[Introduction] Sensitized patients comprise a significant portion (30%) of candidates on the transplant waiting list. Unfortunately for sensitized patients, the presence of donor-specific antibodies (DSA) leads to antibody-mediated rejection (AMR) and decreased graft survival. Thus, major research efforts are required to understand the mechanisms of DSA production and identify therapeutic targets that reduce DSA in these patients. To address this, we evaluated a desensitization protocol using Daratumumab (anti-CD38mAb) and Mozobil (CXCR4 antagonist) in a model of sensitization that has been previously established in rhesus macaques.

[Methods] Monkeys were first sensitized by two sequential skin grafts between maximally MHC mismatched donor-recipient pairs. Six weeks prior to kidney transplantation, weekly IV doses of Mozobil (0.24mg/kg) and Daratumumab (16mg/kg) for desensitization were given (n=4) and outcomes were compared to animals without desensitization (n=4).

[Result] Circulating plasma cells (CD20^–CD38⁺IgG⁺) initially declined (0.7% vs. 6.7%) but returned to baseline levels (10.7%) after desensitization treatment. In parallel analysis, we did not observe a reduction in the BM plasma cell population. However, the level of DSA significantly declined during desensitization compared to untreated controls (57.9 vs. 13% reduction). Interestingly, plasmablasts (CD20^–CD27⁺CD38⁺) in the LN significantly decreased (17.6 vs. 9.5%; p<0.05). while GC-Tfh (CD4⁺ICOS⁺PD-1^hi) cells were not affected. Desensitization with Daratumumab and Mozobil resulted in prolonged graft survival compared to controls (mean survival of 28.0 days vs. 5.2 days; p<0.01), however, all recipients showed rapid rebound of post-transplant de novo DSA with AMR (g+ptc+c4d) and profound T-cell mediated rejection (v+t+i).

[Conclusions] Targeting plasma cells and memory B cells with Daratumumab and Mozobil significantly reduced DSA and prolonged graft survival but did not modulate the Tfh cell population. Based on the depletion of PC cells in different immune compartments, the combination of daratumumab/mozobil may efficiently target plasmablasts but not long-lived plasma cells in the bone marrow. Collectively, CD38 is expressed on several immune cell subsets and eliminating CD38⁺ B cells may reduce B cells with regulatory properties and promote cell-mediated rejection.

CITATION INFORMATION: Kwun J., Brian E., Manook M., Park J., Freischlag K., Yoon J., Yi J., Stegall M., Knechtle S. Targeting Plasma Cells with Anti-CD38mAb (Daratumumab) and CXCR4 Antagonist (Plerixafor) for Desensitization Am J Transplant. 2017;17 (suppl 3).

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