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CD22

CD22, also known as Siglec-2, is a B-cell-restricted transmembrane glycoprotein that serves as an inhibitory receptor modulating B-cell receptor (BCR) signaling to regulate humoral immunity and prevent excessive B-cell activation.^[1]^[2] Structurally, CD22 is a type I membrane protein with a molecular weight of approximately 140 kDa, featuring seven extracellular immunoglobulin-like domains—the most membrane-distal of which (domain 1) is a V-set domain responsible for ligand binding—an intracellular tail with three immunoreceptor tyrosine-based inhibitory motifs (ITIMs) containing six tyrosine residues, and 12 N-linked glycosylation sites that influence its function and interactions.^[3]^[2] Expression of CD22 begins in the cytoplasm of early B-cell precursors, appears on the surface of mature B cells where it reaches maximal levels, and is downregulated on plasma cells, making it a hallmark marker of mature B lymphocytes across species including humans and mice.^[2]^[4] Functionally, CD22 binds specifically to α2,6-linked sialic acid residues on glycoproteins such as surface IgM (sIgM) and CD45 in cis (on the same cell) or in trans (on adjacent cells like T cells or endothelial cells), which triggers tyrosine phosphorylation of its ITIMs and recruitment of the phosphatase SHP-1 to dephosphorylate BCR signaling molecules, thereby dampening calcium mobilization, proliferation, and cytokine production in response to antigens or innate signals.^[3]^[2] This inhibitory role is essential for establishing B-cell signaling thresholds, maintaining peripheral B-cell tolerance, and averting autoimmunity, as evidenced by hyperresponsive B cells and increased autoantibody production in CD22-deficient mice.^[2]^[5] Given its restricted expression and regulatory function, CD22 has emerged as a prime therapeutic target for B-cell disorders; inotuzumab ozogamicin, a CD22-directed antibody-drug conjugate, received FDA approval in 2017 for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (B-ALL) and was expanded on March 6, 2024, to include pediatric patients aged 1 year and older with relapsed or refractory CD22-positive disease, demonstrating complete remission rates of up to 81% in clinical trials.^[6]^[7] Additionally, CD22-targeted chimeric antigen receptor (CAR) T-cell therapies have shown promise in B-ALL, particularly for patients relapsing after CD19-directed treatments, with over 100 clinical studies conducted, many ongoing as of 2025, evaluating their safety and efficacy in addressing antigen escape and improving durable responses.^[8]

Introduction

Definition and Discovery

CD22, also known as sialic acid-binding immunoglobulin-like lectin 2 (Siglec-2), is a transmembrane glycoprotein that functions as a co-receptor on B lymphocytes, modulating B-cell receptor (BCR) signaling to regulate B-cell activation and inhibit excessive immune responses, thereby contributing to immune homeostasis.^[9] As a member of the Siglec family of lectins, CD22 recognizes sialylated glycans, primarily in cis on the same cell surface, which influences its inhibitory role in B-cell responses.^[10] This regulatory function helps prevent autoimmunity by setting a threshold for BCR activation and promoting tolerance.^[9] CD22 was initially identified in the early 1980s as a B-lymphocyte-restricted cell surface antigen through screening with monoclonal antibodies that specifically bound to human B cells but not T cells or other leukocytes.^[11] It was formally designated as CD22 during the Second International Workshop on Human Leukocyte Differentiation Antigens held in Boston in 1984, where clustering of monoclonal antibodies recognizing the same B-cell-specific epitope confirmed its unique expression pattern.^[9] This workshop established the cluster of differentiation (CD) nomenclature system, transitioning the antigen's name from earlier descriptors like B-lymphocyte cell adhesion molecule (BL-CAM) to the standardized CD22.^[9] The molecular characterization of CD22 advanced significantly with the cloning of its full-length cDNA in 1991 from human B-cell lines, revealing a type I transmembrane protein with seven extracellular immunoglobulin-like domains homologous to myelin-associated glycoprotein (MAG), suggesting roles in cell adhesion and signaling. This cloning effort demonstrated that CD22 exists in two isoforms, CD22α and CD22β, arising from alternative splicing, and highlighted its potential as a mediator of B-B cell interactions.^[11] Subsequent studies confirmed its restricted expression to B cells, appearing on the surface from the immature B-cell stage through mature B cells.^[9]

Expression Pattern

CD22 expression is tightly regulated during B-cell ontogeny, beginning with cytoplasmic localization in pro-B cells within the bone marrow.^[11] As B cells progress to the pre-B cell stage, CD22 remains predominantly intracellular, associated with early markers like CD19 but preceding surface expression of CD20.^[12] Surface expression of CD22 emerges at the immature B-cell stage, coinciding with IgM expression, and persists at high levels through mature B-cell differentiation in the bone marrow and periphery.^[13] However, CD22 is absent on the surface of plasma cells and hematopoietic stem cells, marking a loss of expression upon terminal differentiation.^[11] In terms of tissue distribution, CD22 mRNA and protein levels are highest in B-lineage-rich lymphoid organs, including the spleen, lymph nodes, appendix, and bone marrow, where it is selectively expressed on subsets of lymphocytes.^[14] Data from comprehensive tissue profiling indicate CD22 expression across 159 human tissues, but it remains predominantly B-cell specific, with notably lower levels in peripheral blood B cells compared to those in secondary lymphoid tissues.^[15] In chronic lymphocytic leukemia (CLL), CD22 surface protein and mRNA are significantly downregulated on malignant B cells relative to normal counterparts.^[16] The spatiotemporal expression of CD22 is under transcriptional control, with the B-cell-specific coactivator BOB.1/OBF-1 playing a key role in repressing its levels during early development.^[17] In BOB.1/OBF.1-deficient models, surface CD22 expression is selectively upregulated on bone marrow B-lineage cells, highlighting its regulatory influence on CD22 during B-cell maturation.

Molecular Structure

Gene Organization

The CD22 gene is located on the long arm of human chromosome 19 at cytogenetic band 19q13.33, with genomic coordinates 35,319,261–35,347,361 on the forward strand (GRCh38 assembly), spanning approximately 28 kb.^[18] The gene consists of 15 exons in its originally described structure, with the first exon containing the major transcriptional start sites and exons 4–10 encoding the seven immunoglobulin-like domains of the protein.^[19] The canonical transcript (ENST00000341773) is protein-coding and includes 12 exons, though alternative splicing produces up to 40 transcripts. The mouse ortholog, Cd22, maps to chromosome 7 at position 30.56–30.58 Mb (GRCm39 assembly), spanning about 15 kb with transcripts containing up to 15 exons.^[20] There is high sequence conservation between human and mouse CD22, with approximately 60% amino acid identity in the protein, reflecting evolutionary preservation of key functional domains.^[21] The promoter region of CD22 lacks a TATA box but includes potential binding sites for transcription factors such as NF-κB, AP-1, and the B-cell-specific factor Oct-2 within 300 bp upstream of the transcription start sites; a 400-bp promoter fragment drives activity in B cells.^[22] Regulatory elements upstream include multiple Alu repetitive sequences, and B-cell-specific expression is maintained through lineage-restricted mechanisms, though the core promoter shows activity in both B and T cells in reporter assays.^[22] Polymorphisms in the CD22 gene, such as the c.2304C>A synonymous variant (exon 13) in Japanese populations, are associated with reduced surface CD22 expression on B cells and increased susceptibility to autoimmune conditions like systemic sclerosis.^[23] Evolutionarily, CD22 (Siglec-2) resides within a gene cluster on human chromosome 19q13 that includes other Siglec family members, such as myelin-associated glycoprotein (MAG/Siglec-4), highlighting a shared genomic organization among sialic acid-binding lectins involved in immune regulation.^[24] This clustering underscores the co-evolution of Siglecs in modulating leukocyte interactions.^[25]

Protein Domains

CD22 is a type I transmembrane glycoprotein expressed primarily on B cells, with a mature form exhibiting an apparent molecular weight of approximately 140 kDa due to extensive glycosylation.^[26] The human CD22 precursor protein consists of 847 amino acids, including a signal peptide of 19 residues that is cleaved to yield the mature polypeptide.^[27] The protein spans the membrane once, featuring an extracellular domain, a single transmembrane helix, and a cytoplasmic tail. The extracellular region comprises seven immunoglobulin-like (Ig-like) domains, numbered 1 through 7 (d1–d7), which adopt a rod-like conformation extending approximately 300 Å from the cell surface.^[26] Domains d1–d6 are primarily involved in ligand recognition and intermolecular interactions, while d7 is positioned closest to the membrane and contributes to structural proximity and stability. The d1 domain is of the V-set type, whereas d2 is C1-set, and d3–d7 are C2-set, with interdomain angles facilitating an extended architecture.^[26] This domain organization is conserved across species and essential for the protein's surface presentation. The cytoplasmic tail spans 141 amino acids and contains six conserved tyrosine residues (Y773, Y783, Y817, Y828, Y843, Y863 in mature numbering), which serve as phosphorylation sites for signaling regulation.^[28] Among these, three tyrosines (Y783, Y843, Y863) are embedded within canonical immunoreceptor tyrosine-based inhibitory motifs (ITIMs), while Y773 resides in an ITAM-like sequence.^[29] These motifs enable recruitment of SH2 domain-containing phosphatases upon tyrosine phosphorylation.^[28] Post-translational modifications significantly influence CD22's structure and function. The extracellular domain harbors 12 N-linked glycosylation sites, which contribute to the protein's mature mass and conformational integrity.^[26] Additionally, CD22 undergoes sialylation, primarily on its own glycans, which modulates its oligomeric state and domain accessibility.^[26]

Ligands and Binding

Extracellular Ligands

CD22's extracellular domain primarily recognizes α2,6-linked sialic acids present on various glycoproteins, enabling both cis and trans interactions that modulate B-cell function.^[9] In cis interactions, CD22 binds to sialylated glycans on the same B cell, including surface immunoglobulin M (sIgM) and the tyrosine phosphatase CD45, which are abundant self-ligands that maintain CD22 in a masked state on resting B cells.^[30] These cis ligands, along with other B-cell surface molecules bearing α2,6-sialylated N-acetyllactosamine structures, engage the V-set immunoglobulin domain of CD22, preventing excessive activation and ensuring dynamic regulation of receptor availability.^[26] In trans interactions, CD22 engages sialylated glycans on adjacent cells, facilitating homotypic binding between B cells or heterotypic interactions with T cells, erythrocytes, dendritic cells, and endothelial cells such as those in Peyer's patch high endothelial venules.^[9] These trans ligands allow CD22 to mediate cell-cell contacts, with multivalent sialylated antigens capable of overcoming cis masking to promote ligand engagement.^[30] The binding affinity of CD22 for α2,6-sialic acid ligands is moderate, with dissociation constants typically in the range of 100–300 μM for monovalent sialyllactose, primarily mediated by the V-set Ig domain.^[26] This relatively weak interaction, combined with cis ligand masking, ensures that CD22 remains poised for activation only upon high-avidity trans encounters. Functionally, these ligand interactions regulate B-cell homing to lymphoid tissues like the bone marrow and gut-associated structures, while also enabling contact-dependent inhibition of B-cell responses to maintain immune homeostasis.^[9] The specificity for α2,6-linked sialic acids, as opposed to α2,3-linkages, underpins these regulatory roles, with further details on recognition mechanisms addressed elsewhere.^[26]

Sialic Acid Recognition

CD22, as a member of the Siglec family of sialic acid-binding immunoglobulin-like lectins, recognizes sialic acids through a conserved binding pocket in its N-terminal V-set immunoglobulin-like domain (Ig domain 1).^[26] This domain features key arginine residues, notably Arg120, which forms a salt bridge with the negatively charged carboxylate group at the C1 position of sialic acid, stabilizing the interaction.^[26] Additional arginine residues, such as Arg131, contribute to the specificity by interacting with hydroxyl groups on the sialic acid, a signature mechanism shared across the Siglec family that ensures selective binding to sialylated glycans.^[26] These salt bridges are essential for the high-affinity recognition, with mutations in these arginines abolishing binding activity.^[26] Human CD22 exhibits a strong preference for α2,6-linked sialic acids over α2,3 linkages, driven by residues Tyr64 and Arg131 in the binding pocket that accommodate the axial orientation of the α2,6 glycosidic bond while causing steric clashes with the equatorial α2,3 configuration.^[26] It tolerates N-acetylneuraminic acid (Neu5Ac) as the primary sialic acid variant, with a binding affinity of approximately 281 μM, but shows reduced or no binding to other forms like N-glycolylneuraminic acid (Neu5Gc) or 9-O-acetylated sialic acids due to steric hindrance from Trp128.^[26] This selectivity underscores CD22's role in distinguishing subtle glycan differences on cell surfaces.^[31] Structural studies have elucidated these interactions through high-resolution crystal structures of the CD22 ectodomain. The unliganded structure (PDB: 5VKJ) reveals a preformed binding site in Ig domain 1, spanning the F, G, and C–C′ loop regions, while the liganded complex with α2,6-sialyllactose (PDB: 5VKM) shows minimal conformational changes upon binding, with a root-mean-square deviation of 0.35 Å for Cα atoms, indicating the site's readiness for ligand engagement without major unmasking.^[26] These structures highlight how the binding pocket's conserved arginine triad coordinates the sialic acid's carboxylate and hydroxyls, facilitating precise recognition.^[26] Sialidase enzymes modulate CD22's sialic acid recognition by cleaving terminal sialic acids from cis ligands on the same B-cell surface, thereby reducing competition and enhancing trans binding to sialylated ligands on opposing cells.^[32] This unmasking promotes stronger CD22-mediated interactions at immune synapses, amplifying inhibitory signaling thresholds during B-cell activation.^[33] In germinal center B-cells, sialidase activity leads to glycan remodeling, such as desulfation or sialic acid replacement, further boosting trans engagement and fine-tuning immune responses.^[32]

B-Cell Receptor Signaling

Inhibitory Functions

CD22 serves as an inhibitory coreceptor that negatively regulates B-cell receptor (BCR) signaling primarily through its intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Upon BCR crosslinking, Src family kinases phosphorylate the tyrosine residues within CD22's ITIMs, enabling the recruitment of the protein tyrosine phosphatase SHP-1 (PTPN6).^[34] SHP-1 then dephosphorylates key BCR signaling components, such as the ITAMs on Igα (CD79a) and Igβ (CD79b), thereby attenuating downstream signal transduction.^[35] This phosphatase recruitment is essential for CD22's suppressive role, as demonstrated by studies showing that mutations in CD22 ITIMs abolish SHP-1 binding and inhibitory function.^[36] By dampening BCR signaling, CD22 reduces calcium influx and activation of the extracellular signal-regulated kinase (ERK) pathway in B cells.^[2] These effects limit B-cell proliferation and antibody production in response to antigenic stimulation, preventing excessive immune responses.^[37] For instance, CD22-mediated inhibition modulates the strength of BCR-induced signals to maintain appropriate activation thresholds during antigen encounter.^[38] CD22 plays a critical role in setting the signaling threshold for B-cell activation, thereby promoting anergy in response to self-antigens and avoiding hyperactivation.^[39] Defects in CD22 function disrupt this balance, leading to enhanced BCR responsiveness. Experimental evidence from CD22 knockout mice reveals heightened calcium mobilization, increased proliferation, and spontaneous autoantibody production, culminating in autoimmune phenotypes.^[40]

Activating Functions

While primarily recognized for its inhibitory roles, CD22 also exerts positive regulatory effects on B-cell signaling through specific motifs in its cytoplasmic tail, which contains ITIMs alongside ITAM-like sequences capable of recruiting stimulatory effectors.^[41] Upon B-cell receptor (BCR) engagement, the Src family kinase Lyn phosphorylates tyrosine residues within these ITAM-like motifs of CD22, such as the YXXM sequence at position 828 in mice (Y807 in humans), enabling the recruitment of downstream signaling molecules that promote cell survival.^[42] This phosphorylation event activates the PI3K pathway by binding the p85 regulatory subunit of PI3K, leading to the production of PIP3 and subsequent activation of Akt, which delivers anti-apoptotic signals essential for B-cell survival during development and activation.^[43] In addition to PI3K, phosphorylated CD22 interacts with adapter proteins that further modulate positive signaling outcomes. These include Grb2 and SHC1, which form complexes to link CD22 to the Ras-MAPK pathway, enhancing proliferation and cytoskeletal reorganization in response to BCR stimulation, as demonstrated in studies of tyrosine-phosphorylated CD22 immunoprecipitates from activated B cells.^[44] CD22 also binds INPP5D (SHIP), which, in certain contexts, fine-tunes lipid signaling by hydrolyzing PIP3 to PIP2, thereby influencing actin cytoskeleton dynamics and supporting B-cell migration and adhesion without fully abrogating survival signals.^[44] These adapter interactions collectively amplify BCR co-stimulation, contributing to robust B-cell responses. The activating functions of CD22 are highly context-dependent, often triggered by the dissociation of its sialic acid ligands, which unmasks the receptor and allows its closer association with the BCR for enhanced signaling.^[45] For instance, in germinal center B cells, ligand unmasking facilitates CD22-mediated co-stimulation, promoting proliferation and differentiation in response to antigenic challenge.^[41] Experimental evidence from CD22 mutants supports this role; disruption of the ITAM-like motifs, such as through tyrosine-to-phenylalanine substitutions, impairs B-cell maturation and the formation of memory precursors, as observed in transgenic models where such mutations lead to reduced survival and developmental progression in the spleen.^[46]

Physiological Roles

Immune Regulation

CD22 plays a crucial role in maintaining immune homeostasis by setting activation thresholds for B cells, thereby preventing autoimmunity through the inhibition of responses to self-antigens. As an inhibitory co-receptor of the B-cell receptor (BCR), CD22 recruits phosphatases such as SHP-1 upon ligand binding, dampening BCR signaling and reducing the activation of autoreactive B cells.^[39] In CD22-deficient models, this regulatory function is lost, leading to heightened B-cell responsiveness and predisposition to autoimmune conditions, underscoring CD22's essential role in establishing tolerance to self-antigens.^[2] In addition to its signaling roles, CD22 facilitates B-cell trafficking to specific lymphoid tissues, promoting homing to Peyer's patches in the gut via interactions with sialic acid ligands on endothelial cells. The extracellular domain of CD22 binds α2,6-linked sialic acids on vascular endothelium, guiding mature B cells to mucosal sites for immune surveillance and response initiation.^[47] This lectin-mediated homing mechanism ensures efficient B-cell positioning in gut-associated lymphoid tissue, supporting localized immune regulation without excessive systemic activation.^[48] CD22 also fine-tunes humoral immunity by modulating antibody responses to T-dependent antigens, balancing the magnitude and duration of germinal center reactions. Through its inhibitory effects on BCR and CD19 signaling, CD22 prevents overactivation during T cell-dependent responses, allowing for optimal affinity maturation and plasma cell differentiation while avoiding hyperresponsiveness.^[41] This regulatory input helps maintain controlled production of high-affinity antibodies, contributing to effective yet restrained adaptive immunity. Beyond peripheral B-cell functions, CD22 influences neuroimmune regulation in the aging brain by modulating microglial phagocytosis, where its upregulation impairs homeostatic clearance of debris and synapses. In aged microglia, elevated CD22 expression acts as a negative regulator, reducing phagocytic activity and linking to age-related neuroinflammation and cognitive decline.^[49] Blocking CD22 in these contexts restores phagocytic function, highlighting its role in balancing neuroimmune homeostasis during senescence.^[50]

B-Cell Development and Trafficking

Surface expression of CD22 first appears at low levels on immature B cells in the bone marrow, where it modulates B cell receptor (BCR) signaling thresholds through its inhibitory function.^[2] Beyond development, CD22 facilitates B cell trafficking by providing homing signals through sialic acid-mediated adhesion to endothelial cells. Specifically, CD22 recognizes α2,6-linked sialic acid ligands on sinusoidal endothelial cells in the bone marrow and high endothelial venules (HEVs) in lymphoid organs such as Peyer's patches, promoting the entry and retention of recirculating B cells.^[51]^[41] This adhesion mechanism supports the migration of mature B cells back to the bone marrow for long-term survival and to gut-associated lymphoid tissues (GALT) for mucosal immunity.^[41] Studies in CD22-deficient mice provide key evidence for these roles, revealing altered B cell distribution with a marked reduction in recirculating mature B cells in the bone marrow and impaired homing to GALT, including defective formation and B cell accumulation in Peyer's patches.^[52]^[41] These phenotypes underscore CD22's importance in maintaining proper B cell compartmentalization across lymphoid compartments.^[41] CD22's adhesive functions integrate with chemokine receptor signaling to coordinate B cell positioning, enhancing CXCR5-dependent migration and entry into B cell follicles within secondary lymphoid organs.^[41] This synergy ensures efficient follicular localization for antigen encounter and immune responses.^[41]

Pathological Implications

In Autoimmunity

CD22 plays a critical role in maintaining B-cell tolerance, and its dysregulation contributes to the pathogenesis of autoimmune diseases through impaired inhibitory signaling. In autoimmunity, reduced CD22 function diminishes the recruitment of protein tyrosine phosphatases like SHP-1 to immunoreceptor tyrosine-based inhibitory motifs (ITIMs), leading to unchecked B-cell receptor (BCR) activation, enhanced B-cell survival, and increased production of autoantibodies.^[41] This hyperactivation disrupts immune homeostasis, promoting self-reactive B-cell expansion and chronic inflammation characteristic of conditions such as systemic lupus erythematosus (SLE).^[9] Genetic variants in the CD22 gene have been linked to altered protein function and increased susceptibility to specific autoimmune disorders. For instance, the Q152E missense variant in the extracellular domain of CD22 introduces a charge change that may affect protein stability or ligand interactions, though studies have not confirmed it as a major risk factor for SLE in humans.^[53] In cutaneous systemic sclerosis (SSc), the synonymous polymorphism rs34826052 (c.2304C>A, p.P768P) is associated with disease susceptibility, particularly the limited cutaneous subtype, and correlates with decreased CD22 surface expression on B cells, potentially exacerbating B-cell hyperactivity and autoantibody production.^[54] These variants highlight how subtle changes in CD22 can lower the threshold for B-cell activation in fibrotic autoimmune conditions. Mutations in the sialic acid acetylesterase (SIAE) gene, which generates 9-O-acetylated sialic acid ligands essential for CD22 binding, further impair CD22-mediated inhibition and are implicated in multiple autoimmune diseases. Rare loss-of-function SIAE variants reduce ligand availability, leading to diminished ITIM signaling and B-cell hyperresponsiveness; such mutations occur at higher frequency in patients with SLE, rheumatoid arthritis (RA), and primary biliary cholangitis (PBC) compared to healthy controls. In RA, these defects contribute to synovial B-cell accumulation and autoantibody-driven joint inflammation, while in PBC, SIAE variants associate with cholestatic liver autoimmunity through dysregulated B-cell responses against biliary epitopes.^[55] Overall, SIAE alterations underscore the importance of the CD22-sialic acid axis in preventing autoimmunity across diverse tissues. Therapeutic strategies targeting CD22 aim to restore its inhibitory function and have been investigated in preclinical and early clinical studies for autoimmune diseases. The monoclonal antibody epratuzumab engages CD22 on B cells, promoting trogocytosis of BCR-associated proteins and modulating signaling to reduce B-cell activation without depletion; however, the phase 3 EMBODY trials failed to meet primary endpoints for efficacy in reducing SLE disease activity.^[56] As of 2025, development of epratuzumab for SLE has been discontinued. Additionally, synthetic sialoside agonists that bind CD22 with high affinity (e.g., GSC718, GSC839) have been explored to enhance inhibitory signaling by mimicking endogenous ligands, suppressing autoreactive B-cell proliferation in models of autoimmunity while sparing normal responses.^[57] These approaches, with sialosides remaining in preclinical stages as of 2025, highlight the potential of CD22 activation in re-establishing tolerance in SLE and related conditions.

In Malignancies

CD22 is expressed on the surface of malignant B cells in a variety of hematologic malignancies, including non-Hodgkin lymphomas (NHL) and B-cell acute lymphoblastic leukemia (B-ALL). In NHL subtypes such as follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma, CD22 demonstrates strong and consistent expression across tumor cells, making it a viable therapeutic target. Similarly, in B-ALL, CD22 is present on 60–90% of cases, with expression levels often exceeding 90% of blasts in a significant proportion of patients, and it tends to be more uniformly retained on leukemic cells compared to CD19, which can be lost in up to 10–20% of relapses following CD19-targeted therapies. This retention positions CD22 as a complementary antigen in cases of antigen escape.^[58]^[59]^[60] In chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL), CD22 expression is also prevalent but can exhibit functional alterations that contribute to disease progression. Reduced surface sialylation of CD22 or its ligands may diminish cis-interactions that normally inhibit B-cell receptor (BCR) signaling, potentially unmasking activating pathways and enhancing survival signals in these malignancies; for instance, modifications such as 9-O-acetylation of sialic acids impair CD22 ligand binding, which has been linked to leukemia progression. In CLL specifically, CD22 levels are often downregulated at both the mRNA and protein levels compared to normal B cells, correlating with disease advancement. These changes highlight how dysregulated glycosylation influences CD22's inhibitory role, promoting aberrant B-cell survival in the tumor microenvironment.^[26]^[16] The prognostic implications of CD22 expression vary across B-cell malignancies. High CD22 expression has been associated with poorer outcomes in certain aggressive B-cell leukemias, potentially reflecting a more mature or resistant phenotype, while in CLL, downregulation of CD22 during progression predicts worse survival, particularly in IGHV-mutated subtypes. For example, low CD22 mRNA levels negatively correlate with prognosis in CLL patients. Recent studies from 2024 underscore the value of dual CD19/CD22 targeting to mitigate antigen escape; in relapsed/refractory B-ALL, allogeneic bispecific CD19/CD22 CAR T-cell therapy achieved durable complete remissions in treated patients, demonstrating prevention of relapse through combined antigen engagement. These findings emphasize CD22's role as both a biomarker and strategic target in risk stratification and management of B-cell cancers.^[61]^[16]^[62]

Therapeutic Applications

Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) and immunotoxins targeting CD22 represent a targeted approach to deliver cytotoxic payloads directly to malignant B cells expressing this antigen, which is prevalent in various B-cell malignancies such as acute lymphoblastic leukemia (ALL) and hairy cell leukemia.^[63] These agents leverage the specificity of anti-CD22 antibodies to internalize toxins, minimizing off-target effects compared to traditional chemotherapy.^[64] Inotuzumab ozogamicin is a humanized IgG4 anti-CD22 monoclonal antibody conjugated to the calicheamicin derivative N-acetyl-γ-calicheamicin via an acid-labile linker.^[64] Upon binding to CD22 on the cell surface, the conjugate is internalized into lysosomes, where the linker cleaves to release the calicheamicin payload, which binds the minor groove of DNA and induces double-strand breaks, leading to apoptosis.^[65] The U.S. Food and Drug Administration (FDA) approved inotuzumab ozogamicin in 2017 for adults with relapsed or refractory B-cell precursor ALL, with expanded approval in 2024 for pediatric patients aged 1 year and older.^[63]^[66] Moxetumomab pasudotox is a recombinant immunotoxin consisting of the Fv portion of an anti-CD22 antibody fused to a truncated form of Pseudomonas exotoxin A (PE38).^[67] It binds CD22, undergoes receptor-mediated endocytosis, and translocates to the endoplasmic reticulum, where the exotoxin inhibits protein synthesis by ADP-ribosylating elongation factor 2, ultimately triggering caspase-mediated apoptosis.^[68] The FDA granted accelerated approval to moxetumomab pasudotox in 2018 for adults with relapsed or refractory hairy cell leukemia after at least two prior systemic therapies, though commercial availability was discontinued in 2023 for non-safety reasons.^[69]^[70] In clinical trials, inotuzumab ozogamicin has demonstrated significant efficacy in relapsed or refractory B-ALL, with the pivotal INO-VATE phase 3 trial reporting a complete remission or complete remission with incomplete hematologic recovery rate of 80.7% compared to 29.4% with standard chemotherapy.^[63] This improvement in response rates translated to better overall survival, though common adverse effects include hepatotoxicity (such as sinusoidal obstruction syndrome) and myelosuppression (e.g., thrombocytopenia, neutropenia, and anemia).^[66]^[71] Prior to 2025, inotuzumab ozogamicin has been evaluated in expanded clinical trials for non-Hodgkin lymphoma, including phase 2 studies in combination with rituximab showing objective response rates around 87% in follicular lymphoma, though a phase 3 trial in aggressive non-Hodgkin lymphoma was discontinued due to futility.^[72]^[73]

CAR-T and Other Immunotherapies

CD22-targeted chimeric antigen receptor (CAR) T-cell therapy represents a promising adoptive cellular immunotherapy for B-cell malignancies, where CAR constructs incorporate single-chain variable fragments (scFv) derived from monoclonal antibodies specific to CD22 to redirect T cells against tumor cells expressing this antigen.^[74] Standalone CD22 CAR-T cells, such as the fully human CD22.BB.z construct featuring an anti-CD22 scFv linked to a 4-1BB costimulatory domain, have demonstrated durable clinical activity in relapsed or refractory large B-cell lymphomas, with phase I trials reporting complete responses in a subset of patients.^[75] To address antigen escape and relapse commonly observed with CD19-directed therapies, tandem or dual CD19/CD22 CAR-T approaches have been developed, either as sequential administration or co-expression in a single construct, showing improved long-term survival in post-hematopoietic stem cell transplant relapsed B-acute lymphoblastic leukemia (B-ALL), with five-year outcomes indicating superior event-free survival compared to CD19 monotherapy.^[76] Recent advances in 2024–2025 have focused on optimizing dual-targeting designs to enhance efficacy and persistence. A novel loop-structure-based bispecific CD19/CD22 CAR-T (BS LoopCAR-T) has shown safety and effectiveness in high-risk diffuse large B-cell lymphoma (DLBCL) patients with hemophagocytic lymphohistiocytic syndrome, achieving high response rates with manageable cytokine release syndrome.^[77] At the ESMO Congress in October 2025, CAR2119, a dual-targeting CD19/CD22 CAR-T, demonstrated a 100% overall response rate in patients with relapsed/refractory LBCL following standard first-line therapy.^[78] In B-ALL trials, these dual CAR-T constructs have reported improved complete remission rates, particularly in minimal residual disease-positive cases, by mitigating single-antigen loss.^[79] Preclinically, single-domain antibody (sdAb)-based CD22 CAR-T derived from llama immunization has exhibited potent antitumor activity in Jurkat cell models and primary T cells, with hinge and transmembrane optimizations enhancing specificity and reducing off-target effects independent of affinity variations.^[80] Beyond CAR-T, other immunotherapies leverage CD22 for immune redirection or modulation. Bispecific T-cell engagers (BiTEs) targeting CD22 and CD3, such as novel constructs with in vitro cytotoxicity against CD22-positive cells, have demonstrated synergistic activity with CD19-directed BiTEs like blinatumomab in preclinical models of acute lymphoblastic leukemia, promoting T-cell-mediated tumor lysis without excessive cytokine release.^[81] Siglec agonists, including cis-binding synthetic glycopolypeptides that engage CD22 on B cells, offer a modulatory approach by inducing inhibitory signaling to suppress aberrant B-cell activation, with potential applications in controlling B-cell hyperactivity in malignancies through targeted sialic acid mimicry.^[82] Key challenges in CD22-targeted immunotherapies include variability in antigen density on tumor cells, which can diminish CAR-T potency and lead to incomplete responses, as lower CD22 expression correlates with reduced T-cell activation and persistence in preclinical and clinical settings.^[83] Ongoing phase II and III trials are evaluating CD22 CAR-T and dual constructs in refractory lymphomas, aiming to refine dosing and combination strategies to overcome these hurdles and expand applicability in CD22-expressing B-cell cancers.^[79]

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[12]
CD22 - an overview | ScienceDirect Topics
CD22 is defined as a B cell-specific glycoprotein that acts as an inhibitory receptor, enhancing the threshold of B cell receptor (BCR) induced signals and ...
[13]
CD22 is expressed on B cell progenitors prior to IgM
CD22– early pro-B cells, B220. 1. CD43. 1. CD22lo late pro-B cells and. B220. 1. CD43–CD22lo pre-B cells. The expression of CD22 on IgM. 1 bone marrow cells was.
[14]
Tissue expression of CD22 - Summary - The Human Protein Atlas
Summary of CD22 (SIGLEC-2, SIGLEC2) expression in human tissue. High and selective cytoplasmic expression in subsets of lymphocytes.
[15]
CD22 Gene - GeneCards | CD22 Protein | CD22 Antibody
Summaries for CD22 Gene. NCBI Gene Summary for CD22 Gene. Predicted to enable CD4 receptor binding activity; protein phosphatase binding activity; and sialic ...
[16]
Insights into the transcriptional regulation of CD22 in B cell chronic ...
In this study, we confirmed that the surface CD22 protein and its mRNA are downregulated in the B cells of CLL patients.
[17]
CD22 regulates early B cell development in BOB.1/OBF.1-deficient ...
We therefore investigated whether defects in B cell development in the BOB.1/OBF.1-deficient mice might be due to CD22 up-regulation. Mice were generated ...
[18]
https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000012124
[19]
Genomic structure and chromosomal mapping of the human CD22 ...
The CD22 gene is spread over 22 kb of DNA and is composed of 15 exons. The first exon contains the major transcriptional start sites. The translation initiation ...
[20]
https://www.ensembl.org/Mus_musculus/Gene/Summary?g=ENSMUSG00000030577
[21]
Human CD22 cannot fully substitute murine CD22 functions in vivo ...
Sep 11, 2012 · The murine CD22 and the human CD22 protein share about 60% sequence homology. The human CD22 gene is located on chromosome 19 in the human ...Missing: conservation | Show results with:conservation
[22]
Genomic structure and chromosomal mapping of the human CD22 ...
Jun 1, 1993 · Exons 4 to 10 encode the seven Ig domains of CD22, exon 11 encodes the transmembrane domain, exons 12 to 15 encode the intracytoplasmic domain ...
[23]
Association of CD22 gene polymorphism with susceptibility to ...
Feb 22, 2007 · Surface expression level of CD22 tended to be lower in B cells from the patients with A/A genotype (n = 5) as compared with C/A (n = 7) or C/C ( ...Missing: expression | Show results with:expression
[24]
Siglecs—the major subfamily of I-type lectins - Oxford Academic
In the human genome, the gene for Sn/Siglec-1 is located on chromosome 20, and the genes for CD22/Siglec-2 and MAG/Siglec-4 are located next to each other on ...
[25]
Targeting the Siglec–Sialic Acid Immune Axis in Cancer - NIH
In humans, SIGLEC1 is located on chromosome 20, SIGLEC2 and SIGLEC4 are near each other on chromosome 19, and the majority of the CD33-related Siglecs are ...
[26]
Molecular basis of human CD22 function and therapeutic targeting
Oct 2, 2017 · As a B-cell-restricted antigen, CD22 is targeted in therapies against dysregulated B cells that cause autoimmune diseases and blood cancers.Results · Cd22 Specificity For α2-6... · The Cd22 Ectodomain Adopts A...
[27]
B-cell receptor CD22 - Homo sapiens (Human) | UniProtKB | UniProt
Jul 15, 1999 · Most highly expressed siglec (sialic acid-binding immunoglobulin-like lectin) on B-cells that plays a role in various aspects of B-cell biology.
[28]
Analysis of Tyrosine Phosphorylation-dependent Interactions ...
The results obtained indicate that the three distal tyrosine residues in the cytoplasmic domain of CD22 are involved in the recruitment of stimulatory effector ...
[29]
CD22 Regulates B Cell Receptor-mediated Signals via Two ...
The Two Carboxyl-terminal ITIM Tyrosines Are Required for Recruitment of SHP-1. The cytoplasmic tail of CD22 contains six conserved tyrosine residues and ...<|control11|><|separator|>
[30]
Sialylated multivalent antigens engage CD22 in trans and inhibit B ...
Feb 24, 2009 · We reasoned that a sialylated antigen like 3 could bind CD22 because interactions between CD22 and its cis ligands are weak. Indeed, the ...
[31]
Siglecs and their roles in the immune system - Nature
Discovery of Siglec-14, a novel sialic acid ... Masking and unmasking of the sialic acid-binding lectin activity of CD22 (Siglec-2) on B lymphocytes.
[32]
https://www.jbc.org/article/S0021-9258(20)39515-6/fulltext
[33]
Sialylated multivalent antigens engage CD22 in trans and inhibit B ...
Feb 24, 2009 · Together, these results indicate trans interactions with CD22 suppress antigen-initiated B cell activation. ... J Biol Chem 260, 3440–3450 (1985).
[34]
A role in B cell activation for CD22 and the protein tyrosine ...
Tyrosine-phosphorylated CD22 binds and activates SHP, a protein tyrosine phosphatase known to negatively regulate signaling through mIg.Missing: ITIM paper
[35]
CD22 ligand-binding and signaling domains reciprocally regulate B ...
Jul 8, 2013 · We show that cis-ligand binding of CD22 is crucial for the regulation of B-cell Ca 2+ signaling by controlling the CD22 association to the BCR.
[36]
The inhibitory coreceptor CD22 restores B cell signaling by ...
Mar 1, 2022 · CD22 reduces BCR signaling by recruiting Src homology 2 (SH2) domain–containing protein tyrosine phosphatase 1 (SHP-1) to the ITIMs. CD22 ...
[37]
CD22 and Siglec-G in B cell function and tolerance - PubMed Central
Jun 5, 2012 · CD22 is a B cell-restricted surface protein that modulates BCR signal transduction in mature B cells [24].Cd22 And Siglec-G In B Cell... · Transmembrane Signaling · Cd22 And Siglec-G May...
[38]
Deficiency in CD22, a B Cell–specific Inhibitory Receptor, Is ...
The development of autoantibodies in CD22-deficient mice reveals that a single gene defect exclusive to B cells is sufficient to trigger autoimmunity in a large ...Missing: knockout | Show results with:knockout
[39]
CD22: A Regulator of Innate and Adaptive B Cell Responses ... - PMC
CD22 (Siglec 2) is a receptor predominantly restricted to B cells. It was initially characterized over 30 years ago and named “CD22” in 1984.
[40]
https://rupress.org/jem/article/189/8/1307/25640/Deficiency-in-CD22-a-B-Cell-specific-Inhibitory
[41]
https://pmc.ncbi.nlm.nih.gov/articles/PMC6173129/
[42]
https://doi.org/10.1074/jbc.274.26.18769
[43]
https://doi.org/10.1074/jbc.M105446200
[44]
https://doi.org/10.1074/jbc.M001892200
[45]
Siglec regulation of immune cell function in disease - PubMed Central
A recent report demonstrates that trans ligands of CD22 on blood vessel endothelial cells are involved in trafficking of mature B cells to Peyer's patches.
[46]
Transcriptional programs of lymphoid tissue capillary and high ...
We also elucidate a carbohydrate recognition pathway that targets B cells to intestinal lymphoid tissues, defining CD22 as a lectin-homing receptor for mucosal ...
[47]
Age-dependent Microglial Disease Phenotype Results in Functional ...
Increased CD22 expression in the microglia of geriatric mice results in impairment of their homeostatic phagocytic function.Flow Cytometry And... · Figure 1 · Figure 3
[48]
Phagocytic microglia and macrophages in brain injury and repair
Jun 25, 2022 · For example, CD22 (Siglec 2) is a negative regulator of phagocytosis and its expression is upregulated on aged microglia. 86 , 87 CD22 also ...
[49]
Identification of CD22 Ligands on Bone Marrow Sinusoidal ...
Using a soluble recombinant form of the receptor (CD22-Fc), we demonstrate here that sialylated ligands for CD22 are expressed on sinusoidal endothelial cells ...
[50]
Identification of CD22 Ligands on Bone Marrow Sinusoidal ... - NIH
CD22 is a B cell–specific transmembrane protein known to function as a negative regulator of B cell signaling. It has also been implicated in cell adhesion ...
[51]
Identification of the gene variations in human CD22 - PubMed
No significant association was observed between any of the variations and RA. These findings indicate that a number of genetic variants are present in CD22, and ...
[52]
Associations of genetic polymorphisms of Siglecs with human ...
The authors demonstrated that this polymorphism is correlated with reduced expression of CD22/Siglec-2 protein on B cells (Hitomi et al. 2007) (Figure. 1B).Cd33/siglec-3 And... · Cd22/siglec-2 And... · Cd22/siglec-2 And Infantile...Missing: variability | Show results with:variability
[53]
Association of primary biliary cirrhosis with variants in the CLEC16A ...
Jan 19, 2012 · Functionally deleterious SIAE gene mutations and PBC. To assess whether SIAE gene variants are relevant to risk for PBC, we resequenced all ...
[54]
Targeting CD22 with the monoclonal antibody epratuzumab ...
May 15, 2017 · Abnormal B-cell activation is implicated in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE).
[55]
CD22-Binding Synthetic Sialosides Regulate B Lymphocyte ...
CD22 (also known as Siglec-2) is an inhibitory molecule preferentially expressed in B lymphocytes (B cells) and is constitutively bound and functionally ...<|control11|><|separator|>
[56]
Targeting CD22 for the Treatment of B-Cell Malignancies - PMC - NIH
Jul 6, 2021 · CD22 is an attractive target for B-cell malignancies given its strong expression in the majority of B-lymphoid cells. Mechanisms for CD22 ...Missing: pattern | Show results with:pattern
[57]
CD22 Expression in B-Cell Acute Lymphoblastic Leukemia - MDPI
As is well known, CD22 is expressed by most blasts from the majority (60–90%) of B-cell malignancies. In the Inovate study, CD22 was expressed in >90% of B-ALL ...Cd22 Expression In B-Cell... · 1. B-Cell Acute... · 2. Cd22 Molecule And...
[58]
Characterization of CD22 Expression in Acute Lymphoblastic ... - NIH
The levels of sCD22 were low in both blood and marrow (median 4.2 ng/ml and 0.28 ng/mL respectively. All samples were <40 ng/ml, which is well below the ...
[59]
CD22 Exon 12 Deletion as an Independent Predictor of Poor ...
Our findings provide the first evidence that CD22 exon 12 deletion is associated with a poor treatment outcome in B-ALL.
[60]
Allogeneic CD19/CD22 CAR T-Cell Therapy for B-Cell Acute ...
Apr 18, 2024 · We report durable remissions in 2 patients with relapsed/refractory B-cell ALL treated with allogeneic bispecific CD19/CD22-targeting CAR T cells.
[61]
Inotuzumab ozogamicin for the treatment of acute lymphoblastic ...
Inotuzumab ozogamicin is an anti-CD22 antibody–drug conjugate approved for the treatment of relapsed or refractory B-cell precursor ALL. It improved outcomes ...
[62]
Antitumor Efficacy of a Combination of CMC-544 (Inotuzumab ...
CMC-544 (inotuzumab ozogamicin) is a CD22-targeted cytotoxic agent composed of a humanized IgG4 anti-CD22 antibody covalently linked to N-acetyl-γ-calicheamicin ...
[63]
Inotuzumab ozogamicin: Uses, Interactions, Mechanism of Action
May 18, 2024 · N-acetyl-gamma-calicheamicin binds to the minor groove of the DNA in a sequence-specific manner and induces double-strand DNA breaks in tumour ...Identification · Pharmacology · Interactions · References
[64]
FDA approves inotuzumab ozogamicin for pediatric patients with ...
Mar 6, 2024 · The most common adverse reactions (≥20%), including laboratory abnormalities, were thrombocytopenia, pyrexia, anemia, vomiting, infection, ...
[65]
Moxetumomab Pasudotox: First Global Approval | Drugs
Oct 24, 2018 · The Fv portion of moxetumomab pasudotox binds to CD22, a cell surface receptor expressed on a variety of malignant B-cells, thereby delivering ...
[66]
Moxetumomab pasudotox: Uses, Interactions, Mechanism of Action
This toxin inhibits protein translation which induces an apoptotic state of the high CD22-expressed cancer cell. The toxin included in MxP is the Pseudomonas ...
[67]
Results from an international phase 2 study of the anti-CD22 ...
Moxetumomab pasudotox was approved by the FDA for the treatment of hairy cell leukemia (HCL) based on results from a pivotal phase 3 study. Toxicities unique to ...
[68]
AstraZeneca to Discontinue Moxetumomab Pasudotox in US for ...
Jan 13, 2023 · The 2018 FDA approval of moxetumomab pasudotox was based on findings from a pivotal phase 3 trial (NCT01829711) that showed the CD22-directed ...
[69]
Inotuzumab ozogamicin for the treatment of adult acute ...
May 11, 2024 · INO improved response rates and survival in a randomized study in adults with relapsed/refractory B-cell ALL, leading to its regulatory approval ...
[70]
Inotuzumab ozogamicin in clinical development for acute ... - NIH
Apr 11, 2019 · Clinical trials of inotuzumab ozogamicin in NHL Preclinical Studies confirmed the potency and dose-dependent cytotoxicity of INO on CD22 ...
[71]
Randomized, phase 3 trial of inotuzumab ozogamicin plus rituximab ...
May 20, 2014 · Treatment-related death occurred in 6 pts (4 R-InO, 2 IC). Among R-InO vs IC pts, 28% vs 15% discontinued due to AEs; 53% vs 57% due to PD.
[72]
CD22-targeted chimeric antigen receptor-modified T cells ... - PubMed
Apr 17, 2025 · We tested a novel, fully human anti-CD22/4-1BB CAR T-cell construct, CART22-65s, in parallel phase I studies for pediatric and adult B-ALL.
[73]
Five-year outcome of CD19 followed by CD22 chimeric antigen ...
Our study revealed that, in post-HCT relapsed B-ALL patients, the combination of CD19 and CD22 CAR T-cell therapy significantly improved long-term survival.
[74]
Novel Loop-Structure-Based CD19/CD22 Dual-Target CAR-T First ...
Jul 15, 2025 · The novel CD19/CD22 BS LoopCAR-T therapy is safe and effective in treating high-risk DLBCL patients presenting with HLH.
[75]
Dual-targeting CAR T cells for B-cell acute lymphoblastic leukemia ...
Feb 12, 2025 · One of the main strategies to avoid CD19-negative relapse has been the development of dual CAR T cells targeting CD19 and an additional target, ...
[76]
Discovery and preclinical development of a therapeutically active ...
Mar 21, 2024 · We sought to identify a therapeutically active sdAb-CAR targeting human CD22. Immunization of an adult Llama glama with CD22 protein, sdAb-cDNA library ...
[77]
A Novel bispecific T-cell engager (BiTE) targeting CD22 and CD3 ...
We report here the development of a new BiTE with cytotoxic activity against CD22 + cells which could represent an alternate or complementary therapeutic ...
[78]
Modulation of immune cell reactivity with cis-binding Siglec agonists
Jan 11, 2021 · This approach has been explored to achieve B cell suppression in lupus patients by agonism of CD22 (Siglec-2) (11, 12), and to deplete ...
[79]
Modulation of Target Antigen Density Improves CAR T-cell ...
Chimeric antigen receptor T-cell (CART) therapy targeting CD22 induces remission in 70% of patients with relapsed/refractory acute lymphoblastic leukemia ...