B-cell maturation antigen-Targeted T-cell Engager Therapy Combined with B-cell Depletion for Treatment of Refractory HLA Sensitization

INTRODUCTION: Preformed, high-titer anti-human leukocyte antigen (HLA) antibodies remain a major barrier to successful kidney transplantation, increasing the risk of early graft loss and prolonged time on dialysis. Despite advances in desensitization, current therapies are largely ineffective for patients with extremely high antibody levels. METHODS: Here, we report the case of a 37-year-old woman with kidney failure secondary to NPHS2-related nephrotic syndrome who received no suitable transplant offer despite 20 years of active listing, owing to extreme HLA sensitization (calculated Panel Reactive Antibody [cPRA] over 99.9%). She had previously been transplanted from age six to 17. Following the failure of a daratumumab-based desensitization regimen four years earlier, immunologic evaluation indicated the need for concurrent, potent depletion of memory B cells and plasma cells. This prompted a salvage regimen, administered under compassionate use, combining a type II humanized anti-CD20 antibody (obinutuzumab) with a B-cell maturation antigen (BCMA)-targeted T-cell engager (elranatamab). RESULTS: Both agents were well tolerated; only a transient, asymptomatic cytokine release syndrome occurred after the initial elranatamab dose. The combination produced a profound reduction in anti-HLA antibodies, decreasing the cPRA from 99.96% to 0% within six months. Protective immunity was maintained with immunoglobulin replacement. Apart from a self-limited episode of sapovirus-induced diarrhea, no infectious events occurred. Following successful desensitization, the patient underwent an uneventful kidney transplantation across low-level donor-specific antibodies (DSAs), which did not rebound post-transplant. The immunosuppressive regimen consisted of non-lymphodepletive induction with basiliximab, followed by a triple-drug maintenance therapy, including a prompt conversion from mycophenolic acid to everolimus. At ten months post-transplant, she remained free of rejections, with excellent graft function, low urinary chemokine levels, and persistently negative donor-specific antibodies. CONCLUSIONS: This dual-agent immunotherapeutic strategy achieved unprecedented depletion of high-titer, preformed anti-HLA antibodies and represents a promising approach for patients with prohibitive sensitization.