Daratumumab, marketed as Darzalex, is a monoclonal antibody used in cancer treatment. This targeted therapy is a laboratory-produced protein designed to mimic the antibodies naturally made by the immune system and bind to specific targets on cancer cells. Daratumumab is primarily used for multiple myeloma, a cancer affecting plasma cells in the bone marrow.
Targeting CD38
Daratumumab targets CD38, a protein found on the surface of various immune cells, including certain white blood cells. CD38 is expressed at very high levels on the surface of multiple myeloma cells. This makes CD38 an effective target for cancer therapy, as it is abundantly present on cancerous cells while being less so on healthy cells. By binding exclusively to CD38, daratumumab specifically identifies and interacts with multiple myeloma cells, minimizing harm to healthy tissues.
How Daratumumab Eliminates Cancer Cells
Once daratumumab binds to CD38 on multiple myeloma cells, it initiates a series of powerful immune-mediated responses. These mechanisms work in concert to effectively eliminate the malignant cells.
Apoptosis
Daratumumab directly triggers programmed cell death in myeloma cells, a process known as apoptosis. This direct action occurs after the antibody binds to CD38, causing a signaling cascade within the cancer cell that leads to its self-destruction. This direct induction of cell death contributes to the overall anti-tumor effect.
Antibody-Dependent Cellular Cytotoxicity (ADCC)
Antibody-Dependent Cellular Cytotoxicity (ADCC) is another key mechanism. Daratumumab acts as a flag, marking myeloma cells for destruction by natural killer (NK) cells. Once daratumumab binds to CD38, NK cells recognize and bind to the antibody’s Fc region. This leads to their activation and release of cytotoxic substances that perforate the cancer cell membrane, inducing cell death.
Complement-Dependent Cytotoxicity (CDC)
Complement-Dependent Cytotoxicity (CDC) is another way daratumumab eliminates cancer cells. Daratumumab activates the complement system, a group of proteins in the blood that are part of the immune system. This leads to the formation of a membrane attack complex (MAC) on the myeloma cell surface. This complex creates pores in the cell membrane, causing cell lysis.
Antibody-Dependent Cellular Phagocytosis (ADCP)
Daratumumab also promotes Antibody-Dependent Cellular Phagocytosis (ADCP). Macrophages, a type of immune cell known as “big eaters,” recognize myeloma cells coated with daratumumab. The macrophages then engulf and digest these flagged cancer cells, effectively clearing them from the body.
Immunomodulatory Effects
Beyond direct killing, daratumumab also has immunomodulatory effects. It reduces the number of certain immunosuppressive cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), which also express CD38. By depleting these cells, daratumumab helps to enhance the overall anti-tumor immune response, allowing other immune cells to more effectively fight the cancer.
Daratumumab in Multiple Myeloma Treatment
Multiple myeloma is a cancer characterized by the uncontrolled growth of abnormal plasma cells in the bone marrow. These malignant plasma cells typically exhibit high levels of CD38 on their surface, making them particularly susceptible to the actions of daratumumab. The drug’s ability to target this specific protein is central to its effectiveness in treating the disease.
Daratumumab is approved for use in multiple myeloma patients, either as a standalone therapy or, more commonly, in combination with other anti-myeloma drugs. Combining daratumumab with agents such as proteasome inhibitors or immunomodulatory drugs can enhance its anti-myeloma activity and improve patient outcomes.
Daratumumab has significantly improved the landscape of multiple myeloma treatment. Its multifaceted approach to eliminating cancer cells and modulating the immune system provides a valuable option for patients, including those with newly diagnosed or relapsed and refractory disease.