Anti-CD38 Monoclonals for Treatment of Antibody-mediated Rejection in Renal Allografts

INTRODUCTION Antibody-mediated rejection (AMR) and chronic AMR (cAMR) of kidney allografts are now recognized as the primary causes for kidney allograft failure worldwide.1 Although the primacy of donor-specific antibodies (DSAs) is recognized as a critical component of injury, little is known regarding the mechanism(s) related to this process and its progression. A major barrier to understanding the optimal treatment(s) of AMR is the significant heterogeneity of the disease. AMR presents with significant variation in clinical, serological, pathologic, and molecular features, including patients with active and inactive characteristics associated with acuity and chronicity. This, in part, relates to medication nonadherence. Currently, there are no effective therapies for AMR.1,2 Although AMR and cAMR are strongly linked to poor transplant outcomes, only 1 agent (clazakizumab [anti-IL-6]) evolved to a phase III labeling trial (IMAGINE). However, this trial was discontinued for lack of efficacy.3 Despite these difficulties and disappointments, there is a reason for hope as a recent phase I/II trial has shown.4 The 2019 consensus article from the Transplantation Society Working Group addressed current and future therapies for managing AMR and cAMR.1 The Working Group’s concluded that future treatments should be effective in preserving kidney function, reducing histological injury and reducing DSA levels. The working group unanimously endorsed the urgent need for properly conducted and powered clinical trials of biologic agents aimed at improving patient outcomes. At that time, the focus was on the development of novel therapeutics to reduce or eliminate HLA antibodies and alloreactive B cells/plasma cells. Importantly, an enhanced understanding of B cell and plasma cell biology, and of the pathogenic mechanisms underlying alloantibody-mediated allograft injury, will be critical for the development of new therapeutic approaches to reducing DSAs and their impact on allograft endothelium, limiting or reversing histological features of AMR and cAMR, and improving patient and graft survival.2 Although, logical, there certainly may be other agents that could inhibit or limit the effector functions of pathogenic DSAs (ie, complement-dependent cytotoxicity and/or antibody-dependent cellular cytotoxicity [ADCC] that could have therapeutic benefits. RATIONAL FOR ANTI-CD38 TREATMENT OF AMR CD38 is a transmembrane protein that is highly expressed on myeloma cells, plasma cells, and plasmablasts. However, it is also expressed on multiple other cell types, including B cells, NK cells, monocytes and regulatory T cells.2 Monoclonal antibodies that target CD38 were originally developed for treatment of multiple myeloma by depleting plasma cells. Given the nexus of DSA-producing plasma cells in most forms of AMR, and the lack of anti-CD20 to reduce them, it seemed logical that targeting CD38+ cells would likely interfere with pathways involved in allograft rejection, including reductions in DSAs, ADCC, and complement-dependent cytotoxicity, as well as inducing apoptosis of CD38+ cells directly. In this regard, there could be concerns of induction of cell-mediated rejection (CMR) in patients treated for AMR. There are previous reports of anti-CD38 monoclonals inducing CMR in kidney transplant recipients which was likely because of Treg depletion allowing T-effector cells to emerge.5 In future studies, it will be important to perform an extensive analysis of Treg cell populations as well as NK cells, monocytes and B-cell subsets as part of an in-depth assessment of cell types depleted by anti-CD38 and how this relates to outcomes, including risk for CMR. Importantly, a recent abstract presented at the American Transplant Congress 2024 examined the risk of rejection postkidney transplant in 16 patients treated with daratumumab (anti-CD38).6 The investigators did not observe a clear association of daratumumab use with allograft rejection. Why do anti-CD38 monoclonals which are excellent treatments for multiple myeloma fail to reduce or eliminate anti-HLA antibodies? Vincenti et al7 and our group8 have shown that patients treated with anti-CD38 monoclonals can be divided into responders and nonresponders. However, this may indicate that other DSA IgG secreting cells that are CD38− could be producing pathogenic DSAs (ie, memory B cells). This will be an important question to answer as we move forward with anti-CD38 therapy in desensitization and treatment of AMR. FELZARTAMAB FOR AMR TREATMENT Recently, Mayer et al4 presented data from a phase II trial of the anti-CD38 monoclonal felzartamab for treatment of patients with AMR/cAMR. The trial was a double-blind, randomized, placebo-controlled trial, which examined the safety and limited efficacy end points of felzartamab in 22 adult patients with AMR. Patients participating in the trial had a biopsy-proven diagnosis of AMR and were at least 180 days post-transplantation. Entry estimated glomerular filtration rates (eGFRs) of ≥20 mL/min/1.73 m2 was required. All had HLA DSAs and the majority had chronic AMR at presentation. Patients received 9 infusions of felzartamab (16 mg/kg) or placebo for 6 mo, followed by a 6-mo observation period. Eleven patients were included in each group. Important secondary outcomes included renal biopsy results at 6 and 12 mo, DSA levels, peripheral NK-cell counts, and donor-derived cell-free DNA levels (dd-cf-DNA). Serious adverse events occurred in 1 patient in the felzartamab group and 4 patients in the placebo group. The treatments were well tolerated without significant infectious complications. Importantly, after 6 mo treatment, with no meaningful DSA reductions, resolution of morphologic and molecular features of AMR was seen more frequently in the felzartamab-treated patients 9 of 11 (82%), whereas placebo showed resolution in only 2 of 10 (20%) patients. Another important observation was the value of the noninvasive biomarker dd-cf-DNA in predicting responses to AMR treatment with felzartamab. The level of dd-cf-DNA was significantly lower in patients treated with felzartamab (0.31% versus 0.82%). At 12 mo (6 mo after no therapy), AMR recurrence was seen in 3 of 9 patients, but most patients showed increased molecular scores of AMR on repeat biopsy. Despite this, the 1-y eGFR slope was −0.39 mlLmin/1.73 m2 in the felzartamab group and −4.53 mL/min/1.73 m2 in the placebo group. Thus, felzartzmab treatment resulted in reduction of histologic and molecular features of AMR, dd-cf-DNA and stabilization of eGFR compared with placebo without DSA reductions. No cases of CMR were seen. How can we explain this? IMPORTANCE OF NATURAL KILLER CELLS IN MEDIATION OF AMR One of the most important and unique features of this article was the assessment of circulating CD16bright natural killer (NK) cells in the peripheral blood of patients treated with felzartamab versus placebo. Here, significant reductions of CD16bright NK cells occurred after felzartamab treatment and were sustained at 12 M. Thus, measurement of peripheral blood CD16bright NK cells was an important indicator of treatment efficacy, even more so than monitoring DSAs. Because DSAs were not reduced, we must assume that the incidental depletion of CD38+ CD16bright NK cells and possibly other ADCC inducing cells was the primary pathway for reduction of inflammation and improved eGFR in treated patients. Why are CD16bright NK cells important in the pathogenesis of ARM? Human NK cells are cytotoxic effector cells that constitute a critical component of innate immunity and are primarily responsible for cancer surveillance and elimination of virally infected cells.2 NK cells have been increasingly implicated as effector cells in AMR. In a recent article by Maarten Naesen’s group,9 investigators used transcriptional and spatial profiling of kidney allografts with AMR to confirm a role of FcγRIII+ NK and FcγRIII+ nonclassical monocytes (also CD38+) in AMR, with specificity to the glomerular area. The authors concluded that these results highlight a critical role of innate cellular immunity in the pathogenesis of AMR and identify potential therapeutic targets for prevention and treatment of AMR that are likely to improve allograft outcomes. This study would seem to support the thesis that FcγRIII+ NK and nonclassical monocytes are primary mediators of injury in AMR. However, we must carefully conclude that this is the only pathway for injury in AMR as complement-dependent pathways are also important and these would respond to antibody reduction therapies as well as complement inhibitors.2 CONCLUSIONS The authors are to be congratulated for conducting an excellent study that has revealed so much information regarding the role of anti-CD38 (felzartamab) in treatment of AMR. They confirmed that the unexpected benefits of anti-CD38 aimed primarily at removing DSA-producing plasma cells and plasmablast, likely worked by depleting CD16bright NK cells. This study reveals the importance of flezartamab as a potential new therapy for treatment of AMR and the importance of monitoring other noninvasive biomarkers such as dd-cf-DNA and immune cell monitoring to gauge therapeutic efficacy. DSAs have always been very difficult to decrease or eliminate and DSA rebound often occurs after AMR treatment. A recent publication reported on the comparison of imlifidase + IVIg + rituximab versus plasma exchange (PLEX) + IVIg + rituximab for reduction of DSAs in patients with AMR/cAMR.10 DSA reductions were 97% for imlifidase compared with 42% for PLEX. In addition, imlifidase inhibited complement fixing DSAs, whereas PLEX failed to do so. Despite this, both groups showed rebound DSA development and no meaningful benefits to AMR outcomes. However, we may be able to get around this problem by modifying the effector responses of FcgIII+ cells binding these antibodies. Clearly, robust verification of these initial findings in phase III trials is required to move flezartamab forward for AMR treatment. However, it is off to a very good start.