Belimumab in kidney transplantation: an experimental medicine, randomised, placebo-controlled phase 2 trial

Lancet. 2018 Jun 30;391(10140):2619-2630 doi: 10.1016/S0140-6736(18)30984-X.

B cells produce alloantibodies and activate alloreactive T cells, negatively affecting kidney transplant survival. By contrast, regulatory B cells are associated with transplant tolerance. Immunotherapies are needed that inhibit B-cell effector function, including antibody secretion, while sparing regulators and minimising infection risk. B lymphocyte stimulator (BLyS) is a cytokine that promotes B-cell activation and has not previously been targeted in kidney transplant recipients. We aimed to determine the safety and activity of an anti-BLyS antibody, belimumab, in addition to standard-of-care immunosuppression in adult kidney transplant recipients. We used an experimental medicine study design with multiple secondary and exploratory endpoints to gain further insight into the effect of belimumab on the generation of de-novo IgG and on the regulatory B-cell compartment.


We undertook a double-blind, randomised, placebo-controlled phase 2 trial of belimumab, in addition to standard-of-care immunosuppression (basiliximab, mycophenolate mofetil, tacrolimus, and prednisolone) at two centres, Addenbrooke's Hospital, Cambridge, UK, and Guy's and St Thomas' Hospital, London, UK. Participants were eligible if they were aged 18-75 years and receiving a kidney transplant and were planned to receive standard-of-care immunosuppression. Participants were randomly assigned (1:1) to receive either intravenous belimumab 10 mg per kg bodyweight or placebo, given at day 0, 14, and 28, and then every 4 weeks for a total of seven infusions. The co-primary endpoints were safety and change in the concentration of naive B cells from baseline to week 24, both of which were analysed in all patients who received a transplant and at least one dose of drug or placebo (the modified intention-to-treat [mITT] population). This trial has been completed and is registered with, NCT01536379, and EudraCT, 2011-006215-56.


Between Sept 13, 2013, and Feb 8, 2015, of 303 patients assessed for eligibility, 28 kidney transplant recipients were randomly assigned to receive belimumab (n=14) or placebo (n=14). 25 patients (12 [86%] patients assigned to the belimumab group and 13 [93%] patients assigned to the placebo group) received a transplant and were included in the mITT population. We observed similar proportions of adverse events in the belimumab and placebo groups, including serious infections (one [8%] of 12 in the belimumab group and five [38%] of 13 in the placebo group during the 6-month on-treatment phase; and none in the belimumab group and two [15%] in the placebo group during the 6-month follow-up). In the on-treatment phase, one patient in the placebo group died because of fatal myocardial infarction and acute cardiac failure. The co-primary endpoint of a reduction in naive B cells from baseline to week 24 was not met. Treatment with belimumab did not significantly reduce the number of naive B cells from baseline to week 24 (adjusted mean difference between the belimumab and placebo treatment groups -34·4 cells per μL, 95% CI -109·5 to 40·7).


Belimumab might be a useful adjunct to standard-of-care immunosuppression in renal transplantation, with no major increased risk of infection and potential beneficial effects on humoral alloimmunity.



CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion: This small placebo-controlled trial investigates the use of a novel anti-B lymphocyte stimulator antibody (Belimumab) following renal transplantation. The antibody is designed to reduce B-cell activation and was used in conjunction with standard immunosuppression. This study demonstrated no excess in adverse events or rejections but failed to meet the co-primary endpoint of a significant reduction in concentration of naive B-cells by week 24. The study is interesting, and Belimumab is certainly worthy of further investigation in a larger cohort. The sample size here was small (28 patients) and loss to follow-up and non-compliance with dosing mean that only 8 patients in each group received treatment and provided data as per protocol. It is therefore unclear whether the non-significant reduction in B-cell activity seen is real, and whether this could translate into clinical benefit.
Expert Review
Reviewer: Professor Yvon Y Lebranchu, Emeritus Professor, University of Tours, France.
Conflicts of Interest: No
Clinical Impact Rating 5
Review: To prevent or to treat antibody-mediated rejection, we need immunotherapeutic strategies that target B cells and plasma cells while preserving the immunoregulatory aspects of B-cell function. Activated B cells secrete the cytokine BLyS (Baff) to enhance B cell activation and proliferation. Belimumab,an anti-BLyS antibody previously used in systemic lupus erythematosus,was studied in a double blind, randomised, placebo-controlled phase 2 trial. Belimumab was used in addition to standard of care immunosuppression in 25 adult kidney transplants. Safety was the co-primary endpoint. No excess infection, death, graft loss and acute rejection were observed. The other co-primary endpoint, a reduction of 59 cells per mcL from baseline to Week 24,was not met. Adjusted mean difference was only -34.4 in the mITT population, but - 61.6 in the per protocol population. Despite the modest number of patients included, some very interesting informations on secondary endpoints were observed in the Belimumab group:1) an increased IL10 secretion and a decreased IL6 secretion by ex vivo stimulated B cells, 2) a decrease in activated memory B cells and plasmablasts, 3) a reduced de novo IgG formation, 4) a significant reduction in anti-endothelial cell (anti-EDIL3) and anti-kidney (anti-GDNF) specific antibodies, and 5) interestingly, a reduced expression of cell cycle genes in CD4+ purified T cells. These results suggest the potential efficacy of Belimumab in transplantation, in particular in sensitized patients. Further studies are needed.
Methodological quality
Jadad score 5
Allocation concealment YES
Study Details
Aims: To determine the safety and activity of belimumab, in addition to standard-of-care immunosuppression among adult kidney transplant recipients.
Interventions: Participants were randomised to receive either belimumab (10 mg/kg) or placebo (0·9% sodium chloride solution) in addition to standard-of-care immunosuppression (basiliximab, mycophenolate mofetil, tacrolimus, and prednisolone).
Participants: 28 patients aged 18–75 years with satisfactory liver function, scheduled to receive a kidney transplant.
Outcomes: Primary outcomes measured were changes in the concentration of naive B cells from baseline to week 24 & safety which included adverse events, incidence & severity of infections, vital signs and safety laboratory assessments. Secondary measured outcomes included non-parametric sensitivity analysis of the change in naive B-cell count, transitional B-cell, memory B-cell, activated memory B-cell, circulating plasmablast, activated & regulatory T-cell concentrations, serum creatinine concentrations, estimated glomerular filtration rate, HLA antibody levels, immunosuppressant use & acute rejection.
Follow Up: 6 months
Funding: Industry funding
Publication type: Randomized Controlled Trial, Randomised Controlled Trial
Trial registration: - NCT01536379
Organ: Kidney
Author email:
MeSH terms: Administration, Intravenous; Adult; Aged; Antibodies, Monoclonal, Humanized; Double-Blind Method; Female; Graft Survival; Humans; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; 0 (Antibodies, Monoclonal, Humanized); 0 (Immunoglobulin G); 0 (Immunosuppressive Agents); 73B0K5S26A (Belimumab)