Acute Myeloid Leukemia (AML) is a serious cancer originating in the blood and bone marrow, affecting the body’s ability to produce healthy blood cells. It involves the rapid growth of abnormal myeloid cells. A particular protein marker, CD33, found on the surface of many AML cells, has emerged as a significant focus in developing new treatments. Understanding CD33 helps target these cancerous cells more precisely.
The Role of the CD33 Protein in AML
CD33 is a receptor protein on the surface of cells, belonging to a family called sialic-acid-binding immunoglobulin-like lectins (Siglecs). In healthy individuals, CD33 is normally expressed on early myeloid (bone marrow) cells and plays a part in regulating immune responses. It is involved in controlling leukocyte functions and inflammatory processes.
In most AML cases, the leukemia cells display an abnormally high amount of the CD33 protein on their surface. This overexpression makes CD33 a reliable marker, helping distinguish cancerous cells from healthy ones. The antigen is expressed on the blast cells of most AML cases, making it a suitable tumor-associated target. A higher intensity of this antigen implies increased binding for therapeutic antibodies.
Bone marrow blasts in AML patients can express a wide range of CD33 molecules per cell, averaging around 10,380 molecules per cell, which is significantly higher compared to the average of 2,997 molecules per cell found in normal CD33-positive bone marrow cells. This difference in expression levels underscores its relevance as a target. The widespread overexpression of CD33 across most AML subtypes, including leukemic stem cells, makes it an interesting therapeutic target.
Testing for CD33 Expression in Leukemia Cells
To determine if a patient’s AML cells express the CD33 protein, samples are collected through a blood draw or a bone marrow biopsy. These samples provide the necessary cells for laboratory analysis.
The primary method used for detecting CD33 expression is flow cytometry. This technique involves passing cells from the collected sample through a laser beam. Special tags, which are antibodies designed to attach specifically to the CD33 protein, are added to the cells. As the tagged cells pass through the laser, the tags light up, allowing scientists to count how many cells are “CD33-positive”.
A “CD33-positive” result indicates that the leukemia cells have the targetable marker on their surface. This finding confirms that therapies designed to target CD33 could be a suitable treatment option for the patient. The test also helps in monitoring the effectiveness of treatments aimed at CD33-expressing cells.
Therapies That Target the CD33 Marker
One primary approach to targeting the CD33 marker involves the use of antibody-drug conjugates (ADCs). This innovative design combines the specificity of an antibody with the power of a chemotherapy drug. An engineered antibody component is designed to seek out and attach exclusively to the CD33 protein present on the surface of AML cells.
Once the antibody binds to the CD33 protein, the entire antibody-drug complex is taken inside the cancer cell. Inside the cell, typically within acidic compartments called lysosomes, the potent chemotherapy drug is released. This targeted delivery allows the powerful drug to kill the cancer cell from within by causing DNA damage, which triggers cell death. This mechanism significantly reduces harm to healthy cells that do not have the CD33 marker.
A concrete example of a CD33-targeting ADC approved for AML is Gemtuzumab ozogamicin. This drug consists of a humanized antibody linked to a derivative of calicheamicin, a potent DNA-cleaving agent. Gemtuzumab ozogamicin was initially approved in 2000, withdrawn in 2010, and then reapproved in 2017 with revised dosing and patient populations after further data affirmed its efficacy and safety.
Beyond ADCs, research continues into other methods to target CD33. Chimeric Antigen Receptor (CAR) T-cell therapy is an investigational approach. In this therapy, a patient’s or donor’s T-cells are genetically modified in the laboratory to express a special receptor that recognizes and binds to CD33 on cancer cells. These engineered T-cells are then returned to the patient to seek out and destroy leukemia cells.
Patient Considerations for CD33-Targeted Treatment
Eligibility for CD33-targeted treatment requires a confirmed CD33-positive AML diagnosis. This approach can be considered for newly diagnosed patients, often in combination with standard chemotherapy regimens. It is also an option for patients whose cancer has returned or has not responded to previous treatments (relapsed or refractory AML). A patient’s age and overall health status are also important factors doctors consider when deciding on this treatment path.
Because CD33 is also present on some normal, developing myeloid cells, these therapies can lead to certain side effects. Myelosuppression, a decrease in the bone marrow’s ability to produce blood cells, is a common side effect. This can result in low blood counts, including neutropenia (low white blood cells), thrombocytopenia (low platelets), and anemia (low red blood cells). Regular blood tests are performed to monitor these cell counts.
Other potential side effects associated with Gemtuzumab ozogamicin include infusion-related reactions. Symptoms can include fever, chills, low blood pressure, difficulty breathing, and skin rash. Liver problems, such as hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS), are also significant concerns. These conditions involve the blockage of small blood vessels in the liver and can be severe, requiring close monitoring of liver function tests and symptoms like jaundice or upper right abdominal pain.