Reversing donor-specific antibody responses and antibody-mediated rejection with bortezomib and belatacept in mice and kidney transplant recipients

Active antibody-mediated rejection (AMR) is a potentially devastating complication and consistently effective treatment remains elusive. We hypothesized that the reversal of acute AMR requires rapid elimination of antibody-secreting plasma cells (PC) with a proteasome inhibitor, bortezomib, followed by the sustained inhibition of PC generation with CTLA4-Ig or belatacept (B/B). We show in mice that B/B therapy selectively depleted mature PC producing donor-specific antibodies (DSA) and reduced DSA, when administered after primary and secondary DSA responses had been established. A pilot investigation was initiated to treat six consecutive patients with active AMR with B/B. Compassionate use of this regimen was initiated for the first patient who developed early, severe acute AMR that did not respond to steroids, plasmapheresis, and intravenous immunoglobulin after his third kidney transplant. B/B treatment resulted in a rapid reversal of AMR, leading us to treat five additional patients who also resolved their acute AMR episode and had sustained disappearance of circulating DSA for <= 30 months. This study provides a proof-of-principle demonstration that mouse models can identify mechanistically rational therapies for the clinic. Follow-up investigations with a more stringent clinical design are warranted to test whether B/B improves on the standard of care for the treatment of acute AMR.