Transplant International (May 2025)
Targeting CD38 in Antibody-Mediated Rejection
Abstract
Antibody-mediated rejection (AMR) remains a major challenge in clinical transplantation. Current therapies have yielded inconsistent outcomes, highlighting the need for innovative approaches. CD38, a multifunctional glycoprotein, is highly expressed on plasma cells and natural killer (NK) cells, potentially offering a dual mechanism of action that could intervene in the pathophysiologic course of AMR: depleting alloantibody-producing plasma cells and NK cells. This review focuses on recent results from CD38-targeted therapies, with felzartamab emerging as a promising option. Previous case reports and series suggested that off-label daratumumab treatment could effectively reverse AMR. Felzartamab has now demonstrated safety and efficacy in a phase 2 trial for late AMR. Reductions in microvascular inflammation, downregulation of rejection-associated transcripts, and decreases in donor-derived cell-free DNA paralleled a substantial decrease in NK cell counts. However, felzartamab did not significantly affect donor-specific antibodies, which may reflect its distinct mechanism of action, primarily involving antibody-dependent cellular cytotoxicity and phagocytosis. The effects on rejection activity may have a rapid onset, but are transient. The potential benefits of prolonged therapy are currently being investigated in a recently launched phase III trial. Future studies may expand the applications of CD38 targeting to early AMR or broader indications, such as DSA-negative microvascular inflammation.
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