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CD52

CD52 is a small (GPI)-anchored , also known as the Campath-1 antigen, encoded by the CD52 gene located on 1p36.11 in humans. Consisting of a core of just 12 that is heavily glycosylated, CD52 is tethered to the outer leaflet of the plasma membrane via its GPI anchor at the . CD52 is predominantly expressed on the surface of mature immune cells, including T lymphocytes, B lymphocytes, natural killer (NK) cells, monocytes, dendritic cells, and , with lower levels on granulocytes. It is notably absent from hematopoietic stem cells, progenitor cells, erythrocytes, and platelets. Beyond the , CD52 is found on epithelial cells of the male reproductive tract, such as those in the and , as well as on mature spermatozoa, where it contributes to reproductive processes. Functionally, CD52 plays a role in immune regulation, including the positive modulation of cytosolic calcium ion concentrations in cells and facilitating transendothelial migration. It supports + T-cell , activation, and , while its soluble form (sCD52) exerts effects by binding to the inhibitory receptor Siglec-10 on immune cells, thereby suppressing T-cell activation and broader inflammatory responses. In pathological contexts, CD52 expression is elevated in certain malignancies, such as (CLL), where sCD52 serves as a potential . Clinically, CD52 has gained prominence as a therapeutic target due to its restricted expression on mature lymphocytes, enabling selective immune cell depletion. The (anti-CD52) binds to CD52 on target cells, triggering (ADCC), (CDC), and , which profoundly reduces autoreactive T and B cells. This mechanism underpins its approval for treating relapsing-remitting (RRMS) and B-cell CLL, though it carries risks of prolonged and secondary . Ongoing research also explores CD52's prognostic value in cancers like and , where its expression correlates with immune infiltration and response to .

Genetics and Structure

Gene

The CD52 is located on the short arm of at position 1p36.11, spanning the genomic coordinates 26,317,958 to 26,320,523 on the forward strand in the GRCh38.p14 assembly. This region encompasses approximately 2.57 kilobases, and the is classified as protein-coding, producing the precursor for the CAMPATH-1 , a (GPI)-anchored . The CD52 gene consists of two exons separated by a single intron, with exon 1 encoding the first 18 amino acids of the signal peptide and exon 2 encoding the remaining 6 amino acids of the signal peptide, the 12-amino-acid mature peptide, and the GPI anchor signal sequence. The primary transcript, NM_001803.3, is a validated reference sequence that spans both exons and translates into a 61-amino-acid precursor protein (NP_001794.2), which undergoes post-translational processing to yield the mature CD52 antigen. Alternative splicing yields three transcripts in total, though NM_001803.3 represents the canonical form associated with the full-length protein. CD52 was identified in the 1980s through the development of monoclonal antibodies (CAMPATH-1 series) targeting lymphocytes for potential therapy, with the gene cloned in 1991 from a B-lymphocyte tumor , revealing its sequence as the CAMPATH-1 . The gene exhibits strong evolutionary conservation, with 55 orthologs identified across vertebrates, reflecting its role in a highly preserved family of GPI-anchored proteins, including close in mice and s where the exon-intron organization is maintained. Known polymorphisms include two common alleles differing at codons 40 and 41—rs1071849 (A119G; p.Asn40Ser) and rs17645 (A123G; p.Ile41Met)—which can influence GPI anchor efficiency and antibody recognition by therapeutics like , with the Ser40/Met41 variant showing reduced binding affinity in some populations.

Protein Structure

CD52 is a small glycoprotein characterized by a mature peptide core of 12 amino acids with the sequence Gly-Gln-Asn-Asp-Thr-Ser-Gln-Thr-Ser-Ser-Pro-Ser (GQNDTSQTSSPS), following cleavage of the N-terminal signal peptide and attachment of the C-terminal GPI anchor. An allelic variant has been identified in which the C-terminal serine (Ser12) is substituted with alanine, resulting in a minor species with a molecular mass of approximately 2933.5 Da. This primary structure is highly conserved, with the asparagine at position 3 (Asn3) serving as the key site for post-translational modification. The protein undergoes extensive N-linked at Asn3, featuring a large, complex tetraantennary that is core-fucosylated and enriched in polylactosamine repeats. This , which is heavily sialylated with predominantly α2-6-linked sialic acids and some α2-3 linkages, contributes significantly to the molecule's negative charge and accounts for up to 50% of its total mass. The apparent molecular weight of the fully glycosylated CD52 ranges from 21 to 28 , far exceeding the ~1.2 of the unglycosylated due to these modifications. CD52 is tethered to the plasma membrane via a (GPI) anchor linked to Ser12 through an bridge. The GPI glycan core consists of a tetrasaccharide (Manα1-2Manα1-6Manα1-4GlcNα1-6myo-inositol) with additional phosphoryl substituents on the mannose residues, including full substitution on the third and partial on the first and second. Lipid variations include diacylglycerol forms such as distearoyl-phosphatidylinositol in the PI-PLC-sensitive CD52-I isoform and a 2-palmitoylated stearoyl-arachidonoyl-phosphatidylinositol in the resistant CD52-II isoform. Soluble forms of CD52 arise from enzymatic cleavage of the GPI anchor by phospholipases, such as (PI-PLC), which releases the N-glycosylated into the extracellular milieu while preserving the structure. This process is sensitive in the CD52-I form but resistant in CD52-II due to the additional palmitoylation.

Expression and Function

Cellular Expression

CD52 exhibits high expression across various immune cell types, particularly mature lymphoid and myeloid cells. It is prominently expressed on T lymphocytes, B lymphocytes, natural killer (NK) cells, monocytes, macrophages, and eosinophils, with quantitative mRNA levels showing toward lymphoid tissues such as nodes (RPKM 265.0) and (RPKM 195.7). Among these, B cells the highest surface expression, especially on non-switched memory B cells, while NK cell subsets show more variable levels, with the CD16loCD56hi population expressing the lowest. In contrast, CD52 expression is low or absent on certain immune cell populations, including neutrophils, hematopoietic stem cells, and mature cells. Neutrophils show notably low surface levels compared to other leukocytes, and hematopoietic cells lack significant expression, preserving them from CD52-targeted therapies. Fully differentiated cells in conditions like are predominantly negative for CD52, with 22 out of 23 cases showing no detectable expression. Beyond immune cells, CD52 is expressed in non-immune contexts, notably on the surface of sperm cells where it is acquired from seminal fluid, and on epithelial cells of the male reproductive tract, including the and . Subsets of dendritic cells also express CD52 heterogeneously; for instance, monocyte-derived dendritic cells show abundant levels, while Langerhans cells and dermal-interstitial dendritic cells lack expression. Surface density of CD52 on lymphocytes varies, with heterogeneous expression observed across subsets and higher levels noted on certain activated or populations compared to naive cells. For example, B cells exhibit markedly elevated binding capacity (average 634,692 ABC units) relative to other lymphoid subsets.

Biological Roles

CD52 plays a critical role in immune regulation, primarily through its soluble form, which acts as an immunosuppressive agent. Soluble CD52 inhibits Toll-like receptor (TLR) signaling by suppressing NF-κB activation in innate immune cells such as monocytes, macrophages, and dendritic cells, thereby reducing the production of pro-inflammatory cytokines including TNF-α and IL-6. This mechanism involves sequestration of high-mobility group box 1 (HMGB1), a damage-associated molecular pattern that promotes inflammation; by binding HMGB1's proinflammatory B box via its sialylated glycan, soluble CD52 neutralizes its activity and enhances engagement with the inhibitory receptor Siglec-10. In vivo studies demonstrate that administration of soluble CD52-Fc fusion protein attenuates LPS-induced endotoxic shock by limiting cytokine release, highlighting its physiological dampening of excessive innate immune responses. In T cells, CD52 modulates activation and survival signals depending on the context of ligand engagement. Cross-linking of surface CD52, as occurs with multivalent ligands, triggers intracellular signaling cascades that enhance T cell proliferation and cytokine production, contributing to adaptive immune responses. However, in certain scenarios, such as prolonged or antibody-mediated cross-linking, CD52 engagement promotes by depleting anti-apoptotic proteins like MCL-1 and cFLIP, thereby limiting overactivation and maintaining immune . This dual functionality underscores CD52's role in fine-tuning T cell responses without inducing broad under normal conditions. In the , CD52 expressed on mature spermatozoa (mrt-CD52) provides immune protection and supports fertility. The heavily sialylated of mrt-CD52 imparts a negative charge that facilitates electrostatic repulsion, aiding and preventing aggregation in the female genital tract. Additionally, mrt-CD52 inhibits complement activation via the classical pathway by interfering with C1q binding, shielding sperm from immune-mediated . CD52 serves as an immunodominant on , targeted by antisperm antibodies that can immobilize through complement-dependent mechanisms, linking its expression to in cases of immune dysregulation. The GPI-anchored structure and extensive of CD52 contribute to its solubility and charged properties, enabling these diverse roles.

Clinical Significance

Therapeutic Targeting

, marketed as Campath for and Lemtrada for , is a humanized IgG1 that targets CD52 on the surface of lymphocytes and other immune cells. Its therapeutic effects primarily arise from (ADCC), where natural killer cells and macrophages lyse CD52-expressing cells, and (CDC), which activates the complement cascade to form membrane attack complexes on target cells. Additional mechanisms include direct induction of in targeted cells. Alemtuzumab is approved as a single agent for B-cell (B-CLL) in patients treated with alkylating agents and for whom those are ineffective. For B-CLL, dosing begins with an escalation regimen—3 mg/day intravenously for 3 to 7 days, then 10 mg/day for 3 to 7 days, advancing to a of 30 mg/day three times weekly for up to 12 weeks, administered over 2 hours with to mitigate reactions. In relapsing forms of (MS), including relapsing-remitting and active secondary progressive disease, it serves as a disease-modifying for adults with inadequate response to at least two other MS treatments. The MS regimen involves an initial course of 12 mg/day intravenously over 4 hours for 5 consecutive days (total 60 mg), followed by a second course of 12 mg/day for 3 consecutive days 12 months later (total 36 mg), with additional courses of 12 mg/day for 3 days as needed at least 12 months after the prior dose. Emerging anti-CD52 therapies include investigational antibodies designed to refine targeting and reduce off-target effects. ALLO-647, a non-depleting anti-CD52 , has been evaluated in clinical trials for lymphodepletion prior to allogeneic CAR-T in relapsed/refractory large B-cell lymphoma and , aiming to prevent while enabling T-cell expansion, but its development was discontinued in August 2025 following a death in clinical trials. Bispecific antibodies, such as an IgG1-like construct targeting both CD52 and , have shown preclinical promise for B-cell malignancies like and CLL by enhancing selective depletion of malignant B cells via ADCC and CDC while minimizing T-cell loss. Therapeutic targeting of CD52 induces profound lymphodepletion, which heightens susceptibility to opportunistic infections, including infections overall (71% incidence in MS trials) with viral infections occurring in 16% of MS patients and reactivation (up to 16% in CLL). Infusion reactions occur in over 90% of patients, manifesting as , , pyrexia, and , often requiring premedication with corticosteroids, antihistamines, and antipyretics, along with slow rates and post-infusion for at least 2 hours. Autoimmune disorders, such as immune (up to 2% in CLL and 2% in MS), (37% in MS), and anti-glomerular disease, arise from dysregulated immune reconstitution; management involves monthly of complete blood counts, function, and for 48 months post-treatment, with prompt intervention using immunosuppressants or supportive care as needed. Prophylactic antiviral, antibacterial, and therapies are standard to mitigate risks during lymphopenia.

Role in Disease

CD52 has been implicated in various cancers, particularly through its overexpression on malignant cells and its role as a prognostic . In (CLL), a type of , CD52 is highly expressed on leukemic cells, with soluble CD52 levels serving as an indicator of disease activity and progression. Similarly, CD52 expression is elevated in other lymphomas, such as , where it correlates with tumor burden. In , CD52 is significantly upregulated and associated with the , acting as a favorable prognostic by enhancing anti-cancer immune infiltration while inhibiting pro-tumor M2 macrophages. In , CD52 mRNA levels predict and response to , with higher expression potentially indicating better outcomes in treatment-responsive cases. In autoimmune and inflammatory diseases, alterations in CD52 expression contribute to pathological immune dysregulation. Reduced levels of CD52-positive T cells are associated with increased risk of acute (GVHD) following allogeneic , where CD52-negative T cells enriched for alloreactive specificity exacerbate tissue damage. This suggests that diminished CD52 expression on T cells may impair mechanisms in GVHD. Although CD52-targeted therapies have been explored for , endogenous soluble CD52 levels appear altered in inflammatory states, potentially reflecting disease severity, though direct prognostic links remain under investigation. Beyond oncology and autoimmunity, CD52 exhibits links to metabolic and reproductive disorders. In , CD52 is highly expressed in and preadipocytes from obese individuals compared to lean controls, correlating with mellitus and suggesting a role in . Soluble CD52 may also protect against obesity-associated by modulating immune responses in . In infections, CD52's involvement is indirect; anti-CD52 therapies increase the risk of infections, including , due to profound lymphodepletion in immunocompromised contexts. Regarding reproductive health, CD52 on serves as a key targeted by anti-sperm antibodies, contributing to immunological through complement-dependent immobilization. As of 2025, research gaps persist in understanding CD52's role in solid tumors, where pan-cancer analyses indicate variable expression influencing tumor progression and immune infiltration, warranting further studies. Additionally, CD52 has emerged as a marker for neoplastic stem cells in myelodysplastic syndromes (MDS) and (AML), particularly in 5q-deletion subtypes, highlighting its potential as a prognostic indicator for stem cell-driven relapse. Ongoing investigations explore CD52 as a marker in these hematologic malignancies to refine risk stratification.

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