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

Jean Kwun, Marie Matignon, Miriam Manook, Soulef Guendouz, Vincent Audard, David Kheav, Elsa Poullot, Chantal Gautreau, Brian Ezekian, Diane Bodez, Thibault Damy, Laureline Faivre, Dehbia Menouch, Janghoon Yoon, Jaeberm Park, Karim Belhadj, Dongfeng Chen, Alyssa M. Bilewski, John S. Yi, Bradley CollinsMark D Stegall, Alton B. Farris, Stuart Knechtle, Philippe Grimbert

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1206-1219
Number of pages14
JournalJournal of the American Society of Nephrology : JASN
Volume30
Issue number7
DOIs
StatePublished - Jul 1 2019

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Kidney Transplantation
Antibodies
Transplants
Tissue Donors
Plasma Cells
daratumumab
Kidney
Macaca
Graft Survival
Macaca mulatta
Primates
Antibody Formation
Allografts
Anti-Idiotypic Antibodies
Transplantation
T-Lymphocytes
Skin
Therapeutics

Keywords

  • antibody-mediated rejection
  • daratumumab
  • desensitization
  • nonhuman primate
  • plasma cell

ASJC Scopus subject areas

  • Nephrology

Cite this

Daratumumab in Sensitized Kidney Transplantation : Potentials and Limitations of Experimental and Clinical Use. / 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 D; Farris, Alton B.; Knechtle, Stuart; Grimbert, Philippe.

In: Journal of the American Society of Nephrology : JASN, Vol. 30, No. 7, 01.07.2019, p. 1206-1219.

Research output: Contribution to journalArticle

Kwun, J, Matignon, M, Manook, M, Guendouz, S, Audard, V, Kheav, D, Poullot, E, Gautreau, C, Ezekian, B, Bodez, D, Damy, T, Faivre, L, Menouch, D, Yoon, J, Park, J, Belhadj, K, Chen, D, Bilewski, AM, Yi, JS, Collins, B, Stegall, MD, Farris, AB, Knechtle, S & Grimbert, P 2019, 'Daratumumab in Sensitized Kidney Transplantation: Potentials and Limitations of Experimental and Clinical Use', Journal of the American Society of Nephrology : JASN, vol. 30, no. 7, pp. 1206-1219. https://doi.org/10.1681/ASN.2018121254
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 D ; Farris, Alton B. ; Knechtle, Stuart ; Grimbert, Philippe. / Daratumumab in Sensitized Kidney Transplantation : Potentials and Limitations of Experimental and Clinical Use. In: Journal of the American Society of Nephrology : JASN. 2019 ; Vol. 30, No. 7. pp. 1206-1219.
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abstract = "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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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 D

AU - Farris, Alton B.

AU - Knechtle, Stuart

AU - Grimbert, Philippe

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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.

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