Targeting CD38 Across Autoimmune and Plasma Cell–Driven Immune-Mediated Diseases: Rationale, Clinical Evidence, and Emerging Therapeutic Landscape

Abstract

Autoimmune diseases remain a major cause of chronic morbidity despite substantial advances in targeted immunomodulatory therapies. In many autoantibody-mediated conditions, disease refractoriness and relapse are driven by long-lived plasma cells, which are largely resistant to conventional immunosuppression and upstream B cell–directed strategies. CD38, a surface molecule highly expressed on plasmablasts and plasma cells and functionally involved in immunometabolic regulation, has emerged as a promising therapeutic target to overcome this limitation. Clinical interest in anti-CD38 therapy has been catalyzed by experience in plasma cell dyscrasias, where anti-CD38 monoclonal antibodies induce rapid and profound depletion of antibody-secreting cells. Over recent years, accumulating reports and early-phase studies have explored the repurposing of CD38-directed therapies in severe, treatment-refractory autoimmune diseases. The most compelling evidence has emerged in lupus nephritis and immune thrombocytopenia, with additional proof-of-concept data in autoimmune cytopenias and plasma cell–driven renal disorders such as immunoglobulin light chain (AL) amyloidosis. These experiences suggest that targeting CD38 can lead to meaningful clinical and immunological improvement, often accompanied by rapid reductions in pathogenic autoantibody production. However, the current evidence base remains heterogeneous and largely derived from small cohorts, case series, and early-phase trials, and important questions remain regarding durability of response, optimal treatment strategies, and long-term safety, particularly with respect to hypogammaglobulinemia and infection risk. We summarize the biological rationale for CD38 targeting in autoimmunity and plasma cell–driven immune-mediated diseases, critically appraise the emerging clinical evidence across disease settings, and discuss key challenges and future directions for integrating plasma cell–directed therapies into immunological disease management.

Key Points

This article reviews the biological rationale and emerging clinical evidence supporting CD38-targeted therapies as a strategy to eliminate autoreactive plasmablasts and plasma cells that sustain pathogenic autoantibody production in autoimmune and plasma cell-driven immune-mediated diseases.

Early clinical experiences with anti-CD38 monoclonal antibodies, particularly daratumumab, demonstrate promising efficacy in highly refractory conditions, including lupus nephritis, autoimmune cytopenias, to include immune thrombocytopenia, and plasma cell-driven renal disorders, including AL amyloidosis.

However, current evidence remains largely derived from small cohorts and early-phase studies, highlighting the need for prospective trials to clarify optimal patient selection, treatment strategies, and long-term safety.

Introduction

Autoimmune diseases remain a major cause of chronic morbidity and organ damage worldwide, despite substantial therapeutic advances over the past two decades. While targeted immunomodulatory strategies, most notably B cell depletion, cytokine blockade, and costimulatory pathway inhibition, have transformed outcomes for many patients, a significant proportion continue to experience refractory or relapsing disease [1–5]. This is particularly evident in autoantibody-mediated conditions, where persistent pathogenic humoral immunity drives ongoing inflammation, tissue injury, and irreversible damage despite aggressive immunosuppression [6]. The limited durability of current approaches has highlighted the need to better address immune compartments that are insufficiently targeted by conventional therapies.

B cells play a central role in autoimmune pathogenesis not only through antigen presentation and cytokine production, but critically through differentiation into antibody-secreting cells [7]. While short-lived plasmablasts may respond to standard immunosuppressive strategies, long-lived plasma cells represent a major therapeutic blind spot [7]. These cells reside in protected survival niches within bone marrow and inflamed tissues, persist independently of antigenic stimulation, and are largely resistant to glucocorticoids, alkylating agents, and anti-CD20 therapies [8]. As a consequence, autoantibody production may continue unabated even after profound peripheral B cell depletion, explaining both incomplete responses and disease relapses observed in clinical practice [8].

CD38 has emerged as a particularly attractive target to overcome this limitation. CD38 is a transmembrane glycoprotein highly expressed on plasmablasts and plasma cells, including long-lived autoreactive populations, while also being present on multiple immune cell subsets such as activated T cells, natural killer cells, dendritic cells, and myeloid cells. Beyond serving as a surface marker, CD38 functions as an ectoenzyme regulating nicotinamide adenine dinucleotide (NAD⁺) metabolism and downstream immunometabolic pathways, thereby exerting broader effects on immune activation and inflammatory signaling [9, 10]. CD38 should not be regarded solely as a plasma cell surface marker or as a simple enzymatic target. It is a multifunctional membrane-associated molecule that integrates ectoenzymatic activity, receptor-mediated signaling, adhesion-related functions, and immune-cell crosstalk [11]. Through its enzymatic activity, CD38 regulates NAD⁺ metabolism and contributes to the generation of calcium-mobilizing metabolites and extracellular adenosine, thereby influencing immunometabolic and inflammatory pathways. In parallel, CD38 ligation may induce receptor-mediated signaling events that are not fully reducible to enzymatic inhibition. These effects are likely to be highly context dependent, varying according to cell type, tissue compartment, inflammatory milieu, and the antibody or molecule used for targeting [12]. Therefore, the clinical effects of anti-CD38 monoclonal antibodies in autoimmune and immune-mediated diseases may reflect a combination of plasma cell depletion, Fc-mediated cytotoxicity, modulation of enzymatic activity, receptor-mediated signaling, and broader reshaping of immune-cell networks [13, 14].

These biological features position CD38 at the intersection of humoral autoimmunity and immune regulation, offering a mechanistically distinct strategy compared with upstream B cell–directed therapies.

Clinical interest in CD38 targeting within autoimmunity and plasma cell–driven immune-mediated diseases has largely arisen from experience in hematological malignancies, where anti-CD38 monoclonal antibodies, most prominently daratumumab, have demonstrated potent plasma cell depletion through antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and phagocytosis [9, 14–18]. Notably, incidental observations in patients treated for multiple myeloma revealed reductions in autoantibody titers, including rheumatoid factor and antineutrophil cytoplasmic antibodies, suggesting a direct effect on autoreactive plasma cells [14]. These findings provided the rationale for repurposing CD38-directed therapies in severe autoimmune disease [11]. Over the past few years, accumulating case reports and small case series have documented the use of anti-CD38 therapy in a wide spectrum of therapy-refractory autoimmune diseases, spanning rheumatology, nephrology, neurology, and hematology [15–18]. A recent systematic review identified more than 80 reported patients across 24 autoimmune conditions, most of whom had failed multiple prior immunosuppressive regimens, including B cell depletion [9]. Despite this extreme refractoriness, clinical improvement or remission was observed in the majority of cases, frequently accompanied by autoantibody reduction or depletion, thereby providing compelling proof of concept for CD38-targeted strategies in autoimmunity. At the same time, important uncertainties remain. Optimal patient selection, timing within therapeutic algorithms, dosing strategies adapted from oncological practice, and long-term safety, particularly with respect to hypogammaglobulinemia and infection risk, are not yet well defined. Moreover, CD38 targeting may exert pleiotropic immunomodulatory effects beyond plasma cell depletion, raising both opportunities and challenges for clinical translation. A comprehensive synthesis of the biological rationale and emerging clinical evidence is therefore needed to contextualize anti-CD38 therapies within the evolving therapeutic landscape of autoimmune disease [15].

In this point of view, we summarize the biological rationale for targeting CD38 in autoimmune diseases and plasma cell–driven immune-mediated diseases, and critically appraise the current clinical evidence, encompassing approved and investigational CD38-directed agents. We discuss disease-specific experiences, safety considerations, and future directions, with the aim of defining the potential role of CD38 targeting as a next-generation strategy for refractory immunological disease.

Targeting CD38 in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a prototypical autoantibody-mediated autoimmune disease in which dysregulated B cell differentiation and sustained autoantibody production drive immune-complex formation, interferon activation, and multi-organ damage [19, 20]. While contemporary therapeutic strategies, including B cell depletion, BAFF inhibition, and type I interferon blockade, have improved disease control in many patients, a substantial proportion develop refractory disease, particularly in the presence of persistent autoantibody production and severe organ involvement such as lupus nephritis, hematological cytopenias, or serositis [15, 20]. Increasing evidence indicates that this therapeutic resistance is largely attributable to long-lived plasma cells, which are unresponsive to standard immunosuppressive and B cell-directed therapies and continue to secrete pathogenic autoantibodies despite apparent immunological remission [21–31].

Biological Rationale for CD38 Targeting in Lupus

CD38 is highly expressed on plasmablasts and long-lived plasma cells, positioning it as a rational therapeutic target to directly eliminate the cellular source of pathogenic autoantibodies in SLE [25, 28]. In addition to its role as a surface marker, CD38 functions as an ectoenzyme regulating NAD⁺ metabolism and downstream immunometabolic pathways, which are increasingly recognized as contributors to chronic immune activation in lupus [29]. Beyond plasma cells, elevated CD38 expression has been described on plasmacytoid dendritic cells and activated T cell subsets in SLE, implicating CD38 in the amplification of type I interferon signaling and chronic inflammatory T cell responses [21–23].

Importantly, immune-profiling studies have demonstrated expansion of CD38^high immune populations in patients with active lupus, including CD38-expressing memory T cells enriched in inflamed tissues and urine in lupus nephritis. These observations suggest that CD38 targeting may exert pleiotropic immunomodulatory effects, extending beyond plasma cell depletion to broader dampening of interferon-driven and T cell-mediated inflammation [9, 19, 30].

Daratumumab in Refractory SLE

The most compelling clinical evidence supporting CD38 targeting in lupus derives from the landmark off-label use of daratumumab, a human anti-CD38 monoclonal antibody approved for multiple myeloma. In a pivotal proof-of-concept report, daratumumab was administered to two patients with life-threatening, treatment-refractory SLE, both of whom had failed multiple conventional and biologic therapies, including cyclophosphamide, mycophenolate, rituximab, and proteasome inhibition [21]. In the first patient, who presented with proliferative and membranous lupus nephritis, pericarditis, arthritis, and cutaneous disease, daratumumab induced a marked and sustained clinical response. Proteinuria declined substantially, renal function normalized, extrarenal manifestations resolved, and disease activity, as measured by the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), decreased rapidly and remained low over follow-up, despite significant glucocorticoid tapering. In parallel, serological activity improved, with a pronounced reduction in anti–double-stranded DNA antibody levels and normalization of complement consumption. The second patient, characterized by severe hematological involvement including autoimmune hemolytic anemia and immune thrombocytopenia (ITP), similarly experienced rapid hematological recovery, normalization of the direct antiglobulin test, and resolution of systemic manifestations following daratumumab therapy. These clinical responses were accompanied by a consistent reduction in autoantibody titers and stabilization of immunoglobulin levels, with manageable hypogammaglobulinemia.

Robust clinical evidence supporting CD38 targeting in lupus to date derives from a dedicated case series of patients with biopsy-proven, treatment-refractory lupus nephritis treated with daratumumab monotherapy [22]. In this study, six patients with long-standing SLE and severe renal involvement, unresponsive to standard-of-care induction regimens and multiple rescue therapies, including mycophenolate mofetil, cyclophosphamide, rituximab, belimumab, and calcineurin inhibitors, received intravenous daratumumab following an onco-hematology-derived schedule (eight weekly infusions of 16 mg/kg followed by eight infusions—each administered every two week—and then eight infusions given monthly) adapted to the autoimmune setting. Five of six patients achieved a sustained clinical response over a 12-month follow-up period. Daratumumab treatment was associated with a rapid and marked reduction in proteinuria, with mean values decreasing from the nephrotic range at baseline to sub-nephrotic or near-complete remission levels by 3–6 months, and remaining stable at 12 months. Renal function improved or stabilized in the majority of patients, despite advanced disease at baseline, and global disease activity, as assessed by the SLEDAI-2K, declined substantially over time. These clinical improvements were achieved alongside significant glucocorticoid tapering, with all responders maintained on low-dose prednisone at 1 year. Importantly, the renal responses were paralleled by consistent immunological changes supporting a mechanistic effect of CD38 targeting beyond plasma cell depletion alone. Treatment induced seroconversion or marked reductions in anti–double-stranded DNA antibodies, normalization of complement levels, and profound decreases in circulating biomarkers linked to disease activity and tissue inflammation, including soluble B cell maturation antigen (sBCMA), interferon-γ, and soluble CD163. Conversely, interleukin-10 (IL-10) levels increased, suggesting a shift toward an immunoregulatory milieu. Correlation analyses demonstrated strong associations between sBCMA, interferon (IFN)-related markers, and SLE disease activity, reinforcing the central role of plasma cell–driven immune dysregulation in refractory lupus nephritis. From a safety perspective, daratumumab was generally well tolerated in this highly vulnerable population. Infusion-related reactions were mild and transient, no severe infectious complications were observed, while severe acute respiratory syndrome coronavirus 2 infections occurring during treatment resolved without consequences. Although hypogammaglobulinemia was observed, it was manageable with close monitoring. Collectively, this experience represents a critical step forward in the clinical translation of CD38 targeting in lupus [28]. Unlike earlier reports combining daratumumab with ongoing immunosuppression or maintenance BAFF inhibition, this series demonstrates that selective plasma cell depletion alone can induce meaningful renal and systemic responses in refractory lupus nephritis [21]. These findings strongly support the concept that long-lived plasma cells are key drivers of treatment resistance in lupus nephritis and identify anti-CD38 therapies as a rational rescue strategy when upstream B cell–directed approaches fail [22].

Notably, clinical responses to daratumumab in lupus appeared most pronounced during the initial weeks following plasma cell depletion, raising the question of durability. In the first reported cases [21], small doses of daratumumab (four weekly infusions of 16 mg/kg) were followed by maintenance therapy with belimumab were introduced to suppress regeneration of autoreactive B cell precursors, a strategy conceptually analogous to combination or sequential approaches used in hematological malignancies. This observation underscores the potential for combination or maintenance regimens to sustain remission after CD38-mediated plasma cell depletion in SLE. However, more data are needed to support this rationale [20].

Targeting CD38 in Immunoglobulin Light Chain Amyloidosis

Immunoglobulin light chain (AL) amyloidosis is a plasma cell dyscrasia characterized by the production of monoclonal immunoglobulin light chains that misfold and deposit as insoluble amyloid fibrils in target organs, most frequently the heart and kidneys. AL amyloidosis is associated with substantial morbidity and mortality, largely determined by the extent and rapidity of organ involvement. Renal disease occurs in approximately 70% of patients and is a major determinant of quality of life, risk of progression to end-stage kidney disease, and eligibility for aggressive therapies.

Biological Rationale for CD38 Targeting in AL Amyloidosis

The pathogenic hallmark of AL amyloidosis is continuous production of amyloidogenic light chains by clonally restricted plasma cells [32]. These cells uniformly express high levels of CD38, making this molecule an attractive therapeutic target. Importantly, the therapeutic goal in AL amyloidosis is not merely tumor cytoreduction, but rapid and profound suppression of light-chain production, as even modest delays in hematological response may translate into irreversible organ damage due to ongoing amyloid deposition [33, 34]. Conventional regimens, largely adapted from multiple myeloma, achieve complete hematological responses in only about half of patients, particularly underperforming in those with advanced renal or cardiac involvement [34]. CD38 targeting offers a mechanistically distinct strategy by directly eliminating the plasma cell compartment responsible for light-chain secretion. In addition, CD38 functions as an ectoenzyme regulating NAD⁺ metabolism and extracellular adenosine production, contributing to an immunosuppressive microenvironment that may favor plasma cell survival. Anti-CD38 monoclonal antibodies therefore combine direct plasma cell cytotoxicity with immunomodulatory effects, including depletion of CD38-expressing regulatory immune subsets, potentially enhancing therapeutic efficacy in this fragile patient population [34, 35].

Clinical Evidence: Daratumumab in AL Amyloidosis

Early-phase studies and retrospective cohorts consistently demonstrated rapid and deep hematological responses to daratumumab [34, 35], with response rates exceeding 80% in heavily pretreated patients. However, interpretation of organ responses, particularly renal, has been limited in many series by heterogeneous definitions of organ involvement and the frequent absence of biopsy confirmation [13, 34]. A critical contribution to this field comes from real-world experiences focusing on biopsy-proven renal AL amyloidosis. In a single-center cohort of patients with severe AL amyloidosis and histologically confirmed renal involvement, daratumumab monotherapy induced rapid disappearance of circulating monoclonal proteins, normalization or marked improvement of free light-chain ratios, and stabilization or improvement of renal function in patients treated before advanced irreversible damage [36]. Notably, significant reductions in proteinuria and cardiac biomarkers (N-terminal prohormone of brain natriuretic peptide [NT-proBNP]) were observed, underscoring the systemic impact of effective plasma cell depletion. Importantly, repeat renal biopsies in selected patients demonstrated that while amyloid deposits often persist despite hematological remission, suppression of light-chain production can halt further deposition and translate into meaningful clinical benefit. These findings reinforce the concept that timing of CD38-directed therapy is critical, with earlier intervention offering the greatest potential for organ preservation.

Renal Amyloidosis as a Paradigm for CD38-Directed Therapy

Renal involvement represents a particularly compelling setting for CD38 targeting in AL amyloidosis [35, 36]. Proteinuria and declining glomerular filtration rate not only predict progression to end-stage kidney disease but also limit the tolerability of conventional chemotherapy. Daratumumab monotherapy has shown a favorable safety profile in this context, with low rates of infusion-related reactions and manageable infectious complications, even in patients with advanced renal dysfunction [36]. The observation that renal responses may lag behind hematological responses highlights a fundamental pathophysiological principle of AL amyloidosis: while amyloid removal is slow and often incomplete, rapid suppression of the amyloidogenic precursor is sufficient to stabilize or improve organ function. This paradigm strongly supports the use of potent plasma cell–directed therapies, such as CD38 inhibitors, as early as feasible in the disease course [37].

Broader Implications and Translational Relevance

Beyond AL amyloidosis, the success of CD38 targeting in this setting provides a conceptual framework for other disorders driven by small but pathogenic plasma cell clones. Conditions such as monoclonal immunoglobulin deposition disease, proliferative glomerulonephritis with monoclonal immunoglobulin deposits, fibrillary glomerulonephritis, and type I cryoglobulinemia share a similar pathogenic logic and may similarly benefit from plasma cell–directed strategies. In this regard, AL amyloidosis represents a model disease for extending CD38-targeted therapies [37]. The potential use of anti-CD38 therapies in different conditions is described separately, as follows, and is detailed in Table 1.

Table 1.

Main reported use of daratumumab in refractory AIHA, Evans syndrome, and CAD

Disease, setting	Patients (n)	Prior therapies	Daratumumab regimen	Time to response	Main outcome	Level of evidence
wAIHA and CAD (multicenter cohort) [68]	19 (wAIHA and CAD)	Steroids; rituximab; immunosuppressants; clone-directed therapies (variable)	Daratumumab, different schemes applied (MM-derived schedules)	Median 2–4 weeks	Overall high hematological response rate in refractory wAIHA and CAD; responses observed across both warm and cold phenotypes	Multicenter retrospective cohort
CAD refractory to B cell–clone–directed therapy [70]	1	Rituximab-based and clone-directed regimens	Daratumumab-16 mg/kg (MM-derived schedules)	2 weeks	Hemoglobin improvement and clinical response after failure of B cell–directed strategies	Case report
wAIHA post-HSCT for ALL [39]	1 (19-year-old woman)	Steroids; rituximab (2 courses); high-dose cyclophosphamide; rabbit ATG; alemtuzumab; bortezomib (2 courses); MMF; sirolimus; ibrutinib	16 mg/kg single infusion	2–4 weeks	Marked reduction in red-cell transfusion requirement in a refractory patient	Case report
wAIHA post-HSCT for ALL [40]	3 (pediatric cases)	Steroids; rituximab; plasma exchange; bortezomib; MMF; sirolimus; ATG; cyclophosphamide; ibrutinib; eculizumab	16 mg/kg: Pt1 11 doses/49 days; Pt2 4 doses/17 days; Pt3 7 doses/43 days	Not reported	Clinical response in 2/3 heavily pre-treated patients; 1 transient response with fatal outcome	Case series
wAIHA during HSCT for Langerhans cell histiocytosis [41]	1 (pediatric case)	Steroids; rituximab; IVIG; whole blood exchange	16 mg/kg/day × 2	3 days	Rapid hemoglobin recovery in refractory disease	Case report
wAIHA [42]	1 (60-year-old woman)	Steroids; rituximab	16 mg/kg weekly × 4	10 weeks	Sustained hematological response (~20 weeks)	Case report
wAIHA post-HSCT (case–control series) [47]	3 of 20 pediatric AIC cases	Corticosteroids (75%); rituximab (55%)	Not reported	Mean 1069 days post-HSCT	Daratumumab started late post-HSCT; 2 patients responded with resolution of B cell aplasia	Observational case–control study
Post-HSCT wAIHA with anti-D specificity [69]	1	Multiple prior immunosuppressive therapies	16 mg/kg weekly × 4	Rapid (days–weeks)	Successful control of severe post-transplant AIHA	Case report
wAIHA post-CBT in mucopolysaccharidosis type III [71]	]1	Steroids; prior supportive therapies	Daratumumab-based regimen (not specified)	Not reported	Resolution of post-transplant AIHA	Case report
Evans syndrome post-HSCT for aplastic anemia (wAIHA + ITP) [46]	1 (35-year-old woman)	Steroids; IVIG; cyclosporine; eltrombopag; rituximab; bortezomib	16 mg/kg weekly × 4	2 weeks	Rapid platelet and hemoglobin recovery in a highly pre-treated patient	Case report
Evans syndrome post-HSCT for myelofibrosis (wAIHA + ITP) [45]	1 (pediatric case)	Steroids; IVIG; rituximab; abatacept; bortezomib	16 mg/kg weekly × 6	Immediate	Immediate hematological response in refractory disease	Case report
CAD secondary to lymphoplasmacytic lymphoma [44]	1 (48-year-old man)	Steroids; rituximab; bortezomib; cyclophosphamide–prednisolone	16 mg/kg weekly × 8; then q2w × 9–24; then monthly	2 weeks	Resolution of cold-induced peripheral symptoms, increased hemoglobin, reduced cold agglutinin titers	Case report

AIC autoimmune cytopenia, AIHA autoimmune hemolytic anemia, ALL acute lymphocytic leukemia, ATG antithymocyte globulin, CAD cold agglutinin disease, CBT cord blood transplantation, HSCT hematopoietic stem cell transplantation, ITP immune thrombocytopenia, IVIG intravenous immunoglobulin, MM multiple myeloma, MMF mycophenolate mofetil, Pt patient, q2w every 2 weeks, wAIHA warm autoimmune hemolytic anemia

Autoimmune Hemolytic Anemia

Daratumumab was successfully used in refractory patients with autoimmune hemolytic anemia, both cold agglutinin disease (CAD) [38] and warm forms [39]. CAD is caused by cold reactive autoantibodies inducing complement-mediated hemolysis. The immunoglobulin M (IgM) monoclonal gammopathy and the lymphoid infiltration that characterize CAD indicate that it is primarily driven by B cells and justify the first choice of treatment with anti-CD20 monoclonal antibodies, but plasma cell–directed therapies, such as proteasome inhibitors, also have a role in this disorder. Several reports suggest daratumumab to be effective in CAD resistant to anti-CD20 antibodies, by improving anemia and disabling circulatory peripheral symptoms. At present daratumumab can be fully considered a therapeutic option for refractory diseases [9, 39–46]. Possible immunomodulatory activity in addition to plasma cell depletion have been speculated, including influences on the profile of IL-6, IL-10, IL-17, IFNγ, tumor necrosis factor (TNF)α, transforming growth factor (TGF)β [38].

Immune Thrombocytopenia

ITP is an acquired immune-mediated bleeding disorder characterized by isolated thrombocytopenia, usually defined by a platelet count below 100 × 10⁹/L, in the absence of alternative causes. Its pathogenesis is heterogeneous and involves both increased platelet destruction and impaired platelet production [47–49]. In many patients, autoreactive B cells and plasma cells produce anti-platelet antibodies directed against platelet surface glycoproteins, including GPIIb/IIIa and GPIb/IX. These antibodies opsonize circulating platelets and promote Fc gamma (Fcγ) receptor–mediated phagocytosis, predominantly by splenic and hepatic macrophages. Complement activation, cytotoxic T cell responses, impaired regulatory T cell function, and direct effects on megakaryocytes may further contribute to thrombocytopenia and disease chronicity. This pathogenic framework provides a strong rationale for CD38-directed therapy, because CD38 targeting may reduce autoreactive antibody-producing plasmablasts and plasma cells while also modulating CD38-dependent innate immune effector mechanisms involved in platelet clearance.

It has an annual incidence of two to four cases per 100,000 [47, 48]. Patients have an increased possibility of hospitalization, a propensity for fatigue, and a compromised quality of life. Cutaneous and mucosal bleeding can occur with platelet counts < 30 × 10⁹ per liter.

Mechanistic studies have recently expanded the rationale for CD38 targeting in ITP beyond depletion of antibody-producing plasma cells. In ITP, platelet destruction is largely mediated by anti-platelet antibodies that opsonize platelets and promote Fcγ receptor–dependent phagocytosis by splenic and hepatic macrophages. Recent data indicate that CD38 may amplify this effector phase through NAD⁺ depletion and macrophage metabolic reprogramming [49]. Li et al. [50] showed that CD38-mediated NAD⁺ depletion promotes M1-like macrophage polarization, increases Fc gamma receptor I (FcγRI) expression, and enhances macrophage phagocytosis of opsonized platelets. In experimental models, CD38 inhibition or nicotinamide mononucleotide supplementation restored NAD⁺ levels, reprogrammed macrophages, downregulated FcγRI, and prevented thrombocytopenia. These findings suggest that CD38-directed strategies in ITP may have a dual mechanism of action: reducing pathogenic autoantibody production through effects on plasma cells and attenuating Fcγ receptor–mediated platelet clearance through modulation of macrophage immunometabolism.

This mechanistic framework may help explain the rapid platelet recovery observed after anti-CD38 therapy, which can occur earlier than would be expected from plasma cell depletion alone. It also raises the possibility that non-depleting metabolic strategies targeting the CD38–NAD⁺ axis may complement or, in selected contexts, differ from conventional anti-CD38 monoclonal antibody therapy [49].

Although glucocorticoids frequently induce an initial platelet response, durable remission after steroid discontinuation is achieved only in a subset of patients. Subsequent options include rituximab, thrombopoietin-receptor agonists, fostamatinib, and splenectomy, but a clinically relevant proportion of patients remains refractory or experiences repeated relapse [51]. This has supported the development of therapeutic approaches that target persistent autoreactive plasma cells and downstream effector pathways of platelet destruction.

Among CD38-directed agents under investigation in ITP, CM313 is a novel investigational anti-CD38 monoclonal antibody designed to target CD38-expressing immune cells, including antibody-producing plasmablasts and plasma cells. In contrast to daratumumab, which is an approved anti-CD38 monoclonal antibody widely used in plasma cell dyscrasias and repurposed in autoimmune cytopenias, CM313 is being clinically developed specifically in immune-mediated diseases, including ITP.

In the phase 1–2 open-label study of CM313 in adult patients with ITP, 21 of 22 patients achieved the primary endpoint, defined as at least two consecutive platelet counts of ≥ 50 × 10⁹/L within 8 weeks after the first dose [52]. The median time to the first platelet count of ≥ 50 × 10⁹/L was 1 week, and the median cumulative duration of response was 23 weeks. Approximately half of the enrolled patients had a baseline platelet count < 10 × 10⁹/L. Bleeding manifestations decreased from 68% at baseline to 5% at week 8 and 10% at week 24. Adverse events were mostly grade 1 or 2, with infusion-related reactions and upper respiratory tract infections being the most frequent. Collectively, these findings suggest that CD38-directed therapy may induce rapid platelet recovery and clinically meaningful bleeding improvement in refractory ITP. However, the open-label, single-arm design, small sample size, and limited follow-up require cautious interpretation and support the need for randomized controlled trials. Mechanistically, the CM313 study also investigated CD38 targeting in a passive ITP mouse model. CM313 attenuated anti-platelet antibody–induced thrombocytopenia, providing experimental support for a direct role of CD38-expressing immune compartments in antibody-mediated platelet destruction. These findings are relevant because they suggest that CD38-directed therapy may act at more than one level in ITP: by reducing autoreactive antibody production and by modulating effector pathways involved in platelet clearance. This experimental evidence also helps explain the rapid platelet recovery observed clinically, which may occur earlier than would be expected from plasma cell depletion alone.

CM313 was evaluated in a multicenter, randomized, double-blind, placebo-controlled phase 2 trial in adults with persistent or chronic primary ITP who had relapsed after or failed glucocorticoid therapy. Patients were randomized 2:1 to receive CM313 or placebo, administered intravenously once weekly for 8 weeks [53]. The primary endpoint was overall response at week 8, defined as at least two consecutive platelet counts > 30 × 10⁹/L without bleeding. CM313 was associated with a higher week-8 overall response rate than placebo and induced rapid platelet recovery, with the median time to achievement of platelet counts > 50 × 10⁹/L being approximately 1 week in the CM313 group. The cumulative duration of platelet response was also longer with CM313 than with placebo. Bleeding manifestations decreased during follow-up in the CM313 group, while treatment-emergent adverse events were mostly manageable, with infusion-related reactions and upper respiratory tract infections among the commonly reported events. This randomized study strengthens the evidence base for CD38-directed therapy in ITP by confirming that the rapid platelet responses observed in the earlier single-arm study are unlikely to be explained solely by spontaneous fluctuation or background treatment effects [53].

Clinical evidence in ITP has also expanded beyond CM313. Daratumumab has been evaluated in previously treated adult ITP in both multicenter and single-center phase 2 studies. In the multicenter open-label phase 2 study by Tsykunova et al. [54], 21 patients with previously treated ITP received subcutaneous daratumumab 1800 mg weekly for either eight or ten doses. The median baseline platelet count was 17 × 10⁹/L, and patients had received a median of four prior therapies. Ten patients met the primary efficacy endpoint, and sustained response at week 24 was achieved in eight patients, although two later relapsed. Most treatment-emergent adverse events were grade 1–2, most commonly infections, while two grade 3 adverse events were reported. Daratumumab reduced immunoglobulin levels and depleted CD38-expressing cells in peripheral blood and bone marrow, supporting target engagement but also highlighting the need for monitoring of humoral immunity.

Chen et al. [55] also reported a single-center, open-label, phase 2 trial of daratumumab in adults with ITP, further supporting the feasibility of CD38-directed therapy in this setting. Although the details and populations differ across studies, these daratumumab experiences are relevant because they extend the ITP evidence base to a clinically available anti-CD38 antibody already widely used in plasma cell dyscrasias.

Mezagitamab, also known as TAK-079, is a fully human IgG1 anti-CD38 monoclonal antibody developed as a subcutaneous CD38-directed therapy. Mezagitamab has recently been tested in a randomized, double-blind, placebo-controlled, phase 2 trial in adults with persistent or chronic primary ITP. Participants received weekly subcutaneous mezagitamab at different dose levels or placebo over an 8-week treatment period. Treatment increased platelet counts, with the strongest signal at the 600-mg dose: through week 16, platelet response was reported in ten of 11 participants receiving mezagitamab 600 mg compared with three of 13 participants receiving placebo. The safety profile appeared similar to placebo, with most adverse events being grade 1 or 2. These data broaden the CD38-directed ITP landscape and suggest that antibody-specific properties, dosing, route of administration, and durability of response will be central issues for future comparative development.

Pediatric evidence has also emerged for CD38-directed therapy in relapsed or refractory ITP. Sun et al. [56] reported the use of daratumumab in 20 children with relapsed or refractory pediatric ITP. Daratumumab was administered as 8 weekly infusions, and platelet responses were observed in most patients, with platelet counts increasing rapidly during the first weeks of treatment. A platelet count of ≥ 50 × 10⁹/L without rescue medication or escalation of concomitant therapy during the first 8 weeks was achieved in 18 of 20 patients, although the response rate declined during follow-up. Treatment was generally manageable, with infusion-related reactions and upper respiratory tract infections among the reported adverse events. These findings extend the clinical relevance of CD38-directed therapy to pediatric ITP, while also emphasizing the need for longer follow-up, standardized response definitions, and careful monitoring of humoral immunity in children.

Despite the availability of corticosteroids, rituximab, thrombopoietin-receptor agonists, fostamatinib, and splenectomy, a subset of patients remains refractory or experiences recurrent relapse, highlighting the need for therapeutic strategies that directly target persistent autoreactive plasma cells and downstream effector mechanisms of platelet clearance [57]. Taken together, the abovementioned studies indicate that ITP is currently one of the most clinically advanced autoimmune indications for CD38-directed therapy. However, the available studies differ in antibody used, route of administration, treatment duration, response definitions, prior therapies, and follow-up, making cross-trial comparison difficult and reinforcing the need for larger randomized studies and standardized endpoints.

Evans Syndrome

Evans syndrome is an immune-mediated disease characterized by the simultaneous or sequential occurrence of autoimmune cytopenia with anemia and jaundice due to hemolysis and purpura and mucosal bleeding due to thrombocytopenia. Evans syndrome is chronic, has a high risk of relapses, and is frequently refractory [58]. Management is challenging, especially in patients who have significant co-morbidities. These patients can experience several disease relapses over the years despite prolonged administration of corticosteroids either alone or combined with intravenous immunoglobulins. Second- and third-line therapies, such as immunosuppressants, anti-CD20 monoclonal antibodies, and thrombopoietin receptor agonists are often needed. Splenectomy may be considered in extreme cases [59]. These long-term management efforts are further impacted by treatment-associated complications, including infections and thrombotic events (particularly in patients requiring intensive immunosuppression), and a lack of comparative data on the efficacy of immunosuppressive therapies, information that is largely derived from studies in ITP and autoimmune hemolytic anemia. With regard to rituximab, which is included in second-line treatment recommendations, treatment proved to have limited efficacy in some cases, due to persistent autoantibody production from CD20-negative plasma cells [60]. These limitations have paved the way for agents targeting plasma cells, such as daratumumab. The potential of anti-CD38 strategies as an adjunct or subsequent therapy in difficult cases of refractory Evans syndrome has been recently reported [61].

CD38 targeting in Renal Alloimmunity and Antibody-Mediated Rejection

Renal alloimmunity provides an additional disease model in which CD38-directed therapy may be informative beyond classical autoimmunity. Antibody-mediated rejection (ABMR) after kidney transplantation is driven by donor-specific antibodies, microvascular inflammation, endothelial injury, complement-dependent and complement-independent effector mechanisms, and plasma cell persistence. In this setting, felzartamab, an anti-CD38 monoclonal antibody distinct from daratumumab, has recently been investigated as a strategy to target antibody-producing cells and CD38-expressing immune effectors. Molecular biopsy analyses from a randomized trial showed that 6 months of felzartamab reduced molecular ABMR activity scores, with selective suppression of IFNγ-inducible and natural killer cell–associated transcripts. However, suppression was incomplete in patients with intense baseline ABMR activity, and molecular recurrence was frequent after treatment discontinuation by week 52. Interestingly, molecular injury trajectories suggested potential parenchymal benefit beyond the treatment period, raising the possibility that transient suppression of ABMR activity may slow subsequent progression. These findings are relevant for autoimmune kidney disease because they illustrate that CD38-directed therapy may modulate not only antibody-producing plasma cells but also intrarenal inflammatory and natural killer-cell–associated pathways. They also reinforce the need to define optimal treatment duration, maintenance strategies, and disease-specific biomarkers of response [62, 63].

Challenges and Future Perspective

Completed and ongoing CD38-directed studies across autoimmune, alloimmune, renal, hematological, and plasma cell–driven immune-mediated diseases are summarized in Table 2. Despite the fascinating perspectives of targeting CD38 in autoimmune diseases, CD38’s wide multifunctional activity, as an ectoenzyme, had been thought to influence efficacy of anti-CD38 therapies in treating systemic autoimmune diseases by promoting the activity of effector T cells and depleting IL-10–producing regulatory B cells. Indeed, the loss of CD38 was even able to induce autoimmune features in murine models [64]. While regulatory B cells have been found to be reduced in number and functionally impaired in patients with established autoimmune diseases [65], serum IL-10 levels appear to increase in patients with refractory lupus nephritis who are responsive to anti-CD38 therapy [64].

Table 2.

Completed and ongoing CD38-directed studies across autoimmune, alloimmune, renal, hematological, and plasma cell–driven immune-mediated diseases

Agent/CD38-directed strategy	Representative study identifier(s)	Phase/design/status
Systemic lupus erythematosus
Daratumumab	NCT04810754	Phase 2/open-label/status unknown
Primary antiphospholipid syndrome/APS-associated thrombocytopenia
Daratumumab	NCT05671757	Phase 1/2/NA/recruiting
Unspecified anti-CD38 antibody	NCT05983952	Phase 2/open-label/recruiting
Immune thrombocytopenia
CM313	NCT05694767; NCT06199089	Phase 2/single-arm/completed; phase 2/randomized, double-blind, placebo-controlled/active/not recruiting
Daratumumab, alone or with rituximab	NCT06838962; NCT07063199; NCT07297563; NCT07234019; NCT07362199; NCT07362238	Multiple phase 2 studies/various/mostly recruiting
Mezagitamab/TAK-079	NCT04278924	Phase 2/randomized, placebo-controlled/completed
Evans syndrome and autoimmune cytopenias
Unspecified anti-CD38 antibody	NCT06014775	Phase 2/single-arm/recruiting
Acquired hemophilia/hemophilia A with inhibitors
Daratumumab-containing regimens	NCT05849740; NCT05888870	Phase 4 exploratory studies/NA/recruiting
Pemphigus and severe immune-mediated skin disease
Daratumumab	NCT07110662	Phase 1/2/NA/not yet recruiting
CM313	NCT06663943; NCT06904040	Phase 1/2 or exploratory study/NA/not yet recruiting
Antibody-mediated rejection after transplantation
Daratumumab	NCT05913596	Phase not specified/NA/study status unknown
Felzartamab/MOR202	NCT05021484	Phase 2/NA/completed
IgA nephropathy
Felzartamab/MOR202	NCT05065970	Phase 2/randomized placebo-controlled/completed
Anti-PLA2R membranous nephropathy
Felzartamab/MOR202	NCT04145440; NCT04733040; NCT04893096	Phase 1/2–2/NA/completed
AL amyloidosis
Daratumumab-based regimens	NCT06571864; NCT03283917; NCT05898646; NCT06022939; NCT07110844; NCT07335887;	Phase 1–3/NA/mixed completed, recruiting, withdrawn, or not yet recruiting
STI-6129	NCT04316442; NCT05692908	Phase 1/2/open-label dose-finding studies/withdrawn/status unknown
Selective CD38 enzymatic blockade
TNB-738	NCT05215912	Phase 1 healthy-volunteer study/NA/completed

Trial status and phase reflect the uploaded ClinicalTrials.gov export. “Unspecified anti-CD38 antibody” indicates that the registry record did not name the agent in the exported intervention field. AL amyloidosis is included as a plasma cell–driven comparator condition rather than as a classical autoimmune disease

AL amyloid light chain, APS antiphospholipid syndrome, IgA immunoglobulin A, NA data not available, PLA2R phospholipase A2 receptor

Some further drawbacks might be envisaged in treating immune-mediated diseases with anti-CD38 antibodies. For instance, memory B cells and germinal center B cells that lack this surface marker would not be affected. Reactivation of these specific cells could favor disease relapses [66]. The combination of anti-CD38 and anti-CD20 therapy could overcome this limitation by depleting all autoreactive clones. Patients with biopsy-proven focal segmental glomerular sclerosis recurrence post-transplant who were resistant to common therapies, including rituximab and plasma exchange, received anti-CD20 plus anti-CD38 monoclonal antibodies and showed enhanced efficacy over standard approaches [67]. A more extensive use of such a combination strategy in systemic autoimmune diseases is attractive but needs further investigation, especially for safety. A profound depletion of long-lasting antibody-producing plasma cells by anti-CD38 together with other targeted therapies that affect memory cells could reduce the production of protective antibodies to previous infections, such as smallpox and measles, thereby exposing the recipients to an increased infection risk [68–71].

Importantly, anti-CD38 monoclonal antibodies should not be considered interchangeable. Although daratumumab remains the best-characterized agent in autoimmune settings, other anti-CD38 antibodies, including isatuximab, differ in epitope binding, cytotoxic activity, capacity to induce direct cellular effects, and inhibition of CD38 ectoenzymatic function. These differences may influence not only the depth and duration of plasma cell depletion, but also receptor-mediated signaling, immunometabolic effects, and the interpretation of clinical outcomes across diseases. Therefore, evidence generated with one CD38-directed antibody cannot automatically be extrapolated to another, particularly in complex autoimmune and immune-mediated disorders in which plasma cells, innate immune cells, complement activation, and tissue-resident immune populations may contribute differently to pathogenesis [72].

Antibodies specifically designed to block CD38 enzymatic activity may also help clarify the relative contribution of enzyme inhibition versus receptor ligation and Fc-mediated cell depletion. For example, TNB-738 is a biparatopic anti-CD38 antibody engineered to inhibit CD38 enzymatic activity and increase intracellular NAD⁺ without depleting CD38-expressing cells, owing to its silenced IgG4 Fc region. Such agents provide a conceptual framework for separating CD38 enzymatic blockade from the broader effects of conventional cell-depleting anti-CD38 monoclonal antibodies [73].

Safety Considerations and Unmet Challenges of CD38 Targeting in Autoimmune Disease

Despite the compelling biological rationale and emerging clinical signals of efficacy, targeting CD38 in autoimmune diseases raises important safety considerations that warrant careful scrutiny. Anti-CD38 monoclonal antibodies induce profound depletion of antibody-secreting plasma cells, which, while desirable for suppressing pathogenic autoantibodies, may also compromise long-term humoral immunity. Hypogammaglobulinemia is a frequent on-target effect observed in oncology and autoimmune settings, with potential implications for infection susceptibility and impaired vaccine responsiveness, particularly with prolonged or repeated exposure [17, 33]. Experience from multiple myeloma indicates an increased risk of bacterial and viral infections, including respiratory tract infections and herpesvirus reactivation, underscoring the need for vigilant monitoring, immunoglobulin replacement strategies in selected patients, and optimized vaccination schedules prior to treatment initiation [17, 33]. Beyond plasma cells, CD38 is expressed on multiple immune subsets, including regulatory B cells, activated T cells, natural killer cells, and myeloid populations, raising the possibility of broader immunomodulatory effects that may be context dependent [17, 33]. Preclinical data suggest that CD38 deficiency can promote autoimmune features in murine models, highlighting the delicate balance between therapeutic immune reset and disruption of regulatory networks. In addition, CD38-negative memory B cells and germinal center B cells are spared by anti-CD38 therapy, potentially enabling re-emergence of autoreactive clones and disease relapse once plasma cell populations recover. Combination or sequential strategies integrating CD38 targeting with upstream B cell–directed therapies may mitigate this risk but could further amplify immunosuppression and infection burden [17]. Collectively, these considerations emphasize that anti-CD38 therapies should currently be reserved for carefully selected patients with severe, refractory disease, ideally within controlled clinical trials or structured compassionate-use programs, while robust prospective data are generated to define optimal dosing, duration, combination strategies, and long-term safety profiles in autoimmune populations.

Conclusion

Targeting CD38 represents a conceptually important advance in the therapeutic landscape of autoimmune diseases by directly addressing long-lived plasma cells, a compartment largely refractory to conventional immunosuppressive and B cell–directed strategies. Emerging clinical experiences, most notably in refractory lupus nephritis, ITP, and plasma cell–driven disorders such as AL amyloidosis, provide a compelling proof of concept that selective plasma cell depletion can translate into meaningful clinical and immunological benefit in carefully selected patients. At the same time, the current evidence base remains heterogeneous and largely derived from small cohorts, early-phase trials, and off-label use, precluding definitive conclusions regarding optimal patient selection, treatment timing, durability of response, and long-term safety. The pleiotropic biological functions of CD38 further underscore the need for caution, as therapeutic benefit must be balanced against the risk of sustained immunodeficiency and infection-related complications. Future prospective, disease-specific studies will be essential to define the role of CD38-targeted therapies within existing treatment algorithms, to identify rational combination or sequential strategies, and to clarify whether plasma cell–directed approaches can safely deliver durable disease control beyond rescue settings. Until such data are available, anti-CD38 therapies should be viewed as a promising but still evolving strategy at the interface of immunology and clinical medicine.

Funding

Open access funding provided by Università degli Studi di Torino within the CRUI-CARE Agreement. None.

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The authors declare they have no conflicts of interest relevant to the contents of this article.

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Author Contributions

DR conceived the manuscript. DR, SS, DRo, and RF contributed to the literature review, interpretation of the evidence, and drafting of the manuscript. SS and RF critically revised the manuscript for intellectual content. All authors reviewed and approved the final version.