Semaphorin 4D (Sema4D), also identified by the name CD100, is a protein that functions as a signaling molecule within the human body. Its primary role is to transmit instructions that guide the behavior of various cells. This process is often compared to a key fitting into a specific lock; Sema4D binds to designated protein receptors on a cell’s surface to initiate a particular action inside that cell. This interaction is fundamental to cell-to-cell communication. The main “locks,” or receptors, that Sema4D interacts with include Plexin-B1, Plexin-B2, and CD72, ensuring its signals are delivered only to the cells equipped to receive them.
Physiological Roles of Sema4D
In a healthy system, Sema4D performs several well-defined functions, particularly in the development of the nervous system. During embryonic growth, it acts as an axon guidance molecule. This means it helps direct the pathfinding of developing nerve cells, ensuring they form the correct connections to build the intricate wiring of the brain and peripheral nervous system.
The protein is also an important modulator of the immune system. It is found on the surface of immune cells, especially resting T-cells, and its presence increases when these cells are activated. Sema4D facilitates communication between different immune cells, such as T-cells and B-cells. By binding to its receptor CD72 on B-cells, Sema4D helps regulate the activation and response of these cells, contributing to a coordinated defense against pathogens.
Beyond the nervous and immune systems, Sema4D has a distinct role in maintaining skeletal health through bone metabolism. Bone is a dynamic tissue that is constantly being broken down and rebuilt in a process called remodeling. Sema4D is expressed by osteoclasts, the cells responsible for bone resorption, and sends signals to osteoblasts, the cells that form new bone, to pause their activity. This communication helps couple the process of bone breakdown with bone formation.
Involvement in Disease Processes
While Sema4D’s functions are necessary for normal health, when the protein is over-expressed or its signaling becomes dysregulated, it can contribute to the progression of several diseases. In cancer, some tumors appear to exploit Sema4D signaling to their advantage. The elevated presence of this protein can help tumors grow by promoting angiogenesis, the formation of new blood vessels that supply the tumor with nutrients and oxygen. This same signaling can also suppress the body’s natural defenses by preventing immune cells from infiltrating the tumor microenvironment.
In neurodegenerative disorders, the protein’s normal role in communication becomes detrimental. In conditions like multiple sclerosis (MS), Huntington’s disease, and Alzheimer’s disease, Sema4D contributes to chronic neuroinflammation. It activates microglia and astrocytes, the brain’s resident immune cells, causing them to enter a reactive state that can damage neurons and disrupt brain function. This inflammatory activity can also contribute to the breakdown of the blood-brain barrier. A similar inflammatory mechanism links Sema4D to autoimmune conditions like rheumatoid arthritis.
Therapeutic Potential and Research
The discovery of Sema4D’s role in various diseases has made it a target for new therapeutic interventions. Researchers are developing strategies to block its harmful effects, primarily through the use of monoclonal antibodies. These engineered antibodies are designed to recognize and bind to the Sema4D protein. This binding action physically obstructs Sema4D from attaching to its receptors, such as Plexin-B1, on other cells, cutting off the downstream signaling pathways that drive disease processes.
The most prominent investigational drug in this class is pepinemab, also known as VX15 or VX2503. Pepinemab is a humanized monoclonal antibody that has been the subject of numerous clinical trials. Researchers have studied its effects in patients with specific cancers as well as in those with neurodegenerative conditions like Huntington’s disease and Alzheimer’s disease. For Huntington’s, the FDA has granted it Orphan Drug and Fast Track designations to facilitate its development.
Clinical studies are evaluating pepinemab both as a standalone therapy and in combination with other treatments. For example, trials have explored its use alongside existing cancer immunotherapies to see if blocking Sema4D can make those treatments more effective. In Alzheimer’s research, the SIGNAL-AD trial investigated its potential to reduce neuroinflammation. While pepinemab is still an investigational drug, the ongoing research highlights Sema4D as a significant area of focus in the search for new treatments.