept, or cyclosporine. The belatacept regimens included an early phase of 10 mg/kg and a late phase of 5 mg/ kg at 4- or 8-week intervals; belatacept was administered as a 30-minute intravenous infusion. All patients received induction therapy with basiliximab (20 mg on day 0 and day 4), mycophenolate mofetil, and a corticosteroid taper regimen. The incidence of acute rejection at 6 months was similar among the groups: 7% in the intensive belatacept group, 6% in the less intensive group, and 8% in the cyclosporine group. Subclinical rejection at 6 months was 9% in the intensive group, 20% in the less intensive belatacept group, and 11% in the cyclosporine group. The glomerular ﬁltra-tion rate (GFR) was calculated by modi-ﬁcation of diet in renal disease (MDRD); at 12 months the GFR was signiﬁcantly higher in the intensive and less intensive belatacept groups (66.3 mL/min/1.73 m2 and 62.1 mL/min/1.73 m2) than in the cyclosporine group (53.5 mL/min/1.73 m2; p = 0.01).7
In patients who underwent a 12-month biopsy, the incidence of chronic allograft nephropathy was lower in the intensive and less intensive belatacept groups (29% and 20%) than in the cyclosporine group (44%). Four patients in the cyclosporine group passed away (from cardiac causes in two of them), and one patient in the intensive belatacept group passed away from infection.7 The frequency of infection was similar in all three groups. Cancer was reported in two patients in the intensive belatacept group (n = 1 breast cancer, n = 1 post-transplantation lymphoproliferative disorder [PTLD]) and in two patients in the cyclosporine group (n = 1 skin cancer, n = 1 thyroid cancer). PTLD developed in two additional patients in the intensive group at 2 and 13 months after belatacept was replaced with tacrolimus. Two of the patients with PTLD had primary Epstein-Barr virus infections, and the third patient had received a 10-day course of muromon-ab-CD3 for acute rejection. Cardiovascular and metabolic effects were evaluated, and the total cholesterol, LDL, and HDL cho-lesterol were found to be similar among all the groups, with signiﬁcantly more patients in the cyclosporine arm receiving lipid-lowering drugs.7
The Phase 2 study results suggested that belatacept may provide adequate maintenance immunosuppression and possibly have renal sparing effects. Two Phase 3 studies were conducted to assess whether a belatacept-based regimen would achieve adequate renal function as well as patient and graft survival compared with cyclosporine in standard and extended criteria donors.8, 9 The BENEFIT (Belatacept Evaluation of Nephroprotection and Efﬁcacy as First-line Immunosuppression Trial) is a multicenter 3-year randomized trial with primary outcomes assessed at 12 months.8 This study included 686 patients randomly assigned to receive one of three regimens: intensive belatacept, less intensive belatacept, or cyclosporine. Patients received basiliximab induction therapy (20 mg at days 0 and 4), mycophe-nolate mofetil, and corticosteroid taper. At 12 months, there was no difference between the belatacept and cyclosporine groups in patient and graft survival. Renal function was found to be higher in the belatacept arms of the study compared with cyclo-sporine. The measured mean GFR was 13–15 mL/min higher in the belatacept groups compared with the cyclosporine group.8
The prevalence of biopsy-proven chronic allograft nephropathy was 18% in the intensive regimen, 24% in the less intensive regimen, and 32% in the cyclo-sporine group (in the subset of patients who underwent a protocol with 12-month renal biopsy). However, the incidence of acute rejection at 12 months was higher in the belatacept groups compared with the cyclosporine group: 22% in the intensive regimen, 17% in the less intensive regimen, and 7% in the cyclosporine group. The blood pressure and serum lipids were lower in the belatacept groups compared with the cyclosporine group.8 The numerically higher acute rejection rates in the interme-diate-dose arm compared with the high-intensity arm at ﬁrst seems paradoxical, but may simply be a random difference or may indicate a subtle and still to be understood dose/effect relationship or effect on nega-tive signals.
The 2-year BENEFIT data were published and continued to show that patient and graft survival were similar across all three treatment groups (94% intensive, 95% less intensive, and 91% cyclosporine group).10 The mean GFR was higher in the belatacept groups compared with the cyclosporine group. There were eight additional patients with an acute rejection episode between the ﬁrst and second year (n = 4 intensive, n = 4 cyclosporine). The incidence rate of malignancies and infections was the same across all groups with the addition of two cases of PTLD between the ﬁrst and second year in the intensive regimen. Currently, at 24 months, the belatacept regimens are providing similar efﬁcacy and superior renal func-tion compared with cyclosporine.10 At this time point, despite the greater incidence of T-cell-mediated rejection (TCMR), there is no evidence of increase in anti-HLA antibodies in either belatacept arm.
The BENEFIT-EXT (Belatacept Evaluation of Nephroprotection and Efﬁcacy as First-line Immunosuppression Trial-EXTended criteria donors) is a mul-ticenter 3-year randomized trial includ-ing 578 patients who received kidneys from extended-criteria donors and who were randomly assigned to receive one of three regimens: intensive belatacept, less intensive belatacept, or cyclospo-rine.9 This study evaluated the same primary outcomes at 12 months as the BENEFIT study and received the same immunosuppression.<Q3> The belatacept arms showed non-inferiority to cyclo-sporine for patient and graft survival at 1 year, and the proportion of patients surviving with a functioning graft was similar among all groups. The incidence of acute rejection at 12 months was similar among the groups: 17.9% in the intensive group, 17.7% in the less intensive group, and 14.1% in the cyclosporine group. The GFR was 6–8 mL/min higher from the beginning of the study to 12 months in the belatacept arms compared with cyclospo-rine, even though the number of patients with delayed graft function (DGF) was similar among the three groups. The inci-dence of chronic allograft nephropathy was similar among all three treatment groups in the subset of patients who received a biopsy.9
In the intensive belatacept arm, four patients developed malignancies in the ﬁrst 12 months, including Kaposi's sarcoma, breast, and colon cancer. In the less inten-sive arm, four patients developed malignan-cies, including myeolodysplastic syndrome and prostate cancer. In the cyclosporine arm, six patients developed malignancies, including breast cancer, renal neoplasm, thyroid neoplasm, transitional cell carci-noma, and Kaposi's sarcoma.
PTLD was documented in one patient in the intensive belatacept arm and two patients in the less intensive arm during the ﬁrst 12-month period, and one additional patient in each arm developed PTLD after month 12. Of these ﬁve cases, four patients had central nervous system (CNS) involvement, and the two patients who developed PTLD after month 12 had cytomegalovirus (CMV) disease. Three of the ﬁve PTLD patients had negative Epstein-Barr virus (EBV) serology before transplant. There were no cases of PTLD in the cyclosporine arm. The cardiovascular and metabolic effects were more favorable in the belatacept-treated patients: blood pressure was lower, as was the incidence of new-onset diabetes mellitus at 12 months. Non-HDL cholesterol and triglycerides were signiﬁcantly lower in the belatacept groups compared with the cyclosporine group.9
The 2-year BENEFIT-EXT data show similar graft and patient survival amongs the three treatment groups (83% intensive regimen, 84% less intensive, and 83% cyclosporine). The GFR was 8-10 mL/min higher in the belatacept groups compared with the cyclosporine group. There were three additional episodes of acute rejection after the first year (n = 1 less intensive group, n = 1 cyclosporine). The incidence of malignancies and serious infections was similar among the treatment groups, with the same number of PTLD cases (five patients). Currently, the beneﬁts of belatacept seem to be similar to those found in the BENEFIT study, but in patients with extended-criteria donors.11
The belatacept investigators have pooled safety data from the Phase II and Phase III studies, using 1425 intent-totreat patients with a median follow-up of 2.4 years; some of the patients were followed for 7 years. The belatacept-based regimens were found to be generally safe (TableI); the incidence of PTLD was higher in the belatacept groups, especially in EBV serologically negative patients and in those patients assigned to an intensive regimen. There were no cases of PTLD after 18 months in the belatacept groups. The incidence of death and serious infection was lowest in the less intensive belatacept groups. Tuberculosis occurred in 10 patients, mostly in endemic areas. There were no reports of anaphylaxis or hypersensitivity reactions to belatacept.12
Table I. Summary of safety proﬁle of belatacept.*
|Incidence of death (%)||7||5||7|
|Serious adverse events (%)||71||68||69|
|Overall malignancy (%)||10||6||7|
|Overall PTLD (no.)||8||5||2|
|PTLD-CNS involvement (no.)||6||2||0|
|Serious infections (%)||37||32||36|
|Fungal infections (%)||22||17||21|
Five-year safety and efﬁcacy data were recently published that included 78 (out of 102) belatacept patients and 16 (out of 26) cyclosporine patients.13 The mean calculated GFR (mL/min/1.73 m2) at 12 months was 75.8 ± 20.1 for the belatacept-treated patients and 74.4 ± 22.7 for the cyclosporine group. At 60 months, the greatest difference was seen with mean calculated GFR 77.2 ± 22.7 in the belatacept group and 59.3 ± 15.3 in the cyclosporine group. Three belatacept patients died (2 with functioning grafts and 1 after graft loss), and 2 cyclosporine patients died (both with functioning grafts). Six cases of biopsy-proven acute rejection were diagnosed in the belatacept group. Two patients were on the 4-week dosing schedule, and four patients were in the 8-week dosing group. There were no biopsy-proven rejection cases in the cyclosporine group. The most common adverse effects in belatacept patients were nasopharyngitis, urinary tract infection, diarrhea, and upper respiratory infection. There were no new cases of PTLD in this follow-up study. The cardiovascular risk factors favored belatacept over cyclosporine (TableII). 13
Table II. Cardiovascular risk factors in the 5-year follow-up study.*
|Systolic BP in mmHg, mean (SD)|
| Belatacept||129 (15.3)||129 (13.4)||126 (15.6)||125 (13.9)|
| Cyclosporine||132 (20.2)||129 (8.9)||140 (21.0)||138 (18.9)|
|Diastolic BP in mmHg, mean (SD)|
| Belatacept||76 (10.5)||76 (9.5)||76 (9.9)||76 (10.1)|
| Cyclosporine||78 (9.3)||76 (7.5)||77 (11.9)||83 (8.9)|
|Non-HDL cholesterol in mg/dL, mean (SD)|
| Belatacept||150 (35.7)||144 (37.5)||138 (38.8)||128 (37.3)|
| Cyclosporine||140 (44.9)||130 (31.7)||131 (38.6)||119 (29.5)|
| Belatacept||7 (7)||8 (9)||8 (9)||9 (10)|
| Cyclosporine||2 (9)||2 (9)||2 (9)||2 (9)|
Belatacept is a fusion protein that acts as a selective co-stimulation blocker by binding surface ligands (CD80 and CD86) on antigen-presenting cells. In antigen recognition, the binding of the co-stimulation receptor on T cells (CD28) to CD80 and CD86 (signal 2) is required for efﬁcient T-cell activation when the T-cell receptor encounters MHC alloantigens (signal 1). This contrasts with CNIs, which reduce T-cell activation by inhibiting calcineurin and thereby interfering with the pathways from signal 1.
The results from the BENEFIT study showed that the belatacept patients had comparable patient and graft survival and superior renal function; renal biopsy data, while not complete, were encouraging in terms of less interstitial ﬁbrosis and tubular atrophy. However, belatacept-treated patients had higher rates of TCMR and PTLD.8-11 The implications of these findings are being actively studied, but they add a cautionary note to what must be termed an important advance in transplant immunosuppression. As expected, the burden of metabolic disease was decreased and despite the higher rates of TCMR, no increases in anti-HLA antibodies were seen.
Newer biologic agents such as belatacept offer the promise of real change because of their lack of mechanism-related toxic effects. If favorable in clinical trials, they offer the potential for developing new immunosuppressive protocols with less reliance on the traditional small-molecule drugs, thereby reducing the global burden of side effects without sacriﬁcing efﬁcacy. Thus, these protein-based immunosuppres-sives can improve the quality of life and possibly long-term morbidity and mortality in our transplant recipients. The intermit-tent parenteral administration of proteins will likely involve some infrastructural changes, and the impact on compliance will be closely watched. Parenteral administra-tion will take place either at the hospital, physician ofﬁces, dialysis centers, or home infusion centers; the implications of each location will need to be discussed before implementation. Personnel and equipment will also have to be factored into the cost of administration of these medications.
Acute cellular rejection (ACR) was more frequent and histologically more severe in belatacept-treated patients than in cyclosporine-treated patients, it occurred in the ﬁrst 3 months, and was steroid respon-sive, with little or no impact on long-term renal function or short-term graft survival. Additionally, among those with follow-up biopsies, belatacept-treated patients had less atrophy and ﬁbrosis, presumably because the transplanted kidney was spared the nephrotoxic effects of CNIs. In con-trast, there was a numerically higher inci-dence of PTLD, including the uncommon phenotype of CNS involvement, which must be viewed with caution and concern. CNS lymphomas were mainly seen in EBV-negative recipients of mismatched kidneys. It may be prudent to avoid belata-cept in this group of patients. In conclusion, the belatacept studies are a landmark achievement and prove that maintenance biologic therapy without a CNI is not only plausible but can be accompanied by excel-lent mid-term results. The issues of long-term safety and efﬁcacy (as with all agents) must await the test of time. The increased rate of TCMR and possibly CNS PTLD adds an element of caution and points to the need for future studies with this promising agent.