A cute antibody-mediated rejection (ABMR) is a significant cause of graft loss in kidney transplant recipients (1–3). Despite its impact, effective treatments are lacking. Recently, targeting CD38 has garnered attention as a therapeutic option for ABMR (4). CD38 is a transmembrane glycoprotein and is expressed on immune cells (5–7) (such as natural killer [NK] cells, plasma cells, B cells, T cells, and macrophages) and nonimmune cells (such as red blood cells and endothelial cells) (8, 9). CD38 expression is upregulated by inflammatory stimuli (e.g., interferon γ [8–10] and nuclear factor κB [11]) and also has immunomodulatory functions through its dual roles as a receptor for CD31 (or platelet-endothelial cell adhesion molecule 1) and as an ectoenzyme regulating nicotinamide metabolism and calcium signaling (Figure) (12). Binding to CD38 can induce cell death through mechanisms including Fc-mediated cross-linking, complement-dependent cytotoxicity, antibody-dependent cell toxicity, and cellular phagocytosis.
Felzartamab targets CD38 to treat acute antibody-mediated rejection in kidney transplant recipients
Citation: Kidney News 16, 10/11
A recently published phase 2 randomized controlled trial by Mayer et al. reports promising results for felzartamab, a humanized monoclonal anti-CD38 antibody, in treating ABMR (13). This trial included adult kidney transplant recipients with biopsy-confirmed ABMR diagnosed at least 6 months after transplant, with a detectable donor-specific antibody (DSA) and an estimated glomerular filtration rate ≥20 mL/min/1.73 m2. A total of 22 patients were recruited and randomly assigned with a 1:1 ratio to receive felzartamab or placebo over a 20-week treatment period, with follow-up extending to 52 weeks. Randomization was stratified by site and categories of ABMR. The primary outcomes were safety and an adverse-effects profile. Secondary outcomes included resolution of ABMR, change in the immunodominant mean fluorescence intensity of DSA, and other biomarkers such as NK cell counts.
Overall, the study found a greater incidence of adverse effects in the treatment arm compared with placebo (119 vs 81 events), predominately driven by infections and infusion-related reactions. However, no deaths were reported. At 24 weeks, patients who received felzartamab showed greater histological resolution of ABMR compared with those receiving placebo. However, at the end of 52 weeks, three of nine patients assigned to the treatment arm experienced a recurrence of ABMR. Notably, there was no indication of increased T cell-mediated rejection, which could be a theoretical concern, as CD38 is also expressed on regulatory T cells. Additionally, there were no cases of allograft loss at 1 year postrandomization, and findings of all other biochemical markers and changes in the mean fluorescence intensity of DSA were relatively similar between the two groups.
Felzartamab appears to be a safe and promising agent for the treatment of ABMR. A large, well-powered and well-designed phase 3 study is underway. If proven effective, felzartamab may offer a novel approach to managing ABMR and improving long-term patient and graft outcomes.
Footnotes
References
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Deaglio S, et al. Human CD38 ligand. A 120-KDA protein predominantly expressed on endothelial cells. J Immunol 1996; 156:727–734. https://journals.aai.org/jimmunol/article-abstract/156/2/727/110915/Human-CD38-ligand-A-120-KDA-protein-predominantly
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Boslett J, et al. Characterization of CD38 in the major cell types of the heart: Endothelial cells highly express CD38 with activation by hypoxia-reoxygenation triggering NAD(P)H depletion. Am J Physiol Cell Physiol 2018; 314:C297–C309. doi: 10.1152/ajpcell.00139.2017
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Musso T, et al. CD38 expression and functional activities are up-regulated by IFN-gamma on human monocytes and monocytic cell lines. J Leukoc Biol 2001; 69:605–612. https://jlb.onlinelibrary.wiley.com/doi/full/10.1189/jlb.69.4.605
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Kang B-N, et al. Transcriptional regulation of CD38 expression by tumor necrosis factor-alpha in human airway smooth muscle cells: Role of NF-kappaB and sensitivity to glucocorticoids. FASEB J 2006; 20:1000–1002. doi: 10.1096/fj.05-4585fje
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Ramaschi G, et al. Expression of cyclic ADP-ribose-synthetizing CD38 molecule on human platelet membrane. Blood 1996; 87:2308–2313. https://ashpublications.org/blood/article/87/6/2308/124563/Expression-of-cyclic-ADP-ribose-synthetizing-CD38
- 13.↑
Mayer KA, et al. A randomized phase 2 trial of felzartamab in antibody-mediated rejection. N Engl J Med 2024; 391:122–132. doi: 10.1056/NEJMoa2400763
