Kwun J, et al. - Given the association of donor-specific antibodies with increased risk of antibody-mediated rejection and decreased allograft survival, researchers explored therapy targeting plasma cells to reduce the risk in transplantation. They sensitized eight rhesus macaques with two sequential mismatched skin allografts and then desensitized four of them with daratumumab (anti-CD38 mAb) and plerixafor (anti-CXCR4) before transplant. The daratumumab-treated animals vs controls showed significantly decreased donor-specific antibody levels and extended renal graft survival; however, this reduction was not maintained. Two patients (one with therapy-resistant acute kidney antibody-mediated rejection and a highly sensitized heart transplant candidate) were also treated with daratumumab in the context of transplant. These patients displayed a significant reduction in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and heart graft access. These findings justify further investigation of daratumumab as a potential therapeutic strategy.