CD47 is a protein found on the surface of many cells throughout the body. It serves as a signal, helping the immune system differentiate healthy cells from those that are diseased or foreign. Antibodies, which are proteins produced by the immune system, can recognize and bind to specific targets like CD47. This ability makes antibodies valuable tools in medicine, particularly in developing therapies that can precisely interact with cellular processes involved in various diseases.
CD47: The “Don’t Eat Me” Signal
CD47 is a transmembrane protein on nearly all healthy human cells. Its primary function is to act as a “don’t eat me” signal, preventing immune cells, specifically macrophages, from engulfing and destroying them. This interaction occurs when CD47 binds to Signal Regulatory Protein alpha (SIRPα), a receptor on myeloid cells like macrophages and dendritic cells.
When CD47 binds to SIRPα, it inhibits phagocytosis within the macrophage, preventing engulfment of cellular debris or pathogens. This mechanism is essential for maintaining immune homeostasis, ensuring healthy cells are not mistakenly targeted. For instance, young red blood cells have high levels of CD47, which decreases as they age, eventually signaling macrophages to remove older cells.
Targeting CD47 with Antibodies
CD47 antibodies block the “don’t eat me” signal CD47 transmits to immune cells. They bind to the CD47 protein, preventing its interaction with the SIRPα receptor on macrophages, effectively “turning off” the inhibitory signal.
Once the “don’t eat me” signal is disarmed, macrophages are no longer prevented from recognizing and engulfing the target cells. This allows the immune system’s phagocytic cells to identify and eliminate cells that would otherwise be protected. The mechanism of action also involves unmasking “eat me” signals that may be present on the target cells, further promoting their destruction.
CD47 Antibodies in Cancer Therapy
Cancer cells often exploit the CD47 “don’t eat me” signal to evade destruction by the immune system. Many cancer cells overexpress CD47, allowing them to escape immune surveillance and clearance by macrophages. High CD47 expression on cancer cells links to poorer patient outcomes.
CD47 antibodies work in cancer therapy by blocking this deceptive signal, thereby allowing the immune system to detect and destroy cancer cells. When the antibody binds to CD47 on cancer cells, it enables macrophages to phagocytose, or “eat,” these malignant cells. This direct destruction is a primary anti-tumor effect. Furthermore, blocking CD47 can also stimulate a broader anti-tumor immune response, including the activation of T-cells, by allowing antigen-presenting cells like dendritic cells to process and present tumor antigens more effectively. This dual action makes CD47 antibodies a promising strategy in cancer immunotherapy.
Current Research and Development
The development of CD47 antibodies for cancer therapy is an active area of research, with several agents currently in various stages of clinical trials. Researchers are exploring different types of CD47 modulators, including monoclonal antibodies, small molecules, and engineered proteins.
One notable CD47 antibody, magrolimab, has been evaluated in clinical trials for both hematologic malignancies and solid tumors. However, some trials involving magrolimab in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) have faced challenges, leading to clinical holds and discontinuation.
Other CD47-targeting agents, such as lemzoparlimab and letaplimab, are also undergoing investigation, with some showing promising response rates in early-phase trials. A common challenge with CD47-targeting therapies is the potential for side effects, particularly anemia, due to CD47’s presence on healthy red blood cells. To mitigate this, strategies like optimized dosing or developing agents that selectively target cancer cells are being explored. The future outlook includes investigating combination therapies, where CD47 antibodies are used alongside other treatments to enhance anti-tumor effects.