Antibody mediated rejection (AMR) is a major cause of rejection, and there are limited therapeutic options for reversing alloantibody production when it is fully established. We previously reported that CTLA4-Ig successfully disrupted fully-established B cell germinal centers and reduced DSA titers when treatment was initiated by ≤ 7 days post-immunization, but was less efficacious when initiated at ≥ 14 days when the plasma cells had already been generated. Bortezomib (Btz), a proteasome inhibitor, depletes plasma cells and its extended use results in desensitization but also significant toxicity. We reasoned that combining a transient Btz treatment with CTLA4-Ig would deplete existing donor-specific plasma cells and block the formation of new ones, thus would be effective treatment for AMR. Indeed, BTz treatment on D14 & 17 post-sensitization (with allogeneic splenocytes) reduced DSA titers by 34% within 7 days, but these mice rapidly produced high titers of DSA upon secondary challenge. CTLA4-Ig (from D14 given 2X/week) gradually reduced DSA titers by 14 & 40 % after 7 & 14 days treatment, and prevented alloantibody production upon secondary challenge. Combination therapy from D14 post-immunization was most effective, reduced DSA titers by 47 & 70 % after 7 & 14 days treatment, and also prevented DSA responses upon resensitization. This treatment combination was tested in 4 kidney transplant patients who developed high-titer DSA and biopsy-proven acute AMR by POD≤30 that was resistant to standard of care therapy. Belatacept plus Btz (2-4 treatments) rapidly reduced DSA (≤4 weeks) and restored kidney function in 3 patients, with a follow-up of ≥1 year. These observations provide initial proof-of-principle that Belatacept plus Btz reverses de novo B cell responses and rapidly reduce circulating DSA in mice and humans, and successfully ameliorate acute AMR in renal transplant patients.

CITATION INFORMATION: Young J, Vannier A, Bumgardner G, Chong A, Pelletier R. Rapid Depletion of Circulating DSA and Treatment of Acute Antibody-Mediated Rejection with the Combination of CTLA-4Ig/Belatacept and Bortezomib in Mouse and Man. Am J Transplant. 2017;17 (suppl 3).

« Back to 2017 American Transplant Congress