[Introduction] The presence of donor-specific antibodies (DSA) leads to antibody-mediated rejection (AMR) and decreased graft survival. Therefore efforts continue to be made to reduce DSA in these patients. Herein, desensitization through drug therapy using Daratumumab (anti-CD38mAb) and Mozobil (anti-CXCR4mAb) has been studied through a model of sensitization established in rhesus macaques.

[Methods] Monkeys were sensitized by two sequential skin grafts between mismatched donor-recipient pairs. Six weeks prior to kidney transplantation, weekly IV doses of Mozobil (0.24mg/kg) and Daratumumab (16mg/kg) for desensitization was given (n=4) and results compared to animals without desensitization (n=4). We evaluated the impact of the treatment on DSA, plasma cells (PC) and also on upstream components of the humoral response to provide mechanistic insight into Daratumumab and Mozobil treatment.

[Result] Despite early transient changes with therapy, lymphocytes, monocytes, or T and B cells did not change significantly in numbers or percentages. PCs (CD20^–CD38⁺IgG⁺) initially declined in the peripheral blood (0.7% vs. 6.7% of total non T/B cells) but returned to baseline levels (10.7%) after desensitization treatment. The level of DSA significantly declined during desensitization compared to untreated controls (57.9 vs. 13% reduction). Targeting PCs with daratumumab and mozobil induced more Ki67⁺IgD^– B cells, suggesting that the B cell/PC repertoire may change from a donor-specific to non-donor-specific population. Desensitization with Daratumumab and Mozobil resulted in prolonged graft survival compared to controls (28.0d vs. 5.2d; p<0.01).[Conclusions] Targeting PCs and memory B cells with Daratumumab and Mozobil significantly reduced DSA and prolonged graft survival. Based on the repopulation of PC and B cells, daratumumab/mozobil may promote PC and B cell repertoire changes. The treatment prevented AMR, with grafts eventually succumbing to cell-mediated rejection.

CITATION INFORMATION: Kwun J, Ezekian B, Manook M, Branum E, Curfman V, Park J, Freishlag K, Yoon J, Knechtle S. Effective Targeting Plasma Cells with Daratumumab (Anti-CD38) and Mozobil (Anti-CXCR4) in a Sensitized Non-Human Primate Model. Am J Transplant. 2017;17 (suppl 3).

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