Surface proteins act as identifiers on cells, allowing scientists to distinguish one type from another. These proteins are organized into a system called Clusters of Differentiation (CD), where each unique protein is assigned a number, creating a vast catalog of cellular markers. Within this system, CD33 is a specific transmembrane protein that is characteristic of a group of immune cells known as the myeloid lineage.
The CD33 marker is not just a passive tag; it has a functional role in cellular communication and regulation. It is found on the surface of cells that are part of the body’s innate immune system. The concentration and activity of this marker can change in different biological contexts, making it a subject of scientific inquiry.
The Role of CD33 in the Body
The CD33 protein is primarily expressed on the surface of myeloid cells, a diverse category of immune cells that includes monocytes, macrophages, and granulocytes. These cells are fundamental to the body’s first line of defense, responsible for identifying and engulfing pathogens, clearing cellular debris, and initiating inflammatory responses. Myeloid cells originate from progenitor cells in the bone marrow and circulate throughout the body.
CD33 functions as an inhibitory receptor, belonging to a family of proteins called sialic acid-binding immunoglobulin-like lectins (Siglecs). Its job is to recognize and bind to sialic acids, a type of sugar molecule present on the surface of many cells. When CD33 engages with these molecules, it transmits a signal into the myeloid cell that dampens its activation. This process helps to regulate the immune response, preventing it from becoming overactive and causing unnecessary damage to healthy tissues.
CD33 in Acute Myeloid Leukemia
The connection between CD33 and Acute Myeloid Leukemia (AML) is well-established, making the protein a biomarker for the disease. In 85-90% of AML cases, the cancerous white blood cells, known as myeloblasts, display an abnormally high amount of the CD33 protein on their surface. This overexpression distinguishes leukemic blasts from their healthy counterparts; normal myeloid cells have a mean of about 2,997 CD33 molecules per cell, whereas AML blasts can have an average of 10,380.
This overexpression makes CD33 a reliable marker for diagnosing AML. Clinicians use a technique called flow cytometry to analyze a patient’s blood or bone marrow sample. In this process, cells are tagged with fluorescently labeled antibodies that specifically bind to CD33. The instrument then detects the fluorescence, allowing for the precise quantification of CD33-positive cells and confirmation of a myeloid lineage for the cancer.
The level of CD33 expression can offer insights into the nature of the disease. While its direct prognostic value can be complex and influenced by other genetic factors, the density of the CD33 marker on the surface of AML cells remains a standard part of the diagnostic workup for nearly all patients.
Targeting CD33 for Cancer Treatment
The high prevalence of the CD33 marker on the surface of AML cells provides an opportunity for targeted therapies. This approach aims to deliver treatment directly to cancer cells while minimizing harm to healthy ones. The primary strategy involves using antibody-drug conjugates (ADCs), which consist of a monoclonal antibody engineered to seek out and bind to the CD33 protein on leukemic cells.
Attached to this antibody is a potent cytotoxic drug, a payload too powerful for general systemic administration. The antibody serves as the navigation system, circulating through the body until it finds and latches onto a CD33-positive AML cell. Once the ADC binds to the CD33 receptor, the cancer cell internalizes the entire complex. This action brings the toxic payload inside the cell, where it is most effective.
Inside the cell, the chemical linker connecting the antibody to the drug is broken down, releasing the cytotoxic agent. The most prominent example of this technology is a drug named gemtuzumab ozogamicin (Mylotarg). Its payload is released into the AML cell, where it proceeds to cause breaks in the cell’s DNA. This severe DNA damage disrupts cellular processes and triggers apoptosis, or programmed cell death, effectively destroying the cancer cell from within.
The development of gemtuzumab ozogamicin was first approved by the FDA in 2000, later withdrawn due to safety concerns in follow-up studies, and then reintroduced in 2017 with a modified dosing schedule after new data confirmed its benefits for certain AML patients.
CD33 and Other Health Conditions
Beyond its role in leukemia, the CD33 protein has emerged as a factor in neurodegenerative conditions, most notably Alzheimer’s disease. In this context, the focus shifts from cancer cells in the blood to immune cells within the brain. The brain’s resident immune cells are called microglia, and they are responsible for clearing metabolic waste and cellular debris, including the amyloid-beta plaques that are a defining feature of Alzheimer’s.
Genetic research has identified the CD33 gene as a risk factor for developing late-onset Alzheimer’s disease. Certain common genetic variations within the CD33 gene influence how much of the protein is expressed on the surface of microglia. Higher levels of CD33 expression on these brain immune cells are associated with an increased risk for the disease.
When microglia have more CD33 on their surface, their phagocytic activity—the ability to engulf and break down materials like amyloid plaques—is suppressed. This inhibition impairs the brain’s natural cleanup mechanism, allowing toxic amyloid-beta to accumulate and contribute to neurodegeneration. Conversely, genetic variants that lead to lower CD33 expression are considered protective, as they permit microglia to more effectively clear plaques, potentially delaying or preventing the onset of symptoms.