CD38 Antibody Daratumumab for the Treatment of Chronic Active Antibody-mediated Kidney Allograft Rejection

Abstract

Background. Late antibody-mediated rejection (AMR) is a major cause of transplant failure. Potential therapeutic targets are plasma cells and natural killer (NK) cells, both expressing high levels of CD38. Methods. Here, we report the use of CD38 monoclonal antibody daratumumab (9-mo course) in a kidney allograft recipient diagnosed with smoldering myeloma and anti-HLA class II donor-specific antibody-positive chronic active AMR 13 years after transplantation. Patient monitoring included serial HLA single-antigen testing, peripheral blood immune cell phenotyping, as well as follow-up allograft and bone marrow biopsies at 3 and 9 months, including analyses of rejection-related gene expression patterns. Results. Daratumumab led to persistent CD138+ cell depletion in the bone marrow and blood and substantially decreased NK cells counts in blood and graft tissue. At the same time, donor-specific antibody in serum disappeared, and in vitro alloantibody production by CD138+ cells enriched from bone marrow aspirates was abrogated. A 3-month follow-up biopsy revealed a complete resolution of microcirculation inflammation (g+ptc: 3 to 0) and molecular AMR activity (AMR score: 0.79 to <0.2). The same biopsy showed (subclinical) tubulointerstitial inflammation, which prompted steroid treatment. Over an observation period of 12 months, graft function stabilized. Conclusions. Targeting CD38 for plasma cell and NK cell depletion may be an effective strategy to counteract AMR. Our results may encourage the design of future trials to clarify the role of this innovative treatment concept in organ transplantation.

HLA Desensitization in Solid Organ Transplantation: Anti-CD38 to Across the Immunological Barriers

“…In the last decade, several strategies to handle with autoimmune or alloimmune pathologic situations include CD38 antibodies (71)(72)(73).…”

“…A recurrent acute PC-rich rejection on kidney biopsy and significant ascension of DSA were successfully managed with daratumumab. Recently, two others cases were reported: one refractory ABMR after a heart transplant successfully treated with daratumumab and one chronic active ABMR in a kidney allograft recipient diagnosed with myeloma exposed to daratumumab (73,86). In the last one, the exhaustive immuno-monitoring showed that the main mode of action seems to be based on PC depletion, with profound PCs reduction in the bone marrow and peripheral blood and the abrogation of in vitro alloantibody production by PC enriched from bone marrow aspirates, leading to significant reduction in DSA levels (73).…”

“…Recently, two others cases were reported: one refractory ABMR after a heart transplant successfully treated with daratumumab and one chronic active ABMR in a kidney allograft recipient diagnosed with myeloma exposed to daratumumab (73,86). In the last one, the exhaustive immuno-monitoring showed that the main mode of action seems to be based on PC depletion, with profound PCs reduction in the bone marrow and peripheral blood and the abrogation of in vitro alloantibody production by PC enriched from bone marrow aspirates, leading to significant reduction in DSA levels (73). Another observation is that daratumumab led to depletion of NK cells infiltrating the allograft and circulating NK cells, which is major interest knowing the potential role of NK cells in microvasculature inflammation through engagement of their Fc gamma receptor IIIA with endothelium-bound DSA (87).…”

More questions than answers: Current limitations of kidney transplantation treatment

“…We hope that this antibody, possibly in combination with other therapeutic options, can improve treatment of ABMR in the near future. 13,14 All in all, the strategies to improve long-term outcomes of kidney transplantation are manifold and also go beyond clinical interventions. 15 Based on the tremendous improvements in kidney transplantation care over the last decades, it is fair to believe that we as transplant community will find ways to further enhance the survival of our kidney transplant patients in the future.…”

“…Daratumumab, an antibody directed against the B‐cell antigen CD38, was reported to have stopped ABMR in a patient receiving it for the treatment of multiple myeloma. We hope that this antibody, possibly in combination with other therapeutic options, can improve treatment of ABMR in the near future 13,14 …”