*Purpose: “Delayed” antibody-mediated xenograft rejection is the one of the most important obstacles to clinical application of pig organ xenografts. The aim of this study was to assess the impact of a structured desensitization regimen including proteasome inhibition and next-generation costimulation blockade on xenoreactive antibodies.

*Methods: Rhesus macaques with moderate-high pre-treatment xenoreactive antibody titers (N=2) were selected. Recipients received biweekly carfilzomib 20mg/m2), anti-CD154 (20mg/kg) every other week, and CD4 T cell and B cell depletion. Bone marrow was acquired to assess plasma cell depletion in response to proteasome inhibition. A flow cytometry-based xenoreactive crossmatch assay was performed to assess levels of circulating xenoreactive antibodies.

*Results: The desensitization regimen resulted in a >50% depletion of CD38+CD27+ bone marrow plasma cells (Panel A); these changes were progressive over the duration of the desensitization treatment period. The desensitization strategy and plasma cell depletion resulted in a progressive reduction in anti-pig IgG antibodies (Panel B); in both cases, anti-pig antibody titers were reduced from a level consistent with a high-titer control NHP to a level approaching a low-titer NHP. There were no adverse effects or toxicities associated with the desensitization protocol, though low level CMV viremia but not CMV associated disease was noted.

*Conclusions: A structured desensitization regimen including proteasome inhibition and costimulation blockade results in plasma cell depletion and resultant reduction in circulating xenoreactive anti-pig IgG antibodies. This desensitization regimen has promise for pig-to-NHP xenotransplant models.

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