TY - JOUR
T1 - Daratumumab in sensitized kidney transplantation
T2 - Potentials and limitations of experimental and clinical use
AU - Kwun, Jean
AU - Matignon, Marie
AU - Manook, Miriam
AU - Guendouz, Soulef
AU - Audard, Vincent
AU - Kheav, David
AU - Poullot, Elsa
AU - Gautreau, Chantal
AU - Ezekian, Brian
AU - Bodez, Diane
AU - Damy, Thibault
AU - Faivre, Laureline
AU - Menouch, Dehbia
AU - Yoon, Janghoon
AU - Park, Jaeberm
AU - Belhadj, Karim
AU - Chen, Dongfeng
AU - Bilewski, Alyssa M.
AU - Yi, John S.
AU - Collins, Bradley
AU - Stegall, Mark
AU - Farris, Alton B.
AU - Knechtle, Stuart
AU - Grimbert, Philippe
N1 - Publisher Copyright:
© 2019 by the American Society of Nephrology.
PY - 2019/7
Y1 - 2019/7
N2 - Background 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. Methods 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. Results The animals treated with daratumumab had significantly reduced donor-specific antibody levels compared with untreated controls (57.9% versus 13% reduction; P<0.05) and prolonged renal graft survival (28.0 days versus 5.2 days; P<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. Conclusions 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.
AB - Background 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. Methods 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. Results The animals treated with daratumumab had significantly reduced donor-specific antibody levels compared with untreated controls (57.9% versus 13% reduction; P<0.05) and prolonged renal graft survival (28.0 days versus 5.2 days; P<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. Conclusions 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.
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U2 - 10.1681/ASN.2018121254
DO - 10.1681/ASN.2018121254
M3 - Article
C2 - 31227636
AN - SCOPUS:85069237961
SN - 1046-6673
VL - 30
SP - 1206
EP - 1219
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 7
ER -