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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ADP-ribosyl Cyclase 1 / antagonists & inhibitors
  • ADP-ribosyl Cyclase 1 / physiology
  • Adult
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibody-Dependent Cell Cytotoxicity
  • Graft Rejection
  • HLA Antigens / immunology
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Isoantibodies / blood
  • Kidney Transplantation*
  • Macaca mulatta
  • Male
  • T-Lymphocytes, Regulatory / drug effects

Substances

  • Antibodies, Monoclonal
  • HLA Antigens
  • Heterocyclic Compounds
  • Isoantibodies
  • daratumumab
  • ADP-ribosyl Cyclase 1
  • plerixafor octahydrochloride