A CD38 inhibitor is a type of medication known as a targeted therapy. These drugs are designed to specifically block the activity of a protein called CD38, which is found on the surface of certain cells in the body. By targeting this particular protein, CD38 inhibitors aim to disrupt specific cellular processes. The drugs are antibody-based, engineered proteins that precisely recognize and bind to the CD38 protein.
The Role of CD38 in the Body
The CD38 protein is a multifunctional molecule present on the surface of various immune cells, including B lymphocytes, T lymphocytes, and natural killer cells. It acts as both a receptor and an enzyme. As an enzyme, CD38 plays a role in producing messenger molecules like cyclic ADP-ribose, which are involved in regulating calcium levels inside cells. This calcium signaling is important for cellular activities, including cell growth, motility, and immune responses.
CD38 also participates in cell adhesion, allowing cells to stick to each other, and signal transduction, helping transmit signals from outside the cell to its interior. It can bind to other proteins, such as CD31 on T cells, activating them to produce substances that regulate the immune system. CD38 becomes a target for therapy because it is found in very high quantities on the surface of certain cancer cells, particularly malignant plasma cells in multiple myeloma. Over 90% of malignant plasma cells from multiple myeloma patients show surface expression of CD38. This overexpression makes CD38 a suitable target for drugs designed to selectively target these cancerous cells.
Mechanism of Action
Once a CD38 inhibitor antibody binds to the CD38 protein on target cells, it can trigger several mechanisms to eliminate the cancerous cell. One primary way these drugs work is through Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC). In ADCC, the antibody marks the cancer cell for destruction. Natural killer (NK) cells, a type of immune cell, recognize the antibody bound to the cancer cell and then release toxic substances that cause the cancer cell to die.
Another mechanism is Complement-Dependent Cytotoxicity (CDC, where antibody binding activates a cascade of proteins in the immune system called the complement system. This system then forms pores in the cancer cell’s membrane, leading to its destruction. CD38 inhibitors can also induce Antibody-Dependent Cellular Phagocytosis (ADCP), where immune cells like macrophages engulf the antibody-marked cancer cells. Additionally, some CD38 inhibitors can directly cause the cancer cell to undergo apoptosis, a programmed form of cell self-destruction.
Approved Medications and Applications
Several CD38 inhibitors have received approval for medical use, primarily in the treatment of multiple myeloma. Daratumumab, marketed as Darzalex, was the first anti-CD38 monoclonal antibody approved and is widely used for adult patients with multiple myeloma across various disease settings. Isatuximab, known as Sarclisa, is another approved CD38 inhibitor, administered as part of combination regimens for multiple myeloma, including newly diagnosed patients not eligible for stem cell transplant. Both daratumumab and isatuximab are given as intravenous infusions.
Daratumumab is also available as a subcutaneous injection, which can significantly reduce administration time compared to the intravenous first infusion. This subcutaneous formulation has also been approved for treating newly diagnosed AL amyloidosis, a rare but serious condition related to abnormal protein deposits. These medications are often used alone or in combination with other established therapies.
Common Side Effects and Management
Patients receiving CD38 inhibitors may experience various side effects, with infusion-related reactions being among the most common. These reactions can include symptoms like fever, chills, shortness of breath, nausea, and numbness. Infusion reactions often occur during the first treatment session but can be managed by administering pre-medications such as corticosteroids, antihistamines, and fever reducers before the infusion.
Another notable side effect involves changes in blood counts. Since CD38 is expressed at varying levels on normal blood cells, CD38 inhibitors can lead to lowered counts of different blood cell types. This can include neutropenia, a reduction in white blood cells that increases the risk of infection, and thrombocytopenia, a decrease in platelets that raises the risk of bleeding. Anemia, characterized by low red blood cell counts, can also occur, potentially leading to fatigue.
An important consideration for patients on CD38 inhibitors is their potential interference with blood compatibility testing. The CD38 protein is present at low levels on red blood cells, and the antibody drugs can bind to it, causing false-positive results in routine blood typing tests, specifically the indirect antiglobulin test (IAT). This interference can make it challenging for blood banks to accurately cross-match blood for transfusions. Patients should inform their medical team and any blood bank of their medication to ensure appropriate testing, such as using dithiothreitol (DTT)-treated red blood cells, which helps resolve this interference.