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J Am Soc Nephrol. 2019 Jul;30(7):1206-1219. doi: 10.1681/ASN.2018121254. Epub 2019 Jun 21.

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

Author information

1
Duke Transplant Center, and.
2
Nephrology and Transplantation Department, Cancerology-Immunity-Transplantation-Infectiology, Clinical Investigation Center-Biotherapies, Henri Mondor Hospital, Assistance Publique-Hôpitaux de Paris, INSERM U955, Paris-Est-Créteil University, Paris, France.
3
Department of Cardiology, Assistance Publique-Hôpitaux de Paris, Henri Mondor Hospital, and INSERM Unité 955, Clinical Investigation Center 006, and DHU ATVB, Creteil, France.
4
Department of Immunology and Histocompatibility, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
5
Departments of Pathology.
6
Cardiology, and.
7
Department of Apheresis, Assistance Publique-Hôpitaux de Paris, CHU Henri Mondor, Créteil, France; and.
8
Haematology, Henri Mondor Hospital, Assistance Publique-Hôpitaux de Paris, Créteil, France.
9
Department of Pathology, Duke University Medical Center, Durham, North Carolina.
10
Division of Surgical Sciences, Department of Surgery, Duke University, Durham, North Carolina.
11
Department of Surgery, Mayo Clinic, Rochester, Minnesota.
12
Department of Pathology, Emory School of Medicine, Atlanta, Georgia.
13
Duke Transplant Center, and stuart.knechtle@dm.duke.edu philippe.grimbert@aphp.fr.
14
Nephrology and Transplantation Department, Cancerology-Immunity-Transplantation-Infectiology, Clinical Investigation Center-Biotherapies, Henri Mondor Hospital, Assistance Publique-Hôpitaux de Paris, INSERM U955, Paris-Est-Créteil University, Paris, France; stuart.knechtle@dm.duke.edu philippe.grimbert@aphp.fr.

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.

KEYWORDS:

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

PMID:
31227636
PMCID:
PMC6622431
[Available on 2020-07-01]
DOI:
10.1681/ASN.2018121254

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