Daratumumab in Sensitized Kidney Transplantation: Potentials and Limitations of Experimental and Clinical Use

• Published in: Journal of the American Society of Nephrology Vol. 30; no. 7; pp. 1206 - 1219
• Main Authors: Kwun, Jean, Matignon, Marie, Manook, Miriam, Guendouz, Soulef, Audard, Vincent, Kheav, David, Poullot, Elsa, Gautreau, Chantal, Ezekian, Brian, Bodez, Diane, Damy, Thibault, Faivre, Laureline, Menouch, Dehbia, Yoon, Janghoon, Park, Jaeberm, Belhadj, Karim, Chen, Dongfeng, Bilewski, Alyssa M, Yi, John S, Collins, Bradley, Stegall, Mark, Farris, Alton B, Knechtle, Stuart, Grimbert, Philippe
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 01-07-2019
• Subjects: ADP-ribosyl Cyclase 1 - antagonists & inhibitors; ADP-ribosyl Cyclase 1 - physiology; Adult; Animals; Antibodies, Monoclonal - pharmacology; Antibody-Dependent Cell Cytotoxicity; Basic Research; Graft Rejection; Heterocyclic Compounds - pharmacology; HLA Antigens - immunology; Humans; Isoantibodies - blood; Kidney Transplantation; Macaca mulatta; Male; T-Lymphocytes, Regulatory - drug effects; nonhuman primate; daratumumab; plasma cell; desensitization; antibody-mediated rejection
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2018121254

Donor-specific antibodies are associated with increased risk of antibody-mediated rejection and decreased allograft survival. Therefore, reducing the risk of these antibodies remains a clinical need in transplantation. Plasma cells are a logical target of therapy given their critical role in antibody production.
To target plasma cells, we treated sensitized rhesus macaques with daratumumab (anti-CD38 mAb). Before transplant, we sensitized eight macaques with two sequential skin grafts from MHC-mismatched donors; four of them were also desensitized with daratumumab and plerixafor (anti-CXCR4). We also treated two patients with daratumumab in the context of transplant.
The animals treated with daratumumab had significantly reduced donor-specific antibody levels compared with untreated controls (57.9% versus 13% reduction;
<0.05) and prolonged renal graft survival (28.0 days versus 5.2 days;
<0.01). However, the reduction in donor-specific antibodies was not maintained because all recipients demonstrated rapid rebound of antibodies, with profound T cell-mediated rejection. In the two clinical patients, a combined heart and kidney transplant recipient with refractory antibody-mediated rejection and a highly sensitized heart transplant candidate, we also observed a significant decrease in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and to heart graft access.
Targeting CD38 with daratumumab significantly reduced anti-HLA antibodies and anti-HLA donor-specific antibodies in a nonhuman primate model and in two transplant clinical cases before and after transplant. This supports investigation of daratumumab as a potential therapeutic strategy; however, further research is needed regarding its use for both antibody-mediated rejection and desensitization.