Daratumumab in Sensitized Kidney Transplantation: Potentials and Limitations of Experimental and Clinical Use
Donor-specific antibodies are associated with increased risk of antibody-mediated rejection and decreased allograft survival. Therefore, reducing the risk of these antibodies remains a clinical need in transplantation. Plasma cells are a logical target of therapy given their critical role in antibody production.METHODS:
To target plasma cells, we treated sensitized rhesus macaques with daratumumab (anti-CD38 mAb). Before transplant, we sensitized eight macaques with two sequential skin grafts from MHC-mismatched donors; four of them were also desensitized with daratumumab and plerixafor (anti-CXCR4). We also treated two patients with daratumumab in the context of transplant.RESULTS:
The animals treated with daratumumab had significantly reduced donor-specific antibody levels compared with untreated controls (57.9% versus 13% reduction; P<0.05) and prolonged renal graft survival (28.0 days versus 5.2 days; P<0.01). However, the reduction in donor-specific antibodies was not maintained because all recipients demonstrated rapid rebound of antibodies, with profound T cell-mediated rejection. In the two clinical patients, a combined heart and kidney transplant recipient with refractory antibody-mediated rejection and a highly sensitized heart transplant candidate, we also observed a significant decrease in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and to heart graft access.CONCLUSIONS:
Targeting CD38 with daratumumab significantly reduced anti-HLA antibodies and anti-HLA donor-specific antibodies in a nonhuman primate model and in two transplant clinical cases before and after transplant. This supports investigation of daratumumab as a potential therapeutic strategy; however, further research is needed regarding its use for both antibody-mediated rejection and desensitization.
|LEVEL OF EVIDENCE:||Case Report|
|KEYWORDS:||antibody-mediated rejection; daratumumab; desensitization; nonhuman primate; plasma cell|
|MESH HEADINGS:||ADP-ribosyl Cyclase 1; Adult; Animals; Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; Benzylamines; Cyclams; Graft Rejection; HLA Antigens; Heterocyclic Compounds; Humans; Isoantibodies; Kidney Transplantation; Macaca mulatta; Male; T-Lymphocytes, Regulatory|