Tebentafusp is a targeted immunotherapy medication used to treat metastatic uveal melanoma, an aggressive form of eye cancer. This cancer begins in the uvea and can spread to other areas, most commonly the liver. Tebentafusp is part of an advanced class of drugs called bispecific T-cell engagers, which are engineered proteins that help the body’s own immune system fight cancer. Approved by the FDA, it is the first T-cell receptor therapy authorized for treating a solid tumor. Its function is to actively redirect immune cells to find and destroy tumor cells.
The Unique Structure of Tebentafusp
The effectiveness of tebentafusp originates from its unique molecular architecture. It is a bispecific protein, meaning the single molecule has two distinct ends, each with a different and highly specific binding capability. One side of the molecule is an engineered T-cell receptor, or TCR, which is designed to identify and attach to cancer cells. The other side is an antibody fragment, specifically a single-chain variable fragment (scFv), that is designed to grab onto an immune cell.
This dual-function design allows the tebentafusp molecule to perform two separate but connected actions at the same time. The TCR portion acts as the “tumor-targeting” component, while the antibody fragment serves as the “immune-recruiting” component. This structure is the foundation of its entire mechanism, enabling it to physically link a cancer cell to a powerful immune cell. The fusion of these two distinct parts into one seamless protein is what defines tebentafusp and its therapeutic class.
Identifying the Tumor Cell
The T-cell receptor (TCR) end of the molecule is engineered to be highly specific, recognizing a particular marker on the tumor cell’s surface instead of the cell itself. This marker is a small piece of a protein called glycoprotein 100 (gp100), found in high amounts on uveal melanoma cells. For tebentafusp to see this gp100 marker, it must be presented on the tumor cell’s surface by a human leukocyte antigen (HLA). Specifically, tebentafusp only recognizes the gp100 peptide when held by an HLA molecule known as HLA-A02:01.
This requirement is why tebentafusp is only prescribed to patients who have this specific genetic marker. Before treatment, patients undergo a test to confirm they are HLA-A02:01-positive. This genetic prerequisite ensures the drug will be effective, as the entire mechanism depends on the TCR end successfully locking onto the gp100-HLA complex. Without this precise molecular handshake, the drug cannot anchor itself to the tumor. The affinity of this engineered TCR for the gp100-HLA complex is exceptionally high, about a million times greater than that of a natural T-cell receptor, ensuring a strong and stable connection.
Activating the T-Cell Response
Once anchored to a melanoma cell, the other end of the tebentafusp molecule performs its function. This antibody fragment is designed to bind to a protein called CD3, which is present on the surface of cytotoxic T-cells. These T-cells are the immune system’s primary soldiers for killing infected or cancerous cells. By binding to CD3, the tebentafusp molecule engages any nearby T-cell, redirecting it to focus on the attached tumor cell.
This mechanism activates T-cells in a polyclonal fashion, meaning it can recruit any T-cell in the vicinity, regardless of its original target. The T-cell does not need a natural receptor for the cancer cell; its activation is initiated by the tebentafusp molecule binding to its CD3 protein. This forced engagement activates the T-cell, switching on its cell-killing machinery.
The binding of the anti-CD3 fragment has a lower affinity, which is a deliberate design feature. This ensures that T-cells are not broadly stimulated throughout the body. Instead, they are only activated when the tebentafusp molecule has first found and attached itself to a gp100-positive tumor cell. This localized activation focuses the immune response directly at the site of the tumor, preparing the T-cell to attack.
Bridging the Gap for Cancer Cell Destruction
By attaching to the tumor cell and a T-cell, tebentafusp forms a physical bridge connecting the two. This forced proximity creates an immunological synapse, an interface that allows the T-cell to carry out its destructive function with high precision. By holding the cells together, tebentafusp ensures that the T-cell’s attack is delivered directly to the intended target.
The activation of the T-cell through its CD3 protein triggers a potent cytotoxic response. The T-cell releases a payload of destructive molecules, primarily proteins called perforin and granzymes, into the synapse. Perforin acts first by creating pores or channels in the membrane of the tumor cell, which allows the granzymes to enter the cancer cell’s interior.
Once inside the tumor cell, the granzymes initiate a cascade of biochemical reactions that lead to programmed cell death, a process known as apoptosis. This process instructs the cancer cell to self-destruct from within, leading to its clean and efficient elimination. This targeted delivery of cytotoxic agents ensures that the damage is confined to the melanoma cells, sparing healthy surrounding tissues. The result is the direct lysis, or breakdown, of the uveal melanoma tumor cells.