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CD33

Official Full Name
CD33 molecule
Organism
Homo sapiens
GeneID
945
Background
Enables protein phosphatase binding activity; protein tyrosine phosphatase activator activity; and sialic acid binding activity. Involved in several processes, including immune response-regulating signaling pathway; negative regulation of cytokine production; and negative regulation of monocyte activation. Located in several cellular components, including Golgi apparatus; external side of plasma membrane; and peroxisome. [provided by Alliance of Genome Resources, Feb 2025]
Synonyms
p67; SIGLEC3; SIGLEC-3; CD33rSiglec;
Bio Chemical Class
Immunoglobulin
Protein Sequence
MPLLLLLPLLWAGALAMDPNFWLQVQESVTVQEGLCVLVPCTFFHPIPYYDKNSPVHGYWFREGAIISRDSPVATNKLDQEVQEETQGRFRLLGDPSRNNCSLSIVDARRRDNGSYFFRMERGSTKYSYKSPQLSVHVTDLTHRPKILIPGTLEPGHSKNLTCSVSWACEQGTPPIFSWLSAAPTSLGPRTTHSSVLIITPRPQDHGTNLTCQVKFAGAGVTTERTIQLNVTYVPQNPTTGIFPGDGSGKQETRAGVVHGAIGGAGVTALLALCLCLIFFIVKTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAPTVEMDEELHYASLNFHGMNPSKDTSTEYSEVRTQ
Open
Disease
Acute myeloid leukaemia, Alzheimer disease, BCR-ABL1-negative chronic myeloid leukaemia, Leukaemia, Malignant haematopoietic neoplasm, Mastocytosis, Multiple myeloma, Myelodysplastic syndrome
Approved Drug
1 +
Clinical Trial Drug
25 +
Discontinued Drug
3 +

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Detailed Information

CD33 is a member of the sialic-acid-binding immunoglobulin-like lectins (Siglecs) family and is a transmembrane protein mostly responsible for mediating cell-cell interactions and regulating immunological responses. Monocytes, macrophages, dendritic cells, myeloid lineage cells, and monocytes especially show it most typically in acute myeloid leukemia (AML) cells. Although its role in the central nervous system—more notably, within microglia—implicates probable implications in neurodegenerative diseases like Alzheimer's disease (AD), the frequency of CD33 in AML makes it an interesting target for treatment strategies.

CD33 Structure

CD33 has a somewhat simple structure with a molecular weight of around 67 kDa and an exterior V-set immunoglobulin-like domain that helps sialic acids be identified. This V domain as well as one or more C2-type immunoglobulin-like domains help to mediate connections between cells and transducing signals within the immunological milieu. Crucially for its function in inhibiting signaling pathways, CD33's cytoplasmic tail has two immunoreceptor tyrosine-based inhibitory motifs (ITIM). When engaged by ligands such as sialylated glycoproteins, these ITIMs are phosphorylated by Src-family kinases, providing docking sites for protein-tyrosine phosphatases (PTPs) like PTPN6/SHP-1 and PTPN11/SHP-2. These phosphatases play a pivotal role in regulating downstream signaling pathways by dephosphorylating key signaling molecules, thereby modulating the activity of immune cells.

Figure 1 depicts how the co-localization of hCD33M with an activatory receptor leads to phosphorylation of the ITIM domain of hCD33M, creating a docking site for SH2-containing phosphatases that counteract immune cell signaling pathways.Figure 1. CD33 isoforms and CD33 signaling. (Eskandari-Sedighi G, et al., 2022)

CD33 Signaling Pathways

The expression of CD33 on immune cells is intimately correlated with its activity. The inhibitory receptors containing ITIMs—such as CD33, become phosphorylated and provide PTP docking sites when a ligand binds. This induces downregulation of activating signals, particularly those mediated by receptors comprising immunoreceptor tyrosine activation motifs (ITAMs). For this reason, CD33 acts as a negative regulator of immunological activation. Engaged, CD33 might lower cellular activities like phagocytosis and cytokine production, thus influencing the complete immune response.

Essential for maintaining immunological homeostasis, CD33's regulating effect extends to control of monocyte activation and cytokine production. Negative control of these channels enables CD33 to maintain immunological tolerance and prevent too powerful inflammatory responses.

Clinical Implications of CD33

Mostly regarding Alzheimer's disease and acute myeloid leukemia (AML), CD33's clinical relevance is in its putative therapeutic target. In AML, CD33 is a prominent surface marker because of its low or nonexistent expression in normal hematopoietic stem cells and high expression in leukemic cells. This differential expression makes CD33 a promising target for therapy aimed at targeting cancer cells justly.

One of the most important therapeutic drugs targeting CD33 is gemtuzumab ozogamicin (GO), an antibody-drug combination. GO binds to CD33 on AML cells to induce internalization and concomitant cytotoxic chemical release, hence generating cancer cell death. Originally authorized by the FDA in 2000, GO was later taken off due to safety concerns but was reevaluated and reapproved in 2017 after dosage strategy optimization that lowered hepatotoxicity and early mortality.

Although GO has considerable potential, its utility may be limited by the presence of CD33 isoforms—especially the CD33 ∆E2 variant—which lacks the V-set domain and hence cannot be targeted enough by GO. This has significant implications for treatment strategies as the presence of such isoforms might reduce the overall therapeutic efficacy of medicines aimed at CD33-targeting.

Apart from antibody-drug conjugates, advancements in immunotherapy also include chimeric antigen receptor (CAR) T-cell treatment under investigation for CD33 target. Designed to find CD33 in AML cells, CAR-NK cell therapies show potential in boosting natural killer (NK) cell activity against malignant cells, therefore providing a viable route for AML treatment.

Under the context of Alzheimer's disease, CD33's participation in microglial activity suggests a possible influence on the hallmark of the disorder, amyloid-beta (Aβ) clearance. Neurodegeneration has been associated with lower clearance of Aβ plaques coupled with dysregulation of CD33. Targeting CD33 might assist in slowing down disease progression by increasing microglial activation in clearing Aβ. Therapeutic strategies under investigation include bispecific antibodies and radiolabeled immunoconjugates aimed at changing the activity of CD33 in microglia.

Future Directions and Challenges

The therapeutic targeting of CD33 brings many challenges largely linked to the complexity of CD33 expression isoforms and the risk of off-target effects. Especially in connection to cancer, attempts to design medicines that may effectively activate all isoforms of CD33 are very important to increase the efficacy of therapy. Furthermore, as research develops, the study of CD33 in other diseases outside of AML and AD can provide new insights into its therapeutic prospects and physiological roles. By lowering detrimental effects on normal cells, the specificity of CD33 targeting will aid in improving general patient outcomes. Furthermore, fresh data points hint at the prospect of increasing therapeutic effectiveness and decreasing the resistance risk by adopting combination therapies—that is, CD33-targeted drugs coupled with other modalities.

References:

  1. Amadori S, Suciu S, Selleslag D, et al. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016;34(9): 972-979.
  2. Kovtun Y, Noordhuis P, Whiteman KR, et al. IMGN779, a Novel CD33-targeting antibody–drug conjugate with DNAalkylating activity, exhibits potent antitumor activity in models of AML. Mol Cancer Ther. 2018;17(6):1271-1279.
  3. Atallah EL, Orozco JJ, Craig M, et al. A Phase 2 study of actinium-225 (225Ac)-lintuzumab in older patients with untreated acute myeloid leukemia (AML) - interim analysis of 1.5 μci/Kg/dose. Blood. 2018;132(suppl 1):1457-1457.
  4. Blum W, Ruppert AS, Mims AS, et al. Phase 1b dose escalation study of BI 836858 and azacitidine in previously untreated AML: results from beatAMLS2. Blood. 2018;132(suppl 1):4053-4053.
  5. Eskandari-Sedighi G, Jung J, Macauley MS. CD33 isoforms in microglia and Alzheimer's disease: Friend and foe. Mol Aspects Med. 2023;90:101111.
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