The CD33 marker, also known as Siglec-3, is a protein found on the surface of immune cells, primarily those of the myeloid lineage. This molecule is of significant interest due to its dual involvement in cancer and neurodegeneration. Its expression is a defining feature of Acute Myeloid Leukemia (AML), and its genetic variants are strongly linked to the risk of developing Alzheimer’s disease (AD). Scientists are intensely studying CD33’s presence and function to develop targeted therapeutic strategies for both conditions.
Understanding the CD33 Marker
CD33 is a member of the Siglec family (Sialic acid-binding immunoglobulin-like lectins). These receptors recognize and bind to sialic acid molecules on the surface of other cells, facilitating cellular communication and self-recognition within the immune system. As a transmembrane receptor, CD33 spans the cell membrane, possessing both external and internal domains. The extracellular portion contains two immunoglobulin-like domains, one of which binds to sialic acid ligands.
The intracellular segment contains Immunoreceptor Tyrosine-based Inhibitory Motifs (ITIMs), which are central to the protein’s inhibitory function. When CD33 binds to a ligand, the ITIMs are phosphorylated, creating docking sites for tyrosine phosphatases like SHP-1 and SHP-2. Recruitment of these phosphatases initiates a signaling cascade that dampens activating signals within the cell. This process allows CD33 to function as an immune checkpoint, regulating myeloid cell activity and preventing excessive immune responses, including the inhibition of phagocytosis.
CD33’s Role in Acute Myeloid Leukemia
CD33 is highly relevant in the diagnosis and pathology of Acute Myeloid Leukemia (AML), a cancer of the blood and bone marrow. The protein is abundantly expressed on the surface of leukemic blast cells in 85% to 90% of AML cases. This high surface presence makes CD33 a standard diagnostic marker used in flow cytometry to identify and classify malignant cells.
Leukemic blasts typically express significantly higher levels of CD33 compared to normal myeloid cells; for instance, blasts can express over 10,000 molecules per cell versus 3,000 on normal cells. This overexpression is believed to contribute to the cancer cells’ ability to survive and proliferate, establishing CD33 as a pathological driver. Higher expression levels can also correlate with adverse outcomes in specific AML subtypes.
The prevalence and high density of CD33 on malignant cells established it as an attractive target for immunotherapy. The goal is to use the marker as a delivery mechanism for toxic compounds. This approach leverages the differential expression level between malignant and normal cells, ensuring the treatment selectively attacks the cancer.
CD33’s Role in Alzheimer’s Disease
In the brain, CD33 is expressed primarily on microglia, the resident immune cells of the central nervous system. Microglia use CD33 as an inhibitory receptor to regulate their activity, including phagocytosis. Phagocytosis is the mechanism by which microglia engulf and clear cellular debris and protein aggregates, such as the toxic amyloid-beta (Aβ) plaques characteristic of Alzheimer’s disease (AD).
When CD33 is highly expressed on microglia, its inhibitory nature actively dampens the cell’s ability to clear Aβ plaques. Studies show that increased CD33 expression leads to reduced Aβ peptide uptake, promoting amyloid pathology accumulation. Conversely, a lack of functional CD33 protein enhances microglial clearance capability.
This inhibitory role is strongly supported by genetic findings, specifically the single nucleotide polymorphism (SNP) rs3865444, located near the \(CD33\) gene. This variant is significantly associated with a reduced risk of developing AD. The protective minor allele influences \(CD33\) gene splicing, resulting in the increased production of a shorter, non-functional isoform that lacks the ligand-binding domain. This reduces the total amount of functional CD33 on the microglial surface, lifting the molecular “brake” on phagocytosis and allowing microglia to clear Aβ plaques more effectively.
Therapeutic Strategies Based on CD33 Targeting
The distinct roles of CD33 in AML and AD have led to two fundamentally different therapeutic strategies. In AML, the goal is to leverage the high expression of CD33 to destroy malignant cells. The established approach uses an antibody-drug conjugate (ADC), such as Gemtuzumab ozogamicin, which is approved for AML treatment.
This ADC consists of a humanized antibody directed against CD33, linked to a potent cytotoxic agent, calicheamicin. Upon binding to CD33 on the leukemic cell surface, the complex is internalized. Inside the lysosome, the acidic environment cleaves the linker, releasing the calicheamicin. The released toxin causes DNA double-strand breaks, leading to programmed cell death in the leukemic blast.
For Alzheimer’s disease, the strategy involves modulation of the immune response rather than cellular destruction. Researchers aim to block or reduce the inhibitory signal transmitted by CD33 to restore microglial function.
AD Therapeutic Avenues
One avenue involves using anti-CD33 antibodies that are not conjugated to a toxin, aiming to reduce the amount of CD33 displayed on the microglial surface. Another promising area is gene therapy, where vectors are used to “knock down” the expression of the \(CD33\) gene in the brain. This enhances Aβ clearance and reduces neuroinflammation.