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CD38

CD38 is a multifunctional type II transmembrane that serves as an ectoenzyme, catalyzing the and of cyclic ADP-ribose (cADPR) from NAD⁺ and nicotinic acid dinucleotide phosphate (NAADP) from NADP⁺, which act as second messengers to mobilize intracellular calcium stores. Expressed predominantly on hematopoietic cells such as plasma cells, activated T and B lymphocytes, and natural killer cells, CD38 functions as a receptor in and , particularly through interactions with , and is recognized as a marker of immune cell activation. Structurally, CD38 features a short N-terminal cytoplasmic tail, a single transmembrane , and an extensive C-terminal extracellular rich in residues that form stabilizing bonds, enabling the protein to dimerize. Its enzymatic , centered around a conserved glutamate residue (Glu226), supports bidirectional : at neutral or alkaline , it generates cADPR to trigger calcium release from the , while at acidic , it produces NAADP to mobilize calcium from lysosomes, influencing diverse physiological processes including insulin from pancreatic β-cells, , and during fertilization. In pathological contexts, CD38 is overexpressed in various hematologic malignancies, notably where it serves as both a prognostic and a therapeutic target; as of 2025, anti-CD38 monoclonal antibodies are integrated into standard quadruplet regimens for newly diagnosed , in addition to their established use in relapsed/refractory cases. Monoclonal antibodies like bind CD38 to induce tumor cell death via , , and , achieving significant response rates in relapsed/refractory cases. Beyond cancer, CD38 modulates inflammation by regulating cytokine production (e.g., IL-6, TNF-α) and immune cell recruitment in conditions such as and , while CD38 deficiency accelerates autoimmunity in mouse models of but suppresses disease progression in some models of systemic . High expression is also noted in non-hematopoietic tissues like the , , and , linking CD38 to broader roles in and neurodegeneration.

Molecular Structure and Genetics

Gene Organization and Protein Structure

The CD38 gene is located on the short arm of human chromosome 4 at position 4p15.32, spanning approximately 71 kb of genomic DNA and consisting of 8 exons that encode a 300-amino acid precursor protein. The gene structure includes a CpG island in the 5'-flanking promoter region, which spans about 900 bp and incorporates exon 1, facilitating transcriptional initiation. The CD38 gene is highly polymorphic, with notable single nucleotide polymorphisms (SNPs) such as rs6449182 located in intron 1. This C>G variant affects gene expression levels, with the G allele associated with reduced promoter activity and increased susceptibility to B-cell chronic lymphocytic leukemia and multiple myeloma. The mature CD38 protein is a type II transmembrane with a molecular weight of approximately 45 kDa due to N-linked at four sites in the extracellular . It features a short N-terminal cytoplasmic tail of 21 (residues 1-21), a single hydrophobic of 21 (residues 22-42), and a large C-terminal extracellular of 256 (residues 43-300), which positions the enzymatic and receptor functions on the surface. This topology enables CD38 to act as a bifunctional ectoenzyme and signaling receptor, with the extracellular oriented outward to interact with extracellular substrates and ligands. Key structural motifs in the extracellular domain include the pocket, formed by conserved residues such as Glu-226, Trp-125, Trp-189, Asp-155, Ser-193, Glu-146, Arg-127, and others, which facilitate NAD+ hydrolysis to produce cyclic ADP-ribose (cADPR) and ADP-ribose (ADPR). Additionally, the extracellular region contains sites that mediate interactions with non-substrate ligands, including in the and (PECAM-1) on adjacent cells, supporting and migration functions. CD38 exhibits strong evolutionary across mammalian , with high identity in the catalytic , reflecting its essential physiological roles. In non-mammalian organisms, CD38 show structural and functional to soluble ADP-ribosyl cyclases, such as the from Aplysia californica, which shares a similar dinucleotide-binding fold but lacks the transmembrane . The three-dimensional of the human CD38 extracellular domain has been elucidated through , with the first high-resolution model (PDB entry 1YH3) determined at 1.9 resolution, revealing a compact α/β fold dominated by a central β-sheet flanked by α-helices. This highlights the dinucleotide-binding fold, characterized by a that accommodates NAD+ substrates and supports both cyclase and activities, with conserved motifs aligning closely to those in related enzymes like CD157 and ADP-ribosyl cyclase. Subsequent , such as those complexed with inhibitors or analogs (e.g., PDB 3DZK), further confirm the flexibility of the loop, which undergoes conformational changes during .

Expression Regulation

The expression of the CD38 gene is primarily regulated at the transcriptional level through interactions between its promoter region and various transcription factors activated by cytokines and other signaling molecules. The human CD38 promoter contains binding sites for specificity protein 1 (Sp1), retinoic acid response elements (RARE), and interferon regulatory factor 1 (IRF-1), which facilitate induction by all-trans retinoic acid (ATRA) and interferons. For instance, ATRA stimulates CD38 transcription via RARE located in the first intron, leading to increased mRNA levels in cells such as airway smooth muscle and leukemic B cells. Similarly, interferons (types I and II, including IFN-γ and IFN-α) rapidly upregulate CD38 expression in B cells through IRF-1 binding to the promoter, enhancing ectoenzymatic activity. Although direct evidence for NF-κB and STAT1/3 binding sites in the CD38 promoter is limited, cytokine-induced pathways involving these factors contribute to inducible expression in activated immune cells. Epigenetic modifications play a key role in fine-tuning CD38 expression, particularly in immune cells, by altering accessibility and promoter activity. The CD38 promoter includes a CpG island approximately 900 bp long encompassing 1, where patterns can silence in quiescent states. acetylation, mediated by acetyltransferases like p300 recruited by PTIP (PAX-interacting protein 1), promotes CD38 activation by relaxing structure at cis-regulatory elements in hematopoietic cells. In murine memory B cells, modifications control hallmark genes like CD38, maintaining low expression in resting states but allowing rapid induction upon stimulation. Post-transcriptional regulation of CD38 occurs via microRNAs (miRNAs) that target its mRNA, modulating protein levels during . For example, miR-26a directly suppresses CD38 translation in cells, acting as a tumor suppressor by reducing surface expression and enhancing anti-tumor responses. In , networks of miRNAs, including those identified in human B-cell stimulation models, regulate CD38 alongside other differentiation markers, preventing excessive expression that could impair maturation. CD38 exhibits developmental and inducible expression patterns tightly linked to immune cell activation and lineage commitment. During B-cell differentiation, CD38 is upregulated from early precursors (pre-pro-B to immature stages) in , serving as a marker of progression. In T cells, activation induces CD38 surface expression, correlating with glycolytic shifts and effector functions in both and murine models. These patterns are inducible by inflammatory cytokines, reflecting adaptive responses in immune . Species-specific differences in CD38 promoter elements contribute to variations in expression profiles across mammals. The promoter's CpG-rich structure and sites differ from murine counterparts, leading to distinct ; for instance, CD38 shows broader inducibility by ATRA in hematopoietic cells compared to mice, where expression is more restricted to certain lineages. Phylogenetic analyses of CD38 sequences highlight variations that may influence promoter accessibility, underscoring evolutionary adaptations in immune .

Biological Functions

Enzymatic Activities

CD38 exhibits multifaceted enzymatic activities as a multifunctional ectoenzyme primarily involved in NAD⁺ metabolism. Its core function is NAD⁺ glycohydrolase activity, which hydrolyzes extracellular NAD⁺ into () and ADP-ribose (ADPR), with a minor fraction cyclized to cyclic ADP-ribose (cADPR). This hydrolysis predominates, accounting for over 90% of CD38's catalytic output, and occurs with a Michaelis constant (Kₘ) for NAD⁺ in the range of 15–56 μM. Additionally, CD38 displays ADP-ribosyl cyclase activity, converting NAD⁺ to cADPR, a potent second messenger that mobilizes intracellular calcium stores via ryanodine receptors. The cyclase activity shares a similar Kₘ for NAD⁺ (approximately 15–56 μM) and exhibits optimal efficiency at neutral pH (6–8). CD38 also catalyzes base-exchange reactions, particularly the exchange of the nicotinamide moiety of NADP⁺ with nicotinic acid to produce nicotinic acid-adenine dinucleotide (NAADP), another calcium-mobilizing second messenger. This reaction is favored under acidic conditions ( 4–5). Kinetic parameters vary slightly across activities, with the glycohydrolase showing higher turnover rates than the cyclase, reflecting the enzyme's preference for . These activities differ in localization: the predominant type II transmembrane orientation positions the catalytic domain extracellularly, enabling hydrolysis of NAD⁺ in the cellular microenvironment and contributing to local NAD⁺ depletion. In contrast, type III isoforms localize intracellularly (e.g., in the or mitochondria), where they may modulate NAD⁺ levels within organelles. The catalytic mechanisms are underpinned by the enzyme's , resolved at 1.9 Å resolution, which reveals a bilobal pocket facilitating binding and . Key residues include the catalytic glutamate (Glu²²⁶), which nucleophilically attacks the NAD⁺ anomeric carbon to form a covalent intermediate, and residues (Trp¹²⁵, Trp¹⁸⁹) that position the substrate via hydrophobic interactions; glutamate (Glu¹⁴⁶) and aspartate (Asp¹⁵⁵) residues modulate pH-dependent partitioning between and cyclization pathways.

Receptor and Signaling Roles

CD38 functions as a that mediates heterotypic adhesion between leukocytes and endothelial cells primarily through its interaction with (also known as ), a member of the expressed on vascular . This CD38-CD31 binding promotes transendothelial migration of leukocytes, facilitating their into tissues during inflammatory responses and supporting immune cell homing to lymphoid organs. Additionally, CD38 binds , a component of the , which further regulates leukocyte adhesion and motility by anchoring cells within the stromal environment. Beyond adhesion, CD38 transduces signals upon engagement or crosslinking, often through lateral associations with tetraspanins such as CD9 and , which organize signaling complexes in lipid rafts. These interactions lead to tyrosine phosphorylation of associated proteins, including linker for activation of T cells (LAT) and CD3 chain components, initiating downstream cascades. A key outcome is calcium mobilization, involving influx from extracellular sources and release from intracellular stores, which is essential for cytoskeletal rearrangements and cellular activation. In B cells, CD38 acts as a costimulatory receptor that enhances receptor signaling by associating with the / complex, promoting and upon ligation. Similarly, in T cells, CD38 costimulates activation through its dependence on the ()/CD3 complex, amplifying responses to antigenic stimulation and supporting production. These roles underscore CD38's contribution to adaptive immune responses by integrating and signaling to fine-tune function. Downstream of receptor engagement, CD38 triggers intracellular signaling cascades, including activation of phospholipase C (PLC)-γ, which generates inositol 1,4,5-trisphosphate (IP3) to mediate calcium release from the endoplasmic reticulum. This calcium signaling intersects with the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway via Raf-1 activation, promoting gene transcription and cellular proliferation. Enzymatic products like cyclic ADP-ribose (cADPR), generated by CD38, further contribute to calcium release through ryanodine receptors. The bifunctional nature of CD38 links its receptor functions to enzymatic amplification, where ligand-induced clustering enhances ADP-ribosyl cyclase activity, thereby potentiating intracellular signaling loops.

Expression Patterns

Tissue and Cellular Distribution

CD38 exhibits prominent expression on hematopoietic cells, serving as a key marker for various immune cell types. In humans, it is highly expressed on cells, with nearly 100% of these cells displaying surface CD38 at high levels (approximately 10^5 molecules per cell), as well as on activated T and B lymphocytes, cells, monocytes, macrophages, dendritic cells, and neutrophils, particularly within and lymphoid tissues. This pattern underscores CD38's role as an activation-associated in the . In non-hematopoietic tissues, CD38 shows low to moderate expression. Notable sites include pancreatic islet cells, where it is detected on beta cells; neuronal cells such as and in the ; vascular and cells; as well as prostatic epithelial cells, retinal cells, , and gut tissues. Protein expression is often cytoplasmic and membranous, with enhanced levels in lymphoid tissues compared to other organs, as summarized in human tissue atlases. Developmentally, CD38 is absent or low on early precursors but is induced during maturation and processes. For instance, it appears on B-cell precursors and B cells, persisting at high levels on plasma cells, while mature peripheral B cells show reduced surface expression unless reactivated. Similarly, in T cells, CD38 marks precursors and double-positive ++ cells, with upregulation on mature T cells following . Expression patterns vary across species, with broader distribution in compared to s. In mice, CD38 is retained on mature B cells throughout and on resting T cells, whereas mature B cells lose surface expression post-maturation, and resting T cells lack it until activation; murine plasma cells show lower levels than their counterparts. Detection of CD38 expression typically employs for surface analysis on live cells or for tissue sections, utilizing monoclonal antibodies such as HB-7, which specifically binds the extracellular domain.

Pathological Upregulation

CD38 is pathologically upregulated in various hematological malignancies, particularly (MM), where it is highly and uniformly expressed on nearly all malignant plasma cells, often exceeding 90% positivity in primary samples and cell lines. This overexpression contrasts with lower baseline levels in normal lymphoid and myeloid cells and is influenced by inflammatory cytokines such as IL-6, IFN-γ, TNF-α, and CXCL-16 secreted within the , which induce CD38 transcription via pathways like activation. In MM, such upregulation supports tumor survival and immune evasion, though certain genetic alterations like 1q gain/amplification can lead to paradoxically reduced CD38 levels through enhanced IL-6 receptor signaling and JAK--mediated suppression. In solid tumors, CD38 expression is elevated in , where it correlates with disease progression and is linked to of the PI3K-AKT pathway, promoting and . In ovarian cancer, high CD38 levels enhance immune infiltration and are associated with favorable prognosis. Pathological upregulation of CD38 also occurs in inflammatory conditions, including (RA), where it is significantly increased in synovial tissues and fibroblasts compared to healthy controls, contributing to chronic inflammation through enhanced T cell activation and production. In neuroinflammatory models of , amyloid-β promotes CD38 expression in senescent , exacerbating and neuronal damage via NAD+ depletion and calcium dysregulation. Conversely, CD38 expression is downregulated in certain immunodeficiencies, such as subsets of (CVID), where diminished CD38 on B cells impairs plasma cell differentiation and production, leading to . This contrasts with its upregulation in chronic T cell exhaustion states, though low CD38 on HIV-specific + T cells in elite controllers suggests a protective role against viral persistence in some contexts. Within the , CD38 is upregulated on stromal fibroblasts and tumor-associated macrophages, fostering an immunosuppressive niche that promotes tumor , , and immune evasion through production and altered signaling. In cancer-associated fibroblasts, CD38 enhances pro-tumoral activity by enabling secretion of growth factors, while on tumor-associated macrophages, it modulates toward an M2-like immunosuppressive . Recent studies as of 2024 also highlight upregulated CD38 on cells and immune infiltrates in kidney diseases such as and antibody-mediated rejection.

Physiological and Pathological Roles

Immune Modulation

CD38 serves as a costimulatory on T cells, enhancing their proliferation and production through ligation with on antigen-presenting cells or endothelial cells. This interaction triggers calcium mobilization via cyclic ADP-ribose (cADPR) production, amplifying signaling and leading to increased secretion of pro-inflammatory cytokines such as IFN-γ and IL-12. In experimental models, blockade of CD38- engagement reduces antigen-induced T-cell activation and release, underscoring its role in promoting effector T-cell responses during immune activation. In B-cell development, CD38 expression is dynamically regulated, serving as a key marker of maturation stages. It is highly expressed on immature pro-B and pre-B cells, where ligation induces to maintain B-cell , but diminishes on naive mature B cells. Upon activation in germinal centers, CD38 is reinduced on centroblasts and centrocytes, facilitating and isotype switching through calcium-dependent signaling. During terminal differentiation, sustained high CD38 expression (CD38hi) identifies plasmablasts and plasma cells, correlating with their antibody-secreting capacity; for instance, differentiation of switched-memory B cells yields CD38hiCD138+ plasma cells that produce elevated IgG and IgA levels. CD38 modulates neutrophil function by regulating and through its enzymatic generation of cADPR and ADP-ribose, which mobilize intracellular calcium stores. In CD38-deficient mice, neutrophils exhibit defective toward chemoattractants like fMLP, resulting in delayed to sites such as the lungs during bacterial challenges. This also supports polymerization and granule release, enhancing and responses; human neutrophils with upregulated CD38 show improved chemotactic accuracy and effector functions in inflammatory contexts. In the , CD38 expression on regulatory T cells (Tregs) drives metabolic shifts that enhance their stability and suppressive capacity, thereby inhibiting anti-tumor immunity. CD38-mediated NAD+ depletion redirects pyruvate metabolism toward , elevating phosphoenolpyruvate while limiting α-ketoglutarate accumulation in the cycle; this maintains hypomethylation at the locus, preserving Treg identity and function. Inhibition of CD38 in tumor-bearing models reduces intratumoral Treg frequencies, improves CD8+ T effector-to-Treg ratios, and slows tumor progression, highlighting its role in immune evasion. Elevated CD38 expression on immune cells contributes to hyperactivation in autoimmune diseases such as systemic lupus erythematosus (SLE) and . In SLE, increased CD38 on T cells, B cells, and monocytes correlates with disease activity, promoting calcium flux that exacerbates production and generation; CD38 deficiency in murine models attenuates SLE by reducing type I IFN and autoantibodies. Similarly, in and its experimental model (EAE), upregulated CD38 on T cells and drives and demyelination through NAD+ dysregulation and enhanced T-cell priming, with CD38 knockout mice showing milder disease severity and impaired autoreactive responses.

Metabolic Regulation and Aging

CD38 plays a central role in metabolic regulation by acting as a major NAD+ glycohydrolase, hydrolyzing NAD+ into and other products, which depletes cellular NAD+ pools and impairs activity. Sirtuins, NAD+-dependent deacetylases, are essential for maintaining , oxidative metabolism, and energy homeostasis; reduced NAD+ availability due to CD38 activity leads to diminished sirtuin function, resulting in mitochondrial dysfunction characterized by decreased respiratory capacity and increased production. Additionally, CD38 catalyzes the synthesis of cyclic ADP-ribose (cADPR) from NAD+, which acts as a second messenger to mobilize intracellular calcium stores, thereby influencing calcium-dependent signaling pathways that regulate metabolic gene expression, including those involved in and lipid oxidation. With advancing age, CD38 expression is upregulated in various tissues, notably the brain and heart, contributing to progressive NAD+ depletion. In aged mice, this upregulation correlates with substantial NAD+ reductions, such as approximately 50% drops in brain and cardiac tissues compared to younger counterparts, exacerbating metabolic decline and cellular senescence. This age-related CD38 increase disrupts NAD+ homeostasis, linking it to several degenerative processes. CD38-mediated NAD+ exhaustion has been implicated in age-related diseases through metabolic dysregulation. In neurodegeneration, such as , elevated CD38 promotes and amyloid-beta accumulation by impairing NAD+-dependent , while in cardiovascular aging, it contributes to and vascular stiffness via mitochondrial impairment in cardiac tissues. In , CD38 upregulation in pancreatic beta cells leads to exhaustion and reduced insulin secretion due to depleted NAD+ and altered , accelerating beta-cell failure. Recent studies from demonstrate that pharmacological inhibition of CD38 effectively restores NAD+ levels in aging models, mitigating metabolic deficits and improving physiological outcomes. For instance, CD38 inhibitors have been shown to enhance cognitive function in tauopathy mouse models by reducing and preserving neuronal NAD+ , while also bolstering cardiac performance through improved mitochondrial function and exercise capacity in aged . These findings underscore CD38's potential as a target for countering age-associated metabolic decline.

Clinical Relevance

Disease Associations

CD38 has been implicated as a prognostic marker in hematological malignancies, particularly (MM), where elevated levels of circulating CD38-positive clonal plasma cells at diagnosis correlate with poorer treatment response and overall survival. In extramedullary , lower CD38 expression on tumor cells is associated with worse overall survival compared to higher expression, highlighting CD38's role in disease aggressiveness. These associations underscore CD38's utility in risk stratification for patients, independent of therapeutic targeting. In solid tumors, CD38 overexpression contributes to disease progression and across several cancer types. In epithelial , cancer-cell-derived CD38 promotes tumor growth and metastatic spread both and by modulating the . Similarly, in , CD38 expression in tumor is linked to poorer overall survival and increased risk of recurrence, with epigenetic regulation via influencing its levels. In , CD38 expression on tumor cells is necessary for metastatic potential, as demonstrated in experimental models where its knockdown reduces primary tumor growth and dissemination. CD38 upregulation in is associated with mellitus, where it contributes to impaired insulin secretion through NAD+ depletion and disrupted . A in the CD38 gene has been identified as a factor in insulin secretion defects in non-insulin-dependent diabetes mellitus, linking genetic variants to beta-cell dysfunction. Elevated CD38 activity in diabetic islets exacerbates beta-cell stress, reducing glucose-stimulated insulin release and promoting disease progression. In neurological disorders, CD38 plays a role in HIV-associated neurocognitive decline through its regulation of calcium and , with increased expression correlating to severity in HIV-1 infection. For , CD38 deficiency attenuates amyloid-beta pathology and cognitive deficits in mouse models, primarily via reduced microglial activation and pro-inflammatory responses in the brain. CD38's dual influence on microglial function—promoting activation while also inducing —links it to exacerbated neurodegeneration in these conditions. Regarding cardiovascular diseases, CD38 contributes to by driving cholesterol-induced via NAD+ depletion, which promotes accumulation and plaque instability. Recent studies highlight CD38's involvement in the heart-brain axis, where its overexpression links cardiac dysfunction to neurological outcomes, including in ischemic conditions as of 2025. In infectious diseases, particularly , CD38 facilitates viral persistence and chronic by sustaining T-cell exhaustion and immune activation during . Elevated CD38 expression on + T cells correlates with progression and higher levels of pro-inflammatory markers, contributing to ongoing even in treated chronic viral infections.

Diagnostic Biomarkers

CD38 serves as a valuable diagnostic in various hematological malignancies and inflammatory conditions due to its overexpression on malignant cells and involvement in immune activation. In , is widely employed to detect CD38-positive plasma cells for assessing (MRD), where CD38 is combined with markers like CD138 and CD45 to achieve high sensitivity in samples, enabling detection limits as low as 10^{-5} to 10^{-6}. This approach has been standardized in consensus guidelines, correlating MRD negativity with improved in patients post-therapy. Innovations such as camelid-derived anti-CD38 nanobodies enhance detection specificity, particularly in cases where standard antibodies face masking after prior treatments. Immunohistochemistry (IHC) scoring of CD38 expression in tumor biopsies provides prognostic insights and predicts therapeutic responses, particularly in solid tumors like hepatocellular carcinoma (HCC). High CD38 positivity in the tumor microenvironment, quantified via IHC, is associated with better outcomes in patients receiving anti-PD-1/PD-L1 immunotherapy, with median progression-free survival exceeding 10 months in responders compared to under 5 months in non-responders. This scoring method evaluates both tumor cells and infiltrating immune cells, offering a non-invasive means to stratify patients for immune checkpoint blockade. Soluble CD38 (sCD38) in serum acts as a non-invasive for monitoring and cancer progression, especially in , where elevated plasma levels correlate with tumor burden and disease activity. Assays like nanobody-based detection quantify sCD38, reflecting ectodomain shedding from malignant plasma cells, and levels above 50 ng/mL indicate active and poorer . In inflammatory contexts, such as chronic immune activation, sCD38 contributes to systemic signaling, though its utility is more established in oncological monitoring than broad . High CD38 expression on leukemic cells holds significant prognostic value in leukemias, particularly (CLL), where surface CD38 positivity exceeding 30% identifies patients with aggressive disease and shorter overall survival, independent of other risk factors like IGHV mutation status. In (AML), CD38 levels enhance cytogenetic risk stratification, with overexpression linked to adverse outcomes and reduced event-free survival rates below 40% at five years. Flow cytometric quantification of CD38 thus aids in risk-adapted therapy decisions. As of 2025, emerging (PET) imaging with CD38-targeted radiotracers shows promise for theranostics in solid tumors, extending beyond hematological applications. Agents like ^{68}Ga-labeled peptides specifically bind CD38-overexpressing cells in models, enabling non-invasive visualization of tumor lesions with high tumor-to-background ratios greater than 5:1. Recent developments, including ^{89}Zr-DFO-isatuximab conjugates, demonstrate feasibility in preclinical solid tumor xenografts, supporting diagnostic and therapeutic monitoring. These tracers facilitate personalized theranostics by assessing CD38 heterogeneity prior to targeted interventions.

Therapeutic Applications

Monoclonal Antibodies

is a IgG1κ approved by the U.S. in 2015 for the treatment of in patients who have received at least three prior lines of therapy. It binds to CD38 on myeloma cells, triggering multiple antitumor mechanisms, including (ADCC), (CDC), and antibody-dependent cellular phagocytosis (ADCP), as well as direct through immune-mediated crosslinking. These effects are particularly effective against CD38-expressing myeloma cells, even in the presence of stromal cells that may otherwise shield tumor cells from immune attack. Isatuximab, another anti-CD38 , differs in its enhanced capacity for direct tumor cell killing. It induces in myeloma cells independently of Fc-dependent immune mechanisms, primarily through CD38 receptor crosslinking that activates intracellular signaling pathways, including activation and lysosomal permeabilization. Like , isatuximab also engages ADCC and CDC, but its unique on CD38 allows for more potent direct induction of in CD38-positive malignant cells. In clinical trials, combinations of these antibodies with immunomodulatory drugs (IMiDs) such as have demonstrated high efficacy in relapsed . For instance, the phase 3 POLLUX showed that plus and dexamethasone achieved an overall response rate of 93% in patients with relapsed or disease, compared to 75% with and dexamethasone alone, with deepened responses including complete response rates of 13% versus 6%. Similarly, combined with and dexamethasone in the ICARIA-MM yielded a 60% overall response rate versus 35% for and dexamethasone, highlighting the synergistic enhancement of IMiD activity through CD38 targeting. Resistance to CD38-targeting monoclonal antibodies can emerge through mechanisms such as on tumor cells or , where immune effector cells strip CD38 from the myeloma cell surface during ADCC, reducing target availability. These processes contribute to diminished efficacy over time, particularly in heavily pretreated patients, and underscore the need for strategies to monitor and overcome antigen modulation. As of 2025, next-generation developments include bispecific antibodies such as CD38xCD3 constructs that redirect T cells to CD38-expressing tumors, expanding beyond traditional Fc-mediated effects to enhance T-cell . These agents are under investigation primarily for hematological malignancies but show promise for T-cell redirection in CD38-positive solid tumors, with ongoing preclinical and early-phase trials exploring their broader applicability.

Small Molecule Inhibitors

Small molecule inhibitors of CD38 primarily target its enzymatic activities, including NAD+ glycohydrolase and ADP-ribosyl cyclase functions, to prevent NAD+ depletion and cyclic ADP-ribose (cADPR) production. These compounds offer a pharmacological approach to modulate CD38-mediated signaling without affecting its role as a , distinguishing them from antibody-based therapies. By binding to the or adjacent regions, such inhibitors can selectively block catalysis while exhibiting favorable for . Natural modulators of CD38 include like and , which act as partial inhibitors by occupying a flavone-binding pocket near the enzyme's . , in particular, inhibits CD38 NADase activity at micromolar concentrations, leading to elevated intracellular NAD+ levels and reduced protein in cellular models. Similarly, competes for the same binding site, promoting NAD+ accumulation and demonstrating partial inhibition of both and cyclase activities . These plant-derived compounds highlight the potential for dietary interventions to fine-tune CD38 function, though their low potency limits standalone therapeutic use. Among synthetic small molecules, 78c (a thiazoloquinazolinone nicknamed "" in early studies) stands out as a potent, reversible of CD38, with values of 1.9 nM for CD38 and 7.3 nM for CD38 across and cyclase activities. Other synthetic inhibitors, such as 8-amino-N1-inosine 5'-monophosphate (8-NH2-N1-IMP) , target the to block cADPR , achieving sub-micromolar inhibition and showing selectivity over related enzymes. These compounds are designed based on structural insights into CD38's NAD+- , incorporating mimics or heterocyclic scaffolds to enhance potency and membrane permeability. Lucifer yellow have also been explored as fluorescent probes that bind the , informing the development of non-fluorescent inhibitors with similar structural features. The therapeutic rationale for CD38 small molecule inhibitors centers on restoring NAD+ homeostasis, which declines with age and in pathological states. In aging models, 78c administration reverses tissue NAD+ decline, improves mitochondrial function, and ameliorates metabolic dysfunction in aged , extending median lifespan by approximately 10%. In cancer contexts, CD38 inhibition suppresses tumor growth; for instance, pharmacological blockade or genetic knockout reduces clonogenic growth of cells and attenuates tumor progression in mouse xenografts by limiting NAD+-dependent metabolic reprogramming in tumor cells. These effects underscore CD38's role in supporting immunosuppressive microenvironments and fueling in malignancies. As of 2025, CD38 s remain primarily in for neurodegeneration, with studies demonstrating through NAD+ elevation and reduced in models. Compounds like 78c exhibit favorable safety profiles in rodent toxicity assays, showing minimal off-target effects on related hydrolases and no significant cardiovascular or hepatic liabilities at therapeutic doses. Emerging candidates, such as VRG201 (a CD38 developed by Verge for metabolic diseases), are advancing toward clinical evaluation.